ASCO-SITC Clinical Immuno-Oncology Symposium Scientific Highlights, Orlando

By SITC Communications posted 02-21-2020 00:00

  

e Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights of the latest advances emerging from the ASCO-SITC Clinical Immuno-Oncology Symposium held in Orlando on Feb. 6–8, 2020.

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MEETING HIGHLIGHTS HOMEPAGE

Antibiotic Exposure Worsens Survival and Colitis in Patients With Stage III and IV Melanoma Receiving ICIs

Patients with stage III and stage IV melanoma receiving immune checkpoint inhibitors (ICIs) had decreased overall survival (OS) and increased melanoma-specific mortality and risk for moderate to severe colitis if they were treated with antibiotics, according to a large retrospective study (Abstract 56) presented during the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.

“Antibiotics exert a profound effect on the composition of the gut microbiome. In turn, that change can affect the way that patients respond to immunotherapy,” said Brian Chu, of the University of Pennsylvania Perelman School of Medicine, who presented the results on February 7. The study’s senior author was John N. Lukens, MD, also of the University of Pennsylvania.

Previous reports have suggested that antibiotic exposure could have a negative effect on treatment outcomes with ICIs. Most reports were primarily in patients with stage IV malignancies though, and it was not previously known whether the effect was similar in patients with stage III melanoma.

The new retrospective study included a total of 568 patients with stage III (204 patients) or stage IV (364 patients) melanoma, all treated with ICI therapy (ipilimumab, nivolumab, pembrolizumab, or ipilimumab/nivolumab) between 2008 and 2019. Patients who received a single dose of perioperative antibiotics were excluded. Of the patients with stage III melanoma, 158 had not received antibiotics and 46 patients were exposed to antibiotics within 3 months prior to ICI initiation. Among the patients with stage IV melanoma, 296 had not received antibiotics and 68 had antibiotic exposure.

Baseline characteristics were well balanced, with one exception: in the stage III group, those who were exposed to antibiotics were more likely to have undergone surgical resection (p = 0.0001); this was due to the use of antibiotics for postoperative wound infections.

Patients who received antibiotics had a significantly decreased OS (2.3 years vs. 3.6 years; p = 0.0101), as well as an increased melanoma-specific mortality (p = 0.0278).

Among the entire cohort, the hazard ratio (HR) for OS for those exposed to antibiotics was 1.7 (95% CI [1.3, 2.4]; p = 0.0004). For patients with stage IV melanoma, the HR was 1.6 (95% CI [1.2, 2.3]; p = 0.005); for those with stage III melanoma, the HR was 2.8 (95% CI [1.3, 5.9]; p = 0.008). Specifically among patients stage III disease treated in the adjuvant setting, the HR for those treated with antibiotics was 4.8 (95% CI [1.1, 21.5]; p = 0.038). In a sensitivity analysis that excluded those who received intravenous antibiotics and those who were hospitalized for reasons associated with their antibiotic, the poorer OS persisted, with an HR of 1.7 (95% CI [1.2, 2.4]; p = 0.003).

Patients who were exposed to antibiotics also had an increased risk for moderate to severe colitis, with an HR of 2.1 (95% CI [1.02, 4.52]; p = 0.046).

“We envision validation studies that correlate the receipt of antibiotics with changes in the microbiome,” Mr. Chu said. He added that it has yet to be determined if reconstitution of the microbiome using probiotics, fecal microbial transfer, or other methods could negate the effects observed in this study.

Discussant Jarushka Naidoo, MBBCh, of the Sidney Kimmel Cancer Center at Johns Hopkins University, said these results do confirm previous findings of poorer OS in advanced melanoma as well as lung cancer, and takes a step forward by including stage III melanoma. “The association between antibiotic exposure and high-grade colitis in the stage III population is a new finding, and the authors are to be congratulated on this.”

She added that the study is limited in terms of its sensitivity analysis, which excluded the sickest patients, and that a study examining a larger population including those with an ECOG status of 2 or higher may be warranted. The importance of antibiotic timing is also an outstanding question.

“I think it is very important that this should not be a reason to not give antibiotics to those patients who need it,” she said. “The rationale for giving probiotics as a supplementation may not be valid, as we don’t know which microbes are being depleted by the antibiotics and which need to be supplemented.”

— Dave Levitan

Sociodemographic Disparities Seen in Receipt of Immunotherapy for Metastatic Melanoma

A new study found significant discrepancies in the receipt of immunotherapy for metastatic melanoma according to several sociodemographic factors, including living in Medicaid expansion states under the Affordable Care Act, having private insurance, seeking care at academic medical centers, and living in ZIP codes with higher quartiles of education (Abstract 87).

“Unfortunately, as [immune checkpoint inhibitors] are costly, access has not been universal throughout the country,” said Justin Moyers, MD, of Loma Linda University, who presented the results during the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium on February 8.

The researchers examined the use of immune checkpoint inhibitors (ICIs) recorded in the National Cancer Database, including patients diagnosed through 2016, and mortality data in patients diagnosed through 2015. They analyzed some sociodemographic data using results of the American Community Survey for 2012 to 2016.

Of 583,212 total patients in the National Cancer Database with confirmed melanoma, 9,882 patients had stage IV melanoma in 2013 to 2016. After exclusions for several reasons, including availability of data, 8,990 patients were included for a regression analysis, and 7,027 patients were included for a survival analysis from 2013 to 2015.

The median overall survival in the full cohort was 10.1 months. The median overall survival was 7.5 months among patients who did not receive any immunotherapy compared with 18.4 months in those who did receive ICIs (p < 0.01). The use of immunotherapy has been expanding since the initial approval in 2011: 15.8% received ICIs in 2011 compared with 48.0% in 2016.

Patients were more likely to receive immunotherapy across increasing income quartiles (p < 0.01); the top quartile (median income of at least $63,333 per year) received ICIs 38.2% of the time compared with 31.1% in the lowest quartile (< $40,227 per year). Patients were also more likely to receive ICIs if they had attained a high school degree. The mean age of patients who received ICIs was 62.6 compared with 66.5 for those who did not (p < 0.01). There was no significant difference across patient sexes. Patients were less likely to receive ICIs as Charlson-Deyo Scores increased (p < 0.01), representing increasing medical co-morbidity burden.

Patients who were treated in metropolitan areas (counties with a population of more than 250,000 people) received immunotherapy in 36.8% of cases compared with 32.7% in non-metro areas (p < 0.01). Only 27.5% of patients treated at community cancer programs received ICIs compared with 29.3% of those treated at comprehensive community cancer programs, 34.3% of those treated at integrated network cancer programs, and 42.8% of those treated at academic/research programs (p < 0.01).

A total of 42.7% of patients with private insurance/managed care received ICIs. This rate was higher than receipt with all other insurance statuses, including 32.6% of those with Medicaid, 32.6% of those with Medicare, and 26.4% of those who did not have insurance (p < 0.01). Patients who lived in non–Medicaid expansion states were less likely than those in expansion states to receive immunotherapy (32.5% vs. 37.2%; p < 0.01).

On a regression analysis, being uninsured was the strongest predictor of not receiving immunotherapy; the odds ratio compared with those who had private insurance was 0.45 (95% CI [0.34, 0.59]; p < 0.01). The strongest predictor for receiving ICIs was treatment at an academic/integrated center compared with a community center (odds ratio 1.59, 95% CI [1.45, 1.75]; p < 0.01). The difference between metropolitan areas versus non-metropolitan areas was not significant in this analysis.

Dr. Moyers noted several limitations of the analysis, including its retrospective nature and that only first-line systemic therapy was recorded. Differences between specific immunotherapy agents could not be assessed, and disease-specific survival was not available.

“This is really important because of the difference in survival,” said Heather S. L. Jim, PhD, of the H. Lee Moffitt Cancer Center & Research Institute, who was the discussant for the study.

“The people who received immunotherapy survived on average almost a full year longer than those who didn’t,” Dr. Jim said. Additionally, she noted that other studies have found that under-insured patients are more likely to be diagnosed at a later disease stage.

“But it’s the patients with late-stage disease for whom these immunotherapies are approved for and [who] could potentially really benefit from them,” she added.

— Dave Levitan

Researchers Examine Incidence, Outcomes of Radiation Recall Pneumonitis After Immunotherapy for Lung Cancer

A new study found a statistically significant though modestly higher incidence of immune-related pneumonitis in patients with non–small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors (ICIs) and who were previously treated with thoracic radiation therapy (TRT), compared with those who did not undergo TRT (Abstract 88). The study found no significant risk factors for radiation recall pneumonitis (RRP) pattern and no significant differences in outcome between RRP and other patterns of pneumonitis.

ICI therapy can cause immune-related pneumonitis, in particular in the NSCLC setting. “Some patients have a history of previous TRT, and [can] develop radiation recall pneumonitis after ICI treatment,” said Tadasuke Shimokawaji, MD, PhD, of the Kanagawa Cancer Center, in Japan, who presented the new study’s results on February 7 during the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Previously, only case reports of RRP following ICI treatment were available, and the incidence, risk factors, and clinical characteristics of RRP were unknown. The combination of radiation with ICI has previously been studied in multiple prospective clinical trials and found to be safe.

The new study included 669 patients with NSCLC treated with nivolumab at five institutions between December 2015 and March 2017. An RRP pattern was defined as the presence of fibrosis or consolidation progressing inside the previous radiation field, including those progressing both inside and outside the field. RRP was only diagnosed if it occurred more than 6 months after TRT.

The patients had a median age of 66, and 68.3% of the cohort was male. Most patients had adenocarcinoma (68.0%), and most had stage IV disease (57.7%). The most common biomarker mutation was EGFR (16.0%), followed by ALK (1.5%) and ROS1 (1.2%). Most of the cohort were current or former smokers (78.2%), with a median of 41 pack-years. A total of 412 patients (61.6%) had undergone previous TRT.

The overall incidence of immune-related pneumonitis was 8.8% (59 patients), with 2.6% at grade 3 or higher. The incidence was higher in those with a history of TRT, at 13.2% compared with 6.1% (odds ratio [OR] 2.36; 95% CI [1.37, 4.06]; p = 0.0015).

Of the 34 patients with previous TRT who developed pneumonitis, 16 had RRP, and 18 had other pneumonitis patterns. Two of the 16 with RRP developed the pneumonitis within 6 months following TRT and were excluded from those considered to have RRP.

The researchers examined several potential risk factors for RRP, but none were found to be significantly associated. For example, patients age 65 or older had an OR for RRP of 2.90 (95% CI, [0.57, 14.74]; p = 0.1863). Male patients had an OR of 2.06 (95% CI [0.40, 10.70]; p = 0.3816), and patients who smoked had an OR of 1.71 (95% CI [0.18, 16.03]; p = 0.6348). ECOG performance status of 2 or higher and the presence of background lung disease also were not significantly associated with RRP.

There was no difference in severity of pneumonitis between RRP cases and other patterns. RRP did show slightly better outcomes, but this did not reach significance (p = 0.2366). Eight of the 14 RRP cases achieved a cure, and six achieved remission. In the other pneumonitis patterns in those who received TRT, five were cured, and 13 achieved remission. In those patients who did not receive TRT, seven pneumonitis cases were cured, 14 achieved remission, one was exacerbated, and three resulted in death.

Discussant Jarushka Naidoo, MBBCh, of the Sidney Kimmel Cancer Center at Johns Hopkins University, stressed the importance of differentiation between pneumonitis due to ICI therapy and radiation. “Sifting through these diagnoses is becoming more and more relevant to our clinical practice, particularly in lung cancer, where we’re giving immunotherapy to patients for a year after completion of chemoradiation,” she said.

Dr. Naidoo said that the best opportunity for innovation in this field is to look for biomarkers that may help differentiate immune-related and radiation-related pneumonitis. She also said that the type of thoracic radiation patients receive may be important with regard to development of pneumonitis, and how that factor relates to the incidence and outcomes remains to be seen.

— Dave Levitan

Vitamin D Intake May Reduce Risk of Immune Checkpoint Inhibitor–Induced Colitis

Patients who were taking vitamin D supplements when initiating immune checkpoint inhibitor (ICI) therapy had significantly reduced odds of developing ICI–related colitis, according to a retrospective study (Abstract 89) presented during the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. The findings will require validation through prospective and correlative studies.

“Colitis is one of the most common high-grade adverse events” with ICI therapy, said Kevin Tyan, of Harvard Medical School and the Dana-Farber Cancer Institute, who presented results of the study on February 7. “It often leads to treatment interruption and requires immunosuppressive therapy that is detrimental to the tumor response…. Despite its clinical burden, there is a relative lack of predictive factors or prophylactic measures.”

Previous reports have suggested a number of putative risk factors for ICI–induced colitis, including the type and dose of ICI therapy, use of nonsteroidal anti-inflammatory drugs, pre-existing inflammatory bowel disease (IBD), certain characteristics of the microbiome, and high levels of serum IL-17. Vitamin D has immunomodulatory properties, particularly by polarization toward Th2 and a shift away from Th1, Mr. Tyan said. Also, it has been shown to actively suppress autoimmune disorders.

The new study included a discovery cohort of 213 patients at the Dana-Farber Cancer Institute receiving ICIs (of an original 246 patients, after exclusions for lack of adverse events or receipt of therapies not approved by the U.S. Food and Drug Administration), as well as a validation cohort of 169 patients at Massachusetts General Hospital. In the discovery cohort, 37 patients (17.4%) developed colitis; 49 patients (29.0%) developed colitis in the validation cohort.

The researchers examined 37 variables on a univariate analysis to determine risk factors for colitis, followed by a multivariable model using three identified independent predictors; these included ICI class, baseline neutrophil-to-lymphocyte (NLR) ratio greater than or equal to 5, and pretreatment vitamin D intake.

In the discovery cohort, ipilimumab plus nivolumab had an increased risk for colitis compared with pembrolizumab, with an odds ratio (OR) of 3.34 (95% CI [1.1, 9.8]; p = 0.001), as did ipilimumab monotherapy compared with pembrolizumab, with an OR of 7.48 (95% CI [2.6, 21.8]; p = 0.001). Mr. Tyan said this was consistent with findings in previous studies.

A higher NLR ratio was associated with a lower risk for colitis, with an OR of 0.34 (95% CI [0.1, 0.9]; p = 0.046). Vitamin D intake was also associated with a reduced risk, with an OR of 0.35 (95% CI [0.1, 0.9]; p = 0.01).

These findings were confirmed in the validation cohort, although the NLR OR did not reach significance. Vitamin D intake in that cohort had an OR for colitis of 0.46 (95% CI [0.2, 0.9]; p = 0.03). When vitamin D dosages were stratified into three categories, no difference was seen between doses of up to 1,000 IU and doses above 1,000 IU and the associated risk of colitis. There was also no association between vitamin D intake and durable response to ICI therapy.

Mr. Tyan noted that the study did not determine whether patients had vitamin D deficiency at baseline, or if vitamin D supplementation was done because of underlying diseases or other conditions that could have confounded the results. “This is a hypothesis-generating study and warrants further validation through prospective and correlative studies,” he said.

Jarushka Naidoo, MBBCh, of the Sidney Kimmel Cancer Center at Johns Hopkins University, was the discussant for the study. “It is based on a strong rationale in the IBD literature,” she said, adding that it is a robust analysis due to the discovery and validation cohorts. “It validates pretreatment vitamin D as a potential risk factor for colitis in patients with melanoma mainly treated with the combination of ipilimumab and nivolumab. Interestingly, of course, this is a modifiable risk factor.”

Dr. Naidoo noted that the results are limited by a lack of concrete data on the specifics of vitamin D use, and that ideally there would be a balance in the incidence of colitis between the discovery and validation cohorts; in this study, the validation cohort had nearly twice the incidence.

“Importantly, these data only assess the incidence of colitis in patients with melanoma,” she said, noting that combination immunotherapy has expanded into other tumor types such as renal cell carcinoma and non–small cell lung cancer.

— Dave Levitan

Assessing the True Cost of Cancer Care: Measuring and Mitigating Financial Toxicity

“The long drives, the clinic visits, the missed work. It’s just a lot.” – A patient with metastatic lung cancer.

“I do my best to eat, but $20 for a case [of nutritional supplement] is too much for me.” – A patient with metastatic head and neck squamous cell carcinoma.

These are just a few of the statements we have heard in clinic in the past 2 weeks from patients, and we expect we are not alone in hearing these.

Expenses related to medical care represent one of the largest problems faced by industrialized Western democracies. In the United States, spending on cancer care alone is expected to reach $174 billion in 2020.1 Although, not inherently bad, health care expenditures “crowd out” productive investment in infrastructure, education, and research and development. At the individual patient level, health care expenses from either catastrophic or chronic illness represent a significant cause of personal bankruptcy in the United States. 2 Patients with cancer are particularly at risk; approximately 40% suffer from some form of financial insolvency in the 4 years following diagnosis.3 Moreover, regardless of stage, behaviors caused by, or associated with financial distress, contribute to worse cancer outcomes in low socioeconomic status (SES) groups compared with higher SES groups.4

Short of bankruptcy, health care expenses can directly lead to financial hardship and depletion of patients’ savings and investments in their (and their families’) futures. 2 Physical toxicities of treatment can have long-lasting financial implications, such as the inability to perform certain kinds of labor or the need for expensive long-term medications.5 All together, the ill-defined direct and indirect costs experienced by the patient in the provisioning of medical care make up the financial toxicity of treatment.6

Major out-of-pocket expenditures encountered by patients with cancer include costs of medications, drug administration, follow-up appointments, and hospitalization. 7 Perhaps less well-recognized—but especially relevant to clinical trial participants, or those with limited access—are the costs of transportation and lodging.8 Out-of-pocket costs for novel medications have been the predominant driver of financial toxicity. 7 Although rebates or coupons may reduce financial toxicity of novel therapies to the individual patient, they can also result in higher drug prices.9 Further, many patients do not qualify for financial assistance programs based on individual salary or income. Finally, as oncologists seek to promote enrollment in clinical trials, the financial toxicity to participants needs to be enumerated. Total costs of clinical trial participation, which exist outside of costs covered by the study sponsors, also includes travel and lodging, frequent patient visits, and indirect costs of time spent at the clinic or infusion treatment center.8

MEASURING FINANCIAL TOXICITY IN PATIENTS WITH CANCER

Key to combatting financial toxicity is first developing reliable measures to track it. Measures developed to date include the Comprehensive Score for financial Toxicity (COST), Breast Cancer Finances Survey (BCFS) inventory, and Socioeconomic Wellbeing scale metrics.10 The COST measure is an 11-item questionnaire developed and validated in a socioeconomically diverse population receiving treatment at both academic and community settings.11 It includes questions assessing patients’ frustrations related to spending on care, their lack of agency in financial decision-making, and self-assessed ability to meet monthly expenses. The measure correlates independently with health-related quality of life and psychologic distress. To date, COST has been implemented to describe financial toxicity and draw attention to the problem. Opportunities in the future include incorporating COST as a longitudinal patient-reported outcome measure that can be utilized in clinical decision-making, either within or outside the context of a clinical trial.

At present, markers of higher financial toxicity—number of hospitalizations, clinic visits, or unanticipated emergency department encounters—are not routinely reported in clinical trials. Incorporating either strict cost analysis or these correlated markers into clinical trial design and reporting would provide valuable information about the financial implications of a treatment as it is translated from the world of clinical trials into the real-world setting. Indeed, there are arguments for documenting within the medical record is an important first step in operationalizing financial toxicity and helping it gain a foothold as an important patient-reported outcome measure, as we would any adverse effect of treatment.12

Financial toxicity needs to be examined across space—different locations where it is encountered, scale—that is, considering individual and systems toxicities, and, lastly, time. Financial toxicities can be acute and chronic, impacting finances in the short run, constraining retirement savings, and limiting the ability of long-term survivors to work at full capacity. Management of the dangers posed by the financial toxicity a young patient can expect to encounter 30 years in the future is crucial.13 Populations impacted by cancer-related financial toxicity tend to be working-age, younger, more likely female, and more likely nonwhite.14

HOW ONCOLOGY PROVIDERS CAN HELP MITIGATE FINANCIAL TOXICITY

So, what can oncology providers do? To be sure, a problem so entrenched as cost escalation will require a multidisciplinary approach at the level of the individual practice, and involves care providers, nurses, and financial counselors/advocates.15 Engagement with the question of cost of care should begin early in the care process.15 Financial considerations should not limit a team’s recommendations, but research into incorporation of cost considerations into multidisciplinary tumor board discussion would be welcome.

Knowing the financial risks posed by cancer treatment, to what extent are oncology practices required to be involved? First, in modern interpretations of the law, many legal experts believe there is a duty to disclose costs as part of an informed consent coversation.16 Previously, informed consent conversations were limited to clinical risks, benefits, and treatment alternatives. More recently, disclosure of the known nonbiomedical factors—especially those within a patient’s control—that could reasonably be expected to affect clinical outcomes has become the expectation. Second, as a fiduciary, physicians must strive to incorporate best evidence and relevant guideline recommendations into their treatment conversations. We note that an ASCO policy statement provides a framework to assess value of cancer treatment regimens.17 While the policy statement is not a guideline per se, it recommends a comprehensive approach to value that accounts for clinical benefit, toxicity, palliative benefit, treatment-free interval, and net health benefit, and compares these with cost of treatment.17 How this effort will translate to the clinical space remains an unknown, but prospect theory may suggest that human beings take these decisions in a manner much different than the subjective expected-utility-maximizing model the framework relies upon.

Perhaps more importantly, to what extent should oncology providers be involved? We would argue for a more interventional stance. First, patients want to talk about the issue and consider it a risk that impacts their calculus.18 Oncology care providers are specially positioned to communicate information in a patient-centered way and empowered to modify treatment plans according to patients’ wishes. Unfortunately, the rate at which care providers discuss cost falls short of patients’ desired frequency: Well over half of patients would prefer to talk about cost, but less than one-third reported having spoken with their physician about it.2 Complicating matters further, oncology care providers may think they are having a conversation about cost – anywhere from 10% to 60% report talking about cost with patients – but this is not what patients are hearing.19 Without a doubt, these are uncomfortable conversations, and oncology providers often respond by saying, “I’m not trained to do that” or “I wouldn’t feel comfortable having that discussion.” What is more, there is limited evidence about how to initiate the conversation. From the patient advocate perspective, the best first question is a simple one: “Do you have concerns about the cost of your treatment?”20 This judgment-free question helps normalize the topic, and can be asked of all patients, not just those for whom the clinician is concerned.

Second, oncology providers should help support the building of generic and biosimilar markets for commonly prescribed medications.21 Although many states have provisions in place that allow or require pharmacists to substitute generics for brand-name medications at the time of filling (unless “dispense as written” is directed), mandatory substitution is not the law of the land for biosimilars. Oncology providers should avail themselves of biosimilar clinical trials and where appropriate prescribe.

Finally, oncology providers, community and academic alike, have process improvement responsibilities and are encouraged to participate in growing movements. Interventional pharmacoeconomics intends to use approved medications more intelligently by incorporating dosing schedules inferred from early-phase studies in novel, pharmacokinetic-oriented clinical trial designs. Major goals are to improve patient experience and reduce toxicity (including financial) without sacrificing outcomes.22 Evaluating treatments in terms of both value and cost for the individual patient is sorely needed. Leveraging synergies may allow for extraction of marginal value from high, fixed costs that are likely to be undertaken anyway. Take, for example, chemoradiotherapy. Combined treatment produces better outcomes, shorter durations of treatment, and lower cost. In the modern age, combining of short-beam radiotherapy and immunotherapy may lead to improved patient outcomes without additional cost.

CONCLUDING THOUGHTS

Financial toxicity represents a significant acute and chronic problem for oncology and, more generally, health care in the United States. Care providers will continue to have a role to play in mitigating the toxicity first by naming the problem and normalizing discussion with their patients, and then by using their unique skills to tailor treatment plans to patient goals. The moment is an incredible opportunity to build new markets to exploit cost-effective medicines, combine expensive medicines to extract maximal value, and, above all else, listen to our patients and crafting treatment plans to meet our patients’ life, family, and financial goals is crucial to securing oncology’s future.

– Garth W. Strohbehn, MD, MPhil, and Christine M. Bestvina, MD

REFERENCES

  1. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst . 2011;103:117-128.
  2. Gilligan AM, Alberts DS, Roe DJ, et al. Death or Debt? National Estimates of Financial Toxicity in Persons with Newly-Diagnosed Cancer. Am J Med . 2018;131:1187-1199.e5.
  3. Ramsey S, Blough D, Kirchhoff A, et al. Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. Health Aff (Millwood) . 2013;32:1143-1152.
  4. Ramsey SD, Bansal A, Fedorenko CR, et al. Financial Insolvency as a Risk Factor for Early Mortality Among Patients With Cancer. J Clin Oncol . 2016;34:980-986.
  5. Huang IC, Bhakta N, Brinkman TM, et al. Determinants and Consequences of Financial Hardship Among Adult Survivors of Childhood Cancer: A Report From the St. Jude Lifetime Cohort Study. J Natl Cancer Inst . 2019;111:189-200.
  6. Zafar SY, Peppercorn JM, Schrag D, et al. The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expenses and the insured cancer patient’s experience. Oncologist . 2013;18:381-390.
  7. de Souza JA, Conti RM. Mitigating Financial Toxicity Among US Patients With Cancer. JAMA Oncol . 2017;3:765-766.
  8. Nipp RD, Powell E, Chabner B, et al. Recognizing the Financial Burden of Cancer Patients in Clinical Trials. Oncologist . 2015;20:572-575.
  9. Dusetzina SB, Conti RM, Yu NL, et al. Association of Prescription Drug Price Rebates in Medicare Part D With Patient Out-of-Pocket and Federal Spending. JAMA Intern Med . 2017;177:1185-1188.
  10. Witte J, Mehlis K, Surmann B, et al. Methods for measuring financial toxicity after cancer diagnosis and treatment: a systematic review and its implications. Ann Oncol . 2019;30(7):1061-1070.
  11. de Souza JA, Yap BJ, Wroblewski K, et al. Measuring financial toxicity as a clinically relevant patient-reported outcome: The validation of the COmprehensive Score for financial Toxicity (COST). Cancer . 2017;123:476-484. Epub 2016 Oct 7.
  12. Khera N. Reporting and grading financial toxicity. J Clin Oncol . 2014;32:3337-3338.
  13. Knight TG, Deal AM, Dusetzina SB, et al. Financial Toxicity in Adults With Cancer: Adverse Outcomes and Noncompliance. J Oncol Pract . 2018;14:11, e665-e673.
  14. Yabroff KR, Dowling EC, Guy GP, Jr., et al. Financial Hardship Associated With Cancer in the United States: Findings From a Population-Based Sample of Adult Cancer Survivors. J Clin Oncol . 2016;34:259-267.
  15. Sherman DE. Transforming Practices Through the Oncology Care Model: Financial Toxicity and Counseling. J Oncol Pract. 2017;13:519-522.
  16. Pope TM. The ASCO Post. Informed consent and the oncologist: Legal duties to discuss costs of treatment. ascopost.com/issues/november-25-2017/informed-consent-and-the-oncologist-legal-duties-to-discuss-costs-of-treatment/. Published November 25, 2017. Accessed August 13, 2019.
  17. Schnipper LE, Davidson NE, Wollins DS, et al. American Society of Clinical Oncology Statement: A Conceptual Framework to Assess the Value of Cancer Treatment Options. J Clin Oncol . 2015;33:2563-2577.
  18. Wollins DS, Zafar SY. A Touchy Subject: Can Physicians Improve Value by Discussing Costs and Clinical Benefits With Patients? Oncologist . 2016;21:1157-1160 .
  19. Shih YT, Chien CR. A review of cost communication in oncology: Patient attitude, provider acceptance, and outcome assessment. Cancer . 2017;123:928-939.
  20. Zafar SY, Newcomer LN, McCarthy J, et al. How Should We Intervene on the Financial Toxicity of Cancer Care? One Shot, Four Perspectives. Am Soc Clin Oncol Educ Book . 2017;37:35-39.
  21. Hunter WG, Zhang CZ, Hesson A, et al. What Strategies Do Physicians and Patients Discuss to Reduce Out-of-Pocket Costs? Analysis of Cost-Saving Strategies in 1,755 Outpatient Clinic Visits. Med Decis Making . 2016;36:900-910.
  22. Ratain MJ, Goldstein DA, Lichter AS. Interventional Pharmacoeconomics-A New Discipline for a Cost-Constrained Environment. JAMA Oncol . 2019;5:1097.

Utilizing Multidisciplinary Immunotherapy Strategies in the Treatment of Solid Tumor Brain Metastases

Solid tumor brain metastases are an increasingly common consequence of metastatic disease across multiple malignancies, contributing to morbidity and mortality. Surgical resection and/or radiotherapy are often effective initial local treatments for brain metastases; however, local and distant intracranial progression remain clinical challenges. The development of drugs that effectively treat or prevent solid tumor brain metastases has been fraught with challenges, such as blood–brain barrier penetrability, presence of efflux transporters, limited preclinical models, patient exclusion from clinical trials, and dissociated intracranial/extracranial response to treatment.

We are now in the era of immunotherapy, which is less tied to blood–brain barrier penetrability or drug efflux transporters but more so to an augmented physiologic anticancer immune response. Multidisciplinary approaches that integrate novel approaches to immune activation with newer understanding of the immunologic peculiarities of the central nervous system (CNS) hold promise in overcoming many of the historical barriers to advancing the treatment of solid tumor brain metastases.

DIVERSE IMMUNE MICROENVIRONMENT OF BRAIN METASTASES AND RATIONALE FOR IMMUNOTHERAPY APPROACHES

Subversion of both endogenous and therapeutically induced immune responses, long known to be a hallmark of primary gliomas, is increasingly a recognized characteristic of brain metastases (reviewed in Farber et al.1). Although our concept of the brain as immune-privileged and hermetic has subsided in favor of notions of a compartment that is better described as immunologically “distinct,” one would be remiss not to acknowledge these distinctions as challenges to overcome in the design of immune-based platforms.

The brain has evolved a variety of mechanisms aimed at curbing inflammatory responses that would otherwise be harmful, limiting both the access and scope of would-be T-cell responses. Tumors of the intracranial compartment, in turn, are often able to usurp such mechanisms to restrict the antitumor immune response, even sequestering T cells away in other compartments where they can “do no harm.”2

Brain metastases frequently contain fewer T-cell infiltrates than their peripherally located counterparts, and T cells that do successfully infiltrate are subject to further suppressive influences geared at promoting such dysfunction as tolerance and exhaustion.3,4 Tumor infiltrates within the brain are uniquely heavy in microglia and monocytes, which may function ultimately to dampen the cell-mediated immune response, a function embraced by brain-harbored metastases.

In the end, the systemic and local immunologic consequences of CNS metastasis are not as well characterized as in primary brain tumors, but their location within the brain and the current data suggest contributions by many of the same environmental immunosuppressive factors. For instance, much as with glioma,5 regulatory T cells have been shown to infiltrate experimental models of metastatic melanoma and breast and colon cancers within the brain and have also been seen in human metastatic brain lesions at autopsy.6 Additionally, high levels of PD-1 expression have been seen on lymphocytes infiltrating brain metastases, often in those areas of the tumor staining positively for PD-L1.7

Although the mechanisms underlying the movement and clonal expansion of T cells systemically and within the tumor microenvironment remain under investigation, numerous studies document T-cell ineffectiveness as a result of stand-downs at immune checkpoints (Figure). Accordingly, strategies fostering immune checkpoint blockade (described in the next section) have begun to result in clinically significant improvements in treatment and prognosis. Their future success, however, will depend on deepening our understanding of the interactions between tumor and immune populations within the brain specifically.

IMMUNE CHECKPOINT INHIBITION IN SOLID TUMOR BRAIN METASTASES

Immune checkpoint inhibition (ICI) targeting PD-1/PD-L1 and CTLA-4 has revolutionized the manner in which we treat solid tumors with corresponding improvements in both progression-free and overall survival across many tumor types. Most early ICI trials excluded patients with brain metastases. Two phase III non–small cell lung cancer (NSCLC) clinical trials that included patients with brain metastases showed improved overall survival with ICI over chemotherapy in subset analyses, which was an early clue of intracranial efficacy in this tumor type. We now have results from several prospective clinical trials in untreated and treated melanoma and PD-L1–positive NSCLC brain metastases showing intracranial responses to ICI without major safety concerns (Table 1).

CTLA-4 INHIBITION

Single-agent CTLA-4 inhibition in the treatment of melanoma brain metastases was first evaluated in the Italian NIBIT II trial of ipilimumab in combination with fotemustine,10 revealing a disease control rate of 50%. A follow-up phase II study of ipilimumab alone for patients with melanoma brain metastases.11 demonstrated a response rate of 18% in the asymptomatic cohort compared with 5% in the symptomatic cohort, a clue that steroid treatment abrogates ICI response rates.

PD-1/PD-L1 INHIBITION IN SOLID TUMOR BRAIN METASTASES

Pembrolizumab was studied in a single-arm, phase II trial in patients with melanoma or PD-L1–positive NSCLC untreated/asymptomatic brain metastasis.12 A brain metastasis response was achieved in 22% of patients with melanoma and 33% of patients with PD-L1–positive NSCLC. Clinically significant neurologic adverse events were uncommon. A phase II trial assessed the activity and safety of nivolumab in patients with metastatic renal cell carcinoma (RCC; post-VEGF) and included patients with asymptomatic brain metastases in two cohorts: (A) untreated or (B) locally treated.13 Intracranial response rate was only 12% in cohort A and was limited to those with single brain lesions less than 1 cm. Interestingly, 18% of patients had dissociated intracranial/extracranial response, although all patients who responded in the brain had an extracranial response.

COMBINATION CTLA-4 AND PD-1 INHIBITION

Combining CTLA-4 inhibition (ipilimumab) and PD-1 inhibition (nivolumab) significantly increases intracranial response rates in untreated melanoma brain metastases with the expected increased toxicity.14 A phase II, single-arm study in patients with metastatic melanoma and at least untreated asymptomatic brain metastasis studied nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg). The rate of intracranial clinical benefit was 58.4%, with 26.0% of patients achieving a complete response. Given this impressive intracranial response rate, patients starting dual checkpoint inhibition for metastatic melanoma with small, asymptomatic brain metastases can likely begin systemic treatment and defer local therapy as salvage with close monitoring. At the 2019 ASCO Annual Meeting, Tawbi et al. reported the outcomes from this trial of patients with neurologic symptoms (with or without the use of steroids). Intracranial response rates were lower, revealing an intracranial clinical benefit rate of 22%, with 11% of patients achieving complete response.15

Evaluating this body of literature collectively, we now know that PD-1/PD-L1 inhibition has respectable intracranial activity in PD-L1–positive NSCLC and melanoma. Combination ICI is very effective and the preferred systemic therapy for asymptomatic melanoma brain metastases. We also now understand that patients with asymptomatic brain metastases not requiring steroids have superior responses to ICI than those with larger, symptomatic lesions requiring steroids.

Questions remain, such as, how to best sequence local therapy such as stereotactic radiosurgery (SRS) and/or neurosurgical resection with ICI, either prior to, concurrently, or as a salvage approach. Intracranial response to PD-1 inhibition appears limited in RCC and symptomatic melanoma brain metastases requiring ongoing steroids. On the contrary, patients with asymptomatic brain metastases arising from melanoma receiving first-line ICI may reserve surgery and/or SRS as salvage treatment. We await further studies to make this recommendation across other tumor types.

COMBINATION RADIATION AND IMMUNOTHERAPY APPROACHES

New multidisciplinary care approaches to improve responses to ICI in asymptomatic and symptomatic solid tumor brain metastases are needed. Many exciting clinical trials are underway that use novel concepts specific to patients with brain metastases, which is a vast improvement over the past 5 years. Novel ICI combinations, ICI with concurrent alternating electric field therapy (tumor treating fields), intrathecal ICI administration, bispecific antibody (HER2Bi) armed activated T cells, and HER2 CAR T cells for leptomeningeal disease are a few concepts underway (Table 2). The immunogenic potential of radiation has been of interest for decades and studied extensively in preclinical and retrospective studies. Radiotherapy increases tumor PD‐L1 expression and tumor antigen presentation, thus increasing CD8+ T cells in the tumor microenvironment.16 Preclinical data also suggest that acquired resistance to radiation can be overcome with concurrent PD‐1/PD‐L1 inhibition.17

Several retrospective studies, to date, have suggested that SRS added to immunotherapy improves outcomes safely. The first prospective trial to evaluate concurrent ICI with brain radiation was a pilot study of whole-brain radiotherapy with tremelimumab examining the impact on distant (non-CNS) disease in women with estrogen receptor–negative breast cancer brain metastases.18 The combination was deemed safe with expected immune-related toxicity. Activity was modest and difficult to assess, however, as a result of rapid extracranial disease progression in the majority of patients. There are many ongoing trials studying the efficacy and safety of SRS with concurrent ICI (Table 2). There does appear to be an increase in radiation necrosis (RN) when ICI is given concurrently with SRS, especially in patients with melanoma.19 RN leads to significant morbidity and is often difficult to distinguish from disease progression. The primary treatment of RN is steroids, which can abrogate ICI intracranial response, and bevacizumab is employed in refractory cases. Biopsy can be useful in distinguishing between RN and progressive disease.

REMAINING QUESTIONS AND FUTURE DIRECTIONS

The care of our patients with solid tumor brain metastases is rapidly evolving. The days of excluding patients with brain metastases from clinical trials are behind us, and studies specifically enrolling patients with brain metastases are being increasingly developed. This represents a major shift in the approach toward patients with brain metastases, a shift that will hopefully translate to improved outcome and quality of life in the near future. Existing challenges in the era of immunotherapy include addressing immunologic distinctions within the CNS; deriving highly rational combination approaches; properly timing immunotherapy with available local therapies; refining our selection of patients most likely to benefit from immunotherapy; incorporating clinical parameters with tissue and blood-based biomarkers; deriving elegant ways to diagnose and treat RN; and, ultimately, identifying patients prior to CNS recurrence using strategic screening and prevention programs.

– Sarah Sammons, MD; Peter E. Fecci, MD, PhD; Carey Anders, MD; and David Ashley, MBBS (Hon), FRACP, PhD

REFERENCES

  1. Farber SH, Tsvankin V, Narloch JL, et al. Embracing rejection: Immunologic trends in brain metastasis. OncoImmunology . 2016;5:e1172153.
  2. Chongsathidkiet P, Jackson C, Koyama S, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med . 2018;24:1459-1468.
  3. Fischer GM, Jalali A, Kircher DA, et al. Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases. Cancer Discov . 2019;9:628-645.
  4. Woroniecka K, Chongsathidkiet P, Rhodin K, et al. T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma. Clin Cancer Res . 2018;24:4175-4186.
  5. Fecci PE, Mitchell DA, Whitesides JF, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res . 2006;66:3294-3302.
  6. Sugihara AQ, Rolle CE, Lesniak MS. Regulatory T cells actively infiltrate metastatic brain tumors. Int J Oncol. 2009;34:1533-1540.19424570
  7. Berghoff AS, Ricken G, Widhalm G, et al. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology . 2015;66:289-299.
  8. Fehrenbacher L, von Pawel J, Park K, et al. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol . 2018;13:1156-1170.
  9. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et alKEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med . 2018;378:2078-2092.
  10. Di Giacomo AM, Ascierto PA, Queirolo P, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol . 2015;26:798-803.
  11. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459-465.
  12. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol . 2016;17:976-983.
  13. Flippot R, Dalban C, Laguerre B, et al. Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study. J Clin Oncol. 2019 Jun 13. Epub ahead of print. http://doi.org/10.1200/JCO.18.02218.
  14. Tawbi HA, Forsyth PA, Algazi A, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med . 2018;379:722-730.
  15. Ardeshir-Larijani F, Nelson AA, Martin P, et al. Outcomes of melanoma patients with brain metastases receiving immune checkpoint inhibitor (ICI) therapy. J Clin Oncol. 2019;37 (suppl; abstr e21028).
  16. Meng X, Feng R, Yang L, et al. The Role of Radiation Oncology in Immuno-Oncology. Oncologist . 2019;24(Suppl 1):S42-S52.
  17. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res . 2014;74:5458-5468.
  18. McArthur H, Beal K, Halpenny D, et al. CTLA-4 blockade with HER2-directed therapy (H) yields clinical benefit in women undergoing radiation therapy (RT) for HER2-positive (HER2+) breast cancer brain metastases. Cancer Res. 2017;77(13 Suppl):Abstract nr 4705.
  19. Martin AM, Cagney DN, Catalano PJ, et al. Immunotherapy and Symptomatic Radiation Necrosis in Patients With Brain Metastases Treated With Stereotactic Radiation. JAMA Oncol . 2018;4:1123-1124.

Immunotherapy Combinations Revolutionize the Management of Advanced Renal Cell Carcinoma

Upfront immunotherapy (IO) combinations have shifted the landscape of renal cell carcinoma (RCC) therapy with never-before-seen clinical efficacy. Thus far, three large phase III trials of IO combinations compared to sunitinib, including CheckMate-214,1,2 Keynote-426,3 and Javelin Renal 1014 (Table 1), have expanded treatment options for patients. As these regimens populate clinical practice, we highlight unique aspects to consider, including 1) efficacy and evolving endpoints in clinical trials of immunotherapy regimens; 2) safety and quality of life (QOL) outcomes of combination therapy; 3) patient selection for treatment, including clinical parameters, predictive biomarkers, and variant histology RCC; and 4) future directions of combination therapy.

EFFICACY AND EVOLVING ENDPOINTS

Across all three combination regimens, median OS estimates have not been reached, setting a high bar for future frontline trials for patients with advanced disease. Although overall survival (OS) remains the most compelling endpoint, surrogate markers for long-term outcomes and additional clinically meaningful endpoints may help inform management. Progression-free survival (PFS), which has long been used as an endpoint in trials of VEGF blockade, has limitations for trials of IO–IO combinations. When evaluating PFS, landmark analyses at 18- or 24-months may be more relevant with IO–IO combinations; in contrast, regimens using VEGF-targeting agents have demonstrated more meaningful PFS outcomes.

Increasing evidence demonstrates that depth and duration of response are a critical factors for determining long-term benefit to both checkpoint and VEGF inhibition.5,6 With IO–VEGF combinations, responses are overserved in the majority of patients (59% and 51% with pembrolizumab/axitinib and avelumab/axitinib), with 5.8% and 3.4% achieving complete responses (CRs), respectively. Although cross-trial comparisons are fraught with error, ipilimumab/nivolumab had a lower ORR at 41%, although CRs were observed in 11% of the intention-to-treat population. Impressively, of those who responded to dual checkpoint blockade, 58% had ongoing responses at median follow-up of 32 months, and 88% of patients who achieved a CR maintained this response, although numbers are low across these subsets. Additionally, 50% of responses occurred within the first 3 months of treatment across these three studies, suggesting early onset of action of combination therapies. Longer follow-up is necessary to know if these durable remissions are maintained, but certainly, this gives us hope that this “tail of the curve” may represent long-term disease control.

Another important consideration in the context of IO therapy is that these trials defined responses based on RECIST criteria, which were historically developed to quantify responses to chemotherapy, and may underestimate the benefit of immunotherapy. Several response criteria more suitable for assessing the benefit of IO have been developed, although these have not been systematically integrated in trials of IO agents.7

Although the majority of patients derive clinical benefit from these combinations, intrinsic resistance is observed across all IO combination regimens. Approximately 22% of patients receiving ipilimumab/nivolumab had progressive disease as best objective response. IO–VEGF combination regimens exhibit a lower rate of primary progressive disease at approximately 10% across these trials. These data underscore the need to identify upfront or early predictive biomarkers of not only response but also resistance to therapy to improve patient selection for a given regimen.

SAFETY AND QUALITY OF LIFE

As patients are remaining on treatment for longer durations, other factors, including toxicities, QOL, and practicalities of treatment administration, play a role in clinical decision-making regarding the optimal regimen. Grade ≥ 3 treatment-related adverse events (TRAEs) were lower (47%) with the ipilimumab/nivolumab combination than with pembrolizumab/axitinib and avelumab/axitinib (76% and 71%, respectively). The temporal toxicity patterns for IO–IO and IO–VEGF regimens differ given the distinct mechanisms of actions of these regimens. With ipilimumab/nivolumab, grade 3/4 events arose early and typically resolved within the first 4 to 6 months of treatment, contrasted with the chronic toxicities observed with regimens incorporating a tyrosine-kinase inhibitor (TKI). Rates of high-dose steroid use for management of immune-mediated adverse events (imAEs) were 19% for ipilimumab/nivolumab and 11% for avelumab/axitinib. Close vigilance is required for imAE management to allow for early detection and intervention.

Another important consideration is the overlapping toxicities of IO and VEGF agents, particularly the onset of diarrhea or liver function test elevation, which pose a dilemma in distinguishing the causative agent. Clear guidelines for toxicity management in the context of these combination regimens are needed. Axitinib’s short half-life makes this TKI an ideal partner with a checkpoint inhibitor. Monitoring for resolution of symptoms when axitinib is discontinued can help differentiate etiology of toxicity.

QOL analyses are available from CheckMate-214 and demonstrate improved QOL with ipilimumab/nivolumab compared with sunitinib. More recently, the concept of treatment-free survival (TFS) has emerged. Regan et al. presented data on the application of this novel outcome measure, with and without toxicity, from the CheckMate-214 trial.8 At a minimum follow-up of 30 months, TFS without grade ≥ 3 toxicity was greater for ipilimumab/nivolumab compared with sunitinib (5.5 vs. 2.8 months for intermediate-/poor-risk patients; 9.4 vs. 2.6 months for favorable-risk patients), denoting a critical time when patients did not require systemic anticancer therapy and were free from toxicity. Nearly 20% of patients who received dual checkpoint inhibition and subsequently discontinued therapy remained off treatment for 18 months (4% with sunitinib). The ability to improve QOL by decreasing long-term side effects and hold treatment are compelling reasons to consider dual checkpoint inhibitors.

PATIENT SELECTION AND BIOMARKERS

The International Metastatic RCC Database Consortium risk stratification has historically been used to risk-stratify patients and inform prognosis in the era of frontline VEGF TKI therapy. Although the benefit of IO–IO and IO–TKI therapies in the frontline setting for intermediate-/poor-risk RCC is compelling, there remains significant controversy as to the appropriate therapy for patients with favorable-risk disease. CheckMate-214, Keynote-426, and Javelin Renal 101 differed in their primary endpoints, assessing efficacy parameters in different subsets of patients (Table 1). None of these trials were individually powered for robust subgroup analyses in the favorable-risk group alone.

Of note, Keynote-426 enrolled a higher percentage of favorable-risk patients. Although CheckMate-214 and Keynote-426 demonstrated no difference in outcomes between the combination arms compared with sunitinib for those with favorable risk disease, points estimates for OS favored sunitinib in CheckMate-214 and pembrolizumab/axitinib in Keynote-426. However, CR rates were higher in favorable-risk patients treated with ipilimumab/nivolumab (8%) compared with sunitinib (4%). Avelumab/axitinib demonstrated a statistically significant improvement in PFS over sunitinib in favorable-risk patients. Taken together, patients with favorable-risk disease are likely to do well, and any of the above treatments, including single-agent TKI, combination IO–TKI, and combination ipilimumab/nivolumab, can be tailored to clinical, disease, and patient factors.

One of the most pressing questions is the appropriate selection of patients for a given therapy. Although PD-L1 expression has been prognostic in RCC, its role as a predictive marker remains limited in RCC. Complicating matters, PD-L1 status as a biomarker is inherently difficult to interpret, as different assays were used across the frontline IO trials. Overall, patients treated with checkpoint inhibitors had superior clinical outcomes regardless of PD-L1 status, though the benefit seemed to be more pronounced in the PD-L1–positive population.

Novel biomarkers are needed to identify which patients may derive benefit from dual checkpoint inhibition, from upfront IO–VEGF combination therapy, and from single-agent VEGF TKI. In a biomarker analysis of Javelin Renal 101 presented at the 2019 ASCO Annual Meeting by Choueiri and colleagues, the presence of CD8+ T cells at the invasive margin of the tumor was predictive of improved PFS to avelumab/axitinib, but not sunitinib. Additionally, a unique immune-related signature incorporating pathway indicators for T- and natural killer-cell activation and IFN-γ signaling was able to predict outcomes to avelumab/axitinib.9 Biomarker analyses from phase II IMmotion150 (atezolizumab +/− bevacizumab vs. sunitinib) and phase III IMmotion151 (atezolizumab + bevacizumab vs. sunitinib) revealed that relative expression of angiogenesis and T-effector gene signatures identified differential PFS benefits for atezolizumab +/− bevacizumab versus sunitinib. Prespecified analyses from IMmotion151 demonstrated that patients classified as favorable-risk are characterized predominantly by the angiogenesisHigh signature, possibly explaining improved responses to VEGF TKI in this population of patients.

SARCOMATOID DIFFERENTIATION AND VARIANT HISTOLOGY RCC

Although all the frontline combination trials enrolled patients with clear cell RCC, exploratory post hoc analyses from these studies demonstrate that patients with sarcomatoid differentiation, which has historically been associated with worse prognosis, derive marked benefit from checkpoint inhibitors. ORRs were 57%,10 59%,11 and 47%,12 for patients with sarcomatoid features in CheckMate-214, Keynote-426, and Javelin Renal 101, respectively, with CR rates of 18%, 13%, and 4%, respectively, demonstrating clear benefit of the use of checkpoint inhibition in tumors with sarcomatoid differentiation.

The role of IO combinations in variant histology RCC is still evolving, as these patients were largely excluded from frontline trials. Cohort B of the single-arm phase II Keynote-427 trial evaluating the role of pembrolizumab in variant histology RCC demonstrated ORRs of 25% in papillary, 10% in chromophobe, and 35% in unclassified RCC. Additionally, the single-arm phase II study of atezolizumab/bevacizumab in variant histology RCC demonstrated an ORR of 25% in this patient population. Further studies are ongoing assessing the role of checkpoint inhibitors and combination therapies in variant histology RCC. The phase II CANI trial will evaluate the role of ipilimumab/nivolumab plus cabozantinib in variant histology RCC.

WHERE DO WE GO FROM HERE?

The aforementioned trials demonstrate a huge leap forward in the treatment of advanced RCC, which expand clinical options and improve outcomes for patients. As the field stands now, studies have established anti–PD-1/PD-L1 therapy with either ipilimumab or axitinib as standard first-line therapies for advanced RCC. However, further studies are necessary to address many of the lingering questions raised by the current reported trials.

For instance, the role of frontline single-agent anti–PD-1/PD-L1 therapies remains unknown. Some of these data have been presented, including cohort A of Keynote-427, a phase II study of single-agent pembrolizumab in patients with advanced clear cell RCC, which demonstrated an ORR of 36% with 64% of responders having responses greater than 12 months. For patients who do receive single-agent anti–PD-1/PD-L1 therapy as first-line therapy, the role of salvage combination ipilimumab/nivolumab lingers. To answer these questions, several response adaptive studies, which augment therapy based on disease response, are currently underway. The TITAN-RCC trial was a study of nivolumab monotherapy with additional ipilimumab/nivolumab “boost” cycles based on response in treatment-naive and previously treated patients with advanced RCC. As presented during the 2019 European Society for Medical Oncology Congress, first-line, single-agent nivolumab achieved an ORR in 28.7% of patients and 37.0% in patients with ipilimumab/nivolumab boost. This response rate is similar to the CheckMate-214 trial (41%), but only 1.9% achieved a CR.13 Another adaptive study, OMNIVORE, is also assessing the role of salvage ipilimumab/nivolumab after single-agent nivolumab (NCT03203473). This trial also will evaluate the role of treatment discontinuation in patients who demonstrate a sustained objective response to nivolumab. We hope that correlative studies from these trials may identify patients who may achieve significant benefit from single-agent anti–PD-1/PD-L1, and therefore avoid the toxicities of ipilimumab and TKIs, or those who require therapy escalation.

Lastly, a multitude of trials are ongoing, assessing the role of checkpoint inhibition with alternative TKIs (Table 2). These include CheckMate-9ER (NCT03141177; nivolumab/cabozantinib) and CLEAR (NCT02811861; lenvatinib/everolimus vs. lenvatinib/pembrolizumab vs. sunitinib). Additionally, COSMIC-313 (NCT03937219; nivolumab/ipilimumab/cabozantinib) and PDIGREE (NCT03793166; nivolumab/ipilimumab with salvage addition of cabozantinib) build on the nivolumab/ipilimumab with the addition of cabozantinib. In addition to these trials, novel agents such as cytokines (NCT03729245, bempegaldesleukin [NKTR-214] combined with nivolumab vs. cabozantinib or sunitinib), new checkpoint inhibitors, and unique targeted agents are currently being tested. These trials have the potential to add more treatment options into the armamentarium, although they will equally result in more questions regarding patient selection, treatment sequencing, and balancing the risk and benefit of treatment.

– Tyler F. Stewart, MD, and Rana R. McKay, MD

REFERENCES

  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med . 2018 Apr;378(14):1277-1290.
  2. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol . 2019 Oct;20(10):1370-1385.
  3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med . 2019 Mar;380(12):1116-1127.
  4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med . 2019 Mar;380(12):1103-1115.
  5. Osgood C, Mulkey F, Mishra-Kalyani PS, et al. FDA analysis of depth of response (DpR) and survival across 10 randomized controlled trials in patients with previously untreated unresectable or metastatic melanoma (UMM) by therapy type. J Clin Oncol. 2019 May;37(suppl 15):9508.
  6. Grünwald V, McKay RR, Krajewski KM, et al. Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma. Eur Urol . 2015 May;67(5):952-958.
  7. Anagnostou V, Yarchoan M, Hansen AR, et al. Immuno-oncology Trial Endpoints: Capturing Clinically Meaningful Activity. Clin Cancer Res . 2017 Sep;23(17):4959-4969.
  8. Rini BI, Powles T, Atkins MB, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet . 2019 Jun;393(10189):2404-2415.
  9. Regan MM, Atkins MB, Powles T, et al. Treatment free-survival, with and without toxicity, as a novel outcome applied to immuno-oncology agents in advanced renal cell carcinoma. Presented at: the 18th International Kidney Cancer Symposium; November 15-16, 2019; Miami, Florida
  10. Choueiri TK, Albiges L, Haanen JBAG, et al. Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019 May;37(15_suppl):101-101.
  11. McDermott DF, Choueiri TK, Motzer RJ, et al. CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. J Clin Oncol. 2019 May;37(suppl 15):4513.
  12. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase III KEYNOTE-426 study. J Clin Oncol. 2019 May;37(suppl 15):4500.
  13. Choueiri TK, Larkin JMG, Pal SK, et al. 910PD: Efficacy and biomarker analysis of patients (pts) with advanced renal cell carcinoma (aRCC) with sarcomatoid histology (sRCC): Subgroup analysis from the phase III JAVELIN renal 101 trial of first-line avelumab plus axitinib (A + Ax) vs sunitinib (S). Ann Oncol. 2019 Oct;30(suppl 5):mdz249.009.
  14. Grimm M-O, Schmidinger M, Duran Martinez I, et al. LBA57: Tailored immunotherapy approach with nivolumab in advanced renal cell carcinoma (TITAN-RCC). Ann Oncol . 2019 Oct;30(suppl 5):mdz394.051.

Exploring Updates in Head and Neck Cancer Research

Advanced squamous cell carcinoma of the head and neck (SCCHN) remains a devastating disease with limited effective treatment options. Treatment of locally advanced disease with multimodal therapy, including the use of platinum-based chemotherapy, radiation, and surgery, is often effective; however, curative treatment can come with the risk of significant treatment-related morbidity and toxicity. Although HPV-related oropharyngeal carcinoma often is associated with improved prognosis compared with non-HPV–related carcinomas of the oropharynx,1 it is unclear whether treatments for locally advanced HPV-related oropharyngeal carcinoma should be deintensified and how to deintensify treatment of patients with this disease. For patients with recurrent or metastatic SCCHN who are not candidates for local therapy, as with many other malignancies, the use of anti–PD-1 immunotherapy has expanded patients’ treatment options in both the frontline and second-line treatment settings.

RECENT CLINICAL TRIALS

Although the treatment of patients with locally advanced SCCHN with concurrent chemoradiation involving cisplatin is often successful, with overall survival (OS) rather high with more than 50% of patients alive at 3 years, morbidity associated with treatment-related acute and long-term toxicity can be severe. As a strategy to deintensify therapy, the RTOG 1016 trial investigated whether the use of concurrent cetuximab in patients with low-risk, HPV-positive, locoregionally advanced oropharyngeal squamous cell carcinoma (SCC) was noninferior to treatment with cisplatin administered concurrently with radiation.2

The study included 849 patients with histologically-confirmed, nonmetastatic, HPV-positive oropharyngeal SCC at clinical stage T1–T2, N2a–N3 M0, or T3–T4, N0–N3 M0, per the American Joint Committee on Cancer, Seventh Edition, staging. Patients were randomly assigned to receive either cetuximab at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly or cisplatin at 100 mg/m2 on days 1 and 22 of radiotherapy, with all patients receiving standard accelerated intensity-modulated radiotherapy delivered concurrently with systemic therapy in 70 Gy in 35 fractions over 6 weeks. The primary endpoint was OS. At a median duration of follow-up of 4.5 years, 133 patients had died (58%): 78 (59%) in the cetuximab group and 55 (41%) in the cisplatin group. Radiotherapy plus cetuximab did not meet the criteria for noninferiority to radiotherapy plus cisplatin with a hazard ratio (HR) of 1.45 (95% CI, p = 0.5056). Additionally, the estimated OS was worse at 5 years for patients in the cetuximab group at 77.9% (95% CI [73.4%, 82.5%]) compared with 84.6% (95% CI [80.6%, 88.6%]) for patients treated with cisplatin. Risk of locoregional failure and progression-free survival were also worse with cetuximab (HR 2.05, 95% CI [1.35, 3.10] and HR 1.72, 95% CI [1.29, 2.29], respectively). Regarding acute toxicity, outcomes were similar between the two groups, with the incidence of acute moderate to severe toxicity of 77.4% (95% CI [73, 81.5]) and 81.7% (95% CI [77.5, 85.3]) for cetuximab and cisplatin, respectively (p = 0.1586). Similarly, there was no difference in the proportion of patients with late-moderate to severe toxicity (16.5% vs. 20.4% [p = 0.1904] for cetuximab and cisplatin, respectively). This study clearly solidified cisplatin administered concurrently with radiotherapy as the standard-of-care treatment for all patients with locally advanced SCCHN who are platinum-eligible.

For patients with recurrent or metastatic head and neck cancer who were not candidates for local therapy with salvage surgery or radiation, treatment with cytotoxic chemotherapy with or without cetuximab had long been the mainstay of treatment of frontline therapy, with few effective options in the second-line setting. For patients who had progressed on or after platinum-based therapy in the recurrent/metastatic setting, anti–PD-1 immunotherapy with either nivolumab or pembrolizumab improved OS compared with other second-line options, such as palliative docetaxel, methotrexate, or cetuximab. CheckMate 141 was the first study to demonstrate an improvement in median OS (mOS) for patients with head and neck cancer treated with anti–PD-1 immunotherapy. In this study, 361 patients with recurrent SCCHN who progressed within 6 months of platinum-based therapy were randomly assigned 2:1 in favor of nivolumab to receive nivolumab or investigator’s choice weekly therapy with methotrexate 40 mg/m2, docetaxel 30 to 40 mg/m2, or cetuximab 250 mg/m2 (after the standard 400 mg/m2 loading dose).3 mOS was 7.5 months (95% CI [5.5, 9.1]) for nivolumab compared with 5.1 months (95% CI [4.0, 6.0]) for the group who received investigator’s choice therapy. Improvement in OS was also statistically significant for nivolumab compared with standard therapy (HR for death 0.70, 97.73% CI [0.51, 0.96]; p = 0.01). The incidence of treatment-related adverse events was less for nivolumab than for investigator’s choice therapy (13.1% vs. 35.1%, respectively).

Similarly, KEYNOTE-040 sought to explore the role of pembrolizumab in patients with recurrent and metastatic SCCHN.4 In this study, 495 patients were randomly assigned to either treatment with pembrolizumab 200 mg every 3 weeks or to investigator’s choice of either methotrexate 40 mg/m2 per week, docetaxel 75 mg/m2 every 3 weeks, or cetuximab 250 mg/m2 (after the standard 400 mg/m2 loading dose). The HR for death in the pembrolizumab group was 0.80 (95% CI [0.65, 0.98]) and mOS was prolonged to 8.4 months (95% CI [6.4, 9.4]) in comparison with 6.9 months (95% CI [5.9, 8.0]) in the standard-of-care group. Outcomes in patients with a PD-L1 composite score of 1 or greater were better than in patients whose tumors did not have PD-L1 expression. Notably, in patients who responded to treatment with pembrolizumab, responses were durable at a median duration of 18.4 months (95% CI [5.8, 18.4]) compared with 5.1 months (95% CI [3.6, 18.8]) when using standard-of-care treatments, and patients who received pembrolizumab had fewer grade 3 or worse treatment-related adverse events (13% and 36% for pembrolizumab vs. investigator’s choice therapy, respectively).

Given the improvement in outcomes with anti–PD-1 in the second-line setting, KEYNOTE-048 went one step further to evaluate pembrolizumab in the frontline setting for recurrent/metastatic head and neck cancer.5 In this phase III trial, 882 patients were randomly assigned to receive monotherapy with pembrolizumab 200 mg every 3 weeks; pembrolizumab in combination with chemotherapy comprising platinum (carboplatin with area under the curve of 5 or cisplatin 100 mg/m2) and 5-fluorouracil 1000 mg/m2 per day for 4 consecutive days; or cetuximab at a dose of 250 mg/m2 weekly in combination with platinum and 5-fluorouracil chemotherapy (EXTREME). Chemotherapy was given for a total of six cycles with either pembrolizumab or cetuximab. Patients were stratified based on HPV positivity, PD-L1 combined positive score (CPS), and performance status. Irrespective of PD-L1 CPS, a statistically significant improvement in OS was seen for the pembrolizumab plus chemotherapy arm compared with the EXTREME arm: mOS 13.0 and 10.7 months, respectively (HR 0.77, 95% CI [0.63, 0.93]; p = 0.0034). The improved OS with pembrolizumab plus chemotherapy was also seen in the population with CPS 20 or greater (14.7 vs. 11.0 months; HR 0.60, 95% CI [0.45, 0.82]; p = 0.0004) and CPS 1 or greater (13.6 vs. 10.4 months; HR 0.65, 95% CI [0.53, 0.80]; p < 0.0001).

Furthermore, pembrolizumab monotherapy improved OS in the population with CPS 20 or greater (mOS 14.9 vs. 10.7 months; HR 0.61, 95% CI [0.45, 0.83]; p = 0.0007) as well as in the population with CPS 1 or greater (12.3 vs. 10.3 months; HR 0.78; 95% CI [0.64, 0.96]; p = 0.0086) compared with EXTREME. In the total population, pembrolizumab monotherapy was noninferior to EXTREME. Based on these data, pembrolizumab plus chemotherapy has been U.S. Food and Drug Administration (FDA) approved as frontline treatment of recurrent/metastatic SCCHN. Pembrolizumab monotherapy is also FDA approved as frontline treatment for patients with recurrent/metastatic SCCHN whose tumors have PD-L1 CPS 1 or greater or 20 or greater (Table).

Beyond recurrent or metastatic disease, there are several other exciting trials currently underway for SCCHN that will even further help define treatment strategies involving the use of immunotherapy in earlier-stage head and neck cancer. JAVELIN HEAD AND NECK 100 (NCT02952586) and KEYNOTE-412 (NCT03040999) are phase III studies investigating the use of chemoradiation with or without avelumab and pembrolizumab, respectively, in patients with locally advanced SCCHN. Roche WO40242, a phase III, randomized, placebo-controlled trial involving the adjuvant use of atezolizumab in patients with high-risk, locally advanced SCCHN, is anticipated to complete enrollment soon (NCT03452137). Additional studies are ongoing to evaluate anti–PD-1 immunotherapy in combination with radiation and as neoadjuvant therapy prior to surgery.

CONCLUSION

Indeed, the field of head and neck cancer has continued to rapidly evolve, especially within the past 2 years. RTOG 1016 identified cisplatin as the clear systemic therapy choice over cetuximab for definitive chemoradiation in patients with locally advanced disease, even in low-risk, HPV-positive oropharyngeal cancer. Furthermore, pembrolizumab received approval for use in the frontline recurrent or metastatic setting, both in combination with chemotherapy regardless of PD-L1 CPS score and as monotherapy for patients with tumor PD-L1 CPS of 1 or greater and 20 or greater. Incorporation of anti–PD-1/PD-L1 immunotherapy also may find a role in combination with surgery or radiation in the curative treatment setting and in novel combinations for recurrent and metastatic disease.

– Ashleigh M. Porter, MD, and Deborah J. Wong, MD, PhD

REFERENCES

  1. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul;363():24-35.
  2. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019 Jan;393():40-50.
  3. Ferris RL, Blumenschein G, , Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov;375():1856-1867.
  4. Cohen, EEW, Soulières D, Le Tourneau C, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase III study. Lancet. 2019 Jan;393():156-167.
  5. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov;394():1915-1928.

T-Cell Stemness, Aging, and Cancer Immunotherapy

Immunotherapy is revolutionizing the treatment of cancer given its ability to rejuvenate, modify, and engage the bodies’ own immune system, both innate and adopted, to fight malignancies. Of these, T cells are crucial components that help defend against infections and malignancies as the essential effector. In fact, all current cancer immunotherapies, including adoptive T-cell therapy, vaccines, checkpoint blockade, and CAR T therapy, require effective operation of helper and effector T cells.1,2

Interestingly, the initial enthusiasm associated with cancer immunotherapy is soon encountered with some interesting observations that not all patients respond to immunotherapy and that the duration of remission is variable among pathologically similar diseases. For example, some tumors can resist immune checkpoint inhibitors by creating an inhospitable tumor microenvironment through inhibitory cytokines and immune suppressive cells.3 Another example is the T-cell exhaustion mechanism through up-regulation of checkpoint pathways in patients who relapsed after CAR T therapy for lymphoma.4

These observations suggest that in order to maximize the body’s immune system and its therapeutic effect, one must optimize T-cell function and their ability to fight cancer. Only recently, however, have we begun to understand how intrinsic T-cell development and aging pathways affect the therapeutic effectiveness of cancer immunotherapy.5,6 In this review, we outline recent evidence in cancer immunotherapy and early-stage clinical trials linking T-cell stemness and aging with its therapeutic efficacy. We also provide clinical examples of targeting T-cell development and aging to facilitate and/or augment cancer immunotherapy.

T-CELL EXPANSION, DIFFERENTIATION, AND AGING

Like many other human tissues, the T-cell compartment undergoes expansion, differentiation, and aging in response to antigenic and environmental stimuli. In the presence of cancer neoantigens, naive T cells encounter antigen-presenting cells and initiate proliferation and differentiation into effector T cells after integrating multiple costimulatory and coinhibitory signals.5 T-cell stemness, characterized by the capacity to self-renew, the multipotency, and the persistence of proliferative potential, has recently been discovered in the subset of T memory stem cells (TSCM) and T helper (TH) 17 cells.2 The transcription factor TCF7 is essential for the development and maintenance of T-cell stemness and the TSCM phenotype.7 On the other hand, T cells also undergo aging and senescence, characterized by a decrease in overall lymphoid/myeloid ratio and a progressive increase in CD4+/CD8+ ratios during aging.5,8 Senescence T cells are characterized by the expression of surface CD57 and KLRG1 proteins and the inability to undergo apoptosis.5 Of note, T-cell aging should be differentiated from T-cell exhaustion and anergy, which is characterized by expression of PD-L1 pathway of checkpoint inhibitors resulting in a state of anergy upon persisted antigen exposure overtime.9

Not surprisingly, T lymphocytes transition through progressive stages of differentiation, which are characterized by a stepwise loss of functional and therapeutic potential as cancer-fighting, effector T cells. Several lines of evidence have suggested that T-cell stemness is associated with enhanced therapeutic effectiveness of cancer immunotherapy.10 For example, in a recent study of human melanoma tissue samples using single-cell RNA transcriptome analysis, the presence and the increased frequency of TCF7+/CD8+, stem-like T cells in tumor tissue predicted clinical response and better survival after checkpoint blockade in these patients.11 In the CAR T-cell arena, it was found that the generation of clinical-grade, CD19-specific CAR-modified CD8+ memory stem cells led to enhanced T-cell metabolic fitness and robust, long-lasting antitumor response in a human acute lymphoblastic leukemia xenograft model.12 Moreover, similar strategy has been shown to be effective for viral-specific TSCM for therapy post-allogeneic hematopoietic cell transplantation13 and for therapeutic CAR T-cell production.14

Interestingly, a recent landmark study suggested that a potassium-rich tumor microenvironment can potentiate the stemness of tumor-infiltrating lymphocytes (TILs) through induction of metabolic remodeling. This, in turn, enhances the therapeutic effectiveness of TILs in multiple tumor xenograft models.15 Finally, aging-associated T-cell senescence, marked by the CD8+/CD28– phenotype, has been implicated as an important mechanism contributing to the immune-suppressive microenvironment in multiple human tumors.16

HARNESSING T-CELL STEMNESS FOR CANCER IMMUNOTHERAPY

Several strategies have been proposed to reinvigorate these cancer-fighting T cells, most of them in mouse models, but some have been tested in early-stage clinical trials (Table 1). They have variable practical issues and applicability to different human tumors. First, it is possible to preselect the T-cell subsets with the highest stemness potential for adoptive T-cell or CAR T-cell therapy.17,18 In a seminal study by Sommermeyer et al., a fixed composition of the most potent CD4+ and CD8+ CAR-expressing T-cell subsets provided the highest and synergistic antitumor potency in a mouse model compared with products derived from unselected T cells that varied in phenotypic composition.17 Although current commercial CAR T-cell manufacturing does not require this separation, it may be possible in a large-scale clinical trial setting as shown by Turtle et al., where CAR T cells with a preselected, defined CD4+/CD8+ ratio resulted in increased expansion, persistence, and a higher response rate for patients with relapsed/refractory B-cell non-Hodgkin lymphoma.18 Interestingly, a long-lived, CD4+ TH17 subset of T cells has recently been found to have a molecular signature resembling CD8+ TSCM and its stemness by virtue of expressing TCF7+, which could also be harvested for cancer immunotherapy.19

Second, multiple cytokines, IL-7, IL-15, and IL-21, have all been found to restore and augment T-cell stemness for cancer immunotherapy. These cytokines share the common γ chain (γc-CD132) family, significantly induce TSCM differentiation, and effectively drive CD8+ T cells into stem-like phenotypes in vitro and in vivo. For example, Hinrichs et al. found that in mice and human cell lines, IL-21 enhanced CD8+ T-cell stemness and augmented the efficacy of adoptive T-cell immunotherapy for xenografted tumors, which was opposed by IL-2.20 Subsequently, Alvarez-Fernández et al. showed that a short course of anti-CD3/CD28 costimulation of human naive T cells in the presence of IL-7 and IL-15 significantly expanded TSCM ex vivo for adoptive T-cell therapy.21 In the case of CAR T cells, the addition of soluble recombinant cytokines such as IL-2, IL-7, and IL-15 to the culture medium of CAR T cells ex vivo has been shown to preserve T-cell stemness and enhance the antitumor activities of CAR T cells in vivo.22 Finally, CAR T-cell constructs with innovative design, such as the incorporation of a secretory cytokine IL-12, acquire intrinsic resistance to T regulatory cell-mediated functional inhibition and develop enhanced activity in eliminating tumor xenografts.23

Third, the immune checkpoint pathway has been implicated in generating a hostile tumor microenvironment, causing T-cell exhaustion and anergy.10 Multiple strategies have been proposed to counteract this tumor-evasive mechanism, including systemic administration of checkpoint inhibitors, engineered cells expressing checkpoint receptors, and microRNA knockdown methods. Some of these strategies are currently in clinical trials for solid tumors and hematologic malignancies.10 For example, in a preclinical study of a breast cancer xenograft model, John et al. showed that PD-1 blockade can potently enhance CAR T-cell therapy efficacy.24 Clinically, the combination of CD19-specific CAR T cells and checkpoint inhibitors in a patient with diffuse large B-cell lymphoma refractory to prior CAR T-cell therapy resulted in its re-expansion and significant clinical improvement.25 A similar strategy was explored in patients with neuroblastoma, although less promising results were observed.26

Lastly, several druggable cellular pathways of T-cell stemness and aging have been identified, many of which have immediate potential for therapeutic targeting. For example, Gattinoni et al. found that activation of Wnt/β-catenin pathway through GSK-3β inhibitors blocked T-cell differentiation into effector cells and promoted TSCM.27 In addition, given the importance of the mTOR pathway in T-cell senescence, inhibitors of the mTOR pathway through either caloric restriction or rapamycin have been shown to reduce senescence-associated inflammatory phenotype, promote CD8+ memory T cells, and improve vaccine response to influenza in older patients.28,29 Finally, reprogramming of T-cell metabolism though inhibition of the glycolytic pathway or augmentation of mitochondrial biogenesis may enhance T-cell stemness and antitumor response. For example, an important study by Ho et al. showed that metabolic reprogramming of T cells to produce phosphoenolpyruvate, a metabolite important for sustaining T-cell effector functions, improved T-cell stemness and antitumor response in mouse models.28 In addition, an interesting study by Geiger et al. demonstrated that the combination of adoptively transferred T cells with L-arginine were able to increase OXPHOS in activated T cells and enhance antitumor activity in a mouse model.29

SUMMARY

In summary, accumulating evidence suggests that T-cell stemness and aging play an important modulatory role in cancer immunotherapy. In diverse settings of tumors and adoptive T-cell therapeutic approaches, maintaining the youth and stemness of T cells improves their therapeutic effectiveness. Several attractive, druggable targets have been identified in the T-cell stemness pathway that may offer significant benefits to patients whose T-cell subset composition may not be optimally suited for adoptive or engineered T-cell therapy—for example, in older patients and those who have received multiple lymphodepleting therapies. Prospective trials are ongoing to evaluate the clinical effectiveness of these mechanism-based, biology-driven approaches to enhance cancer immunotherapy.

– Richard J. Lin, MD, PhD

REFERENCES

  1. Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev . 2018;32:1267-1284.
  2. Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer . 2012;12:671-684.
  3. Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell . 2017:168:707-723.
  4. Shah NN, Fry TJ. Mechanisms of resistance to CART cell therapy. Nature Review Clinical Oncology. 2019, 16: 372-385.
  5. Goronzy JJ, Weyand CM. Mechanisms underlying T cell ageing. Nat Rev Immunol . 2019;19:573-583.
  6. Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol . 2018;8:1960.
  7. Gautam S, Fioravanti J, Zhu W, et al. The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity. Nat Immunol . 2019;20:337-349.
  8. Li M, Yao D, Zeng X, et al. Age related human T cell subset evolution and senescence. Immun Ageing . 2019;16:24.
  9. Blank CU, Haining WN, Held W, et al. Defining ‘T cell exhaustion’. Nat Rev Immunol. 2019;19:665-674 .
  10. Mardiana S, Solomon BJ, Darcy PK, Beavis PA. Supercharging adoptive T cell therapy to overcome solid tumor–induced immunosuppression. Sci Transl Med . 2019;11(495).
  11. Sade-Feldman M, Yizhak K, Bjorgaard SL, et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell . 2018;175:998-1013.e20.
  12. Sabatino M, Hu J, Sommariva M, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood . 2016;128:519-528.
  13. Terakura S, Yamamoto TN, Gardner RA, et al. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Blood . 2012;119:72-82.
  14. Blaeschke F, Stenger D, Kaeuferle T, et al. Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. Cancer Immunol Immunother . 2018;67:1053-1066.
  15. Vodnala S, Eil R, Kishton RJ, et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science . 2019;363(6434).
  16. Filaci G, Fenoglio D, Fravega M, et al. CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol . 2007;179:4323-4334.
  17. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia . 2016;30:492-500.
  18. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells. Sci Transl Med . 2016;8:355ra116.
  19. Muranski P, Borman ZA, Kerkar SP, et al. Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity . 2011;35:972-985.
  20. Hinrichs CS, Spolski R, Paulos CM, et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood . 2008;111:5326-5333.
  21. Alvarez-Fernández C, Escribà-Garcia L, Vidal S, et al. A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy. J Transl Med . 2016;14:214.
  22. Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood . 2014;123:3750-3759.
  23. Pegram HJ, Lee JC, Hayman EG, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood . 2012;119:4133-4141.
  24. John LB, Devaud C, Duong CP, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res . 2013;19:5636-5646.
  25. Chong EA, Melenhorst JJ, Lacey SF, et al. PD-1 Blockade Modulates Chimeric Antigen Receptor (CAR) Modified T Cells and Induces Tumor Regression: Refueling the CAR. Blood . 2017;129:1039-1041.
  26. Heczey A, Louis CU, Savoldo B, et al. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol Ther . 2017;25:2214-2224.
  27. Gattinoni L, Zhong XS, Palmer DC, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med . 2009;15:808-813.
  28. Mannick JB, Morris M, Hockey HP, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med . 2018;10(449).
  29. Araki K, Youngblood B, Ahmed R. The role of mTOR in memory CD8 T-cell differentiation. Immunol Rev . 2010;235:234-243.

The Latest Insights Into Cellular Therapies for Solid Tumors

Remarkable responses to CAR T-cell therapies seen in blood cancers over the past decade have prompted the launch of numerous clinical trials exploring their use in solid tumors. There are currently more than 30 open trials in the United States alone, with CAR T cells under investigation in pancreatic, ovarian, and prostate cancers—just to name a few.

In an interview with ASCO Daily News, CAR T-cell pioneer Steven A. Rosenberg, MD, PhD, of the National Cancer Institute’s Center for Cancer Research, and Jennifer M. Specht, MD, of Fred Hutchinson Cancer Research Center, weighed in on the lessons learned so far in solid tumors.

THE LACK OF TUMOR-SPECIFIC TARGETS COMPLICATES CAR T-CELL THERAPY

Although Dr. Rosenberg is optimistic of a future potential role for cell therapies in solid tumor treatment, he doesn’t see any immediate, reasonable application of CAR T cells in this setting currently. The main obstacle, he added, is that CAR T cells require the use of antibody-activating lymphocytes, which are not highly specific to tumor cells.

“Since Kohler and Milstein first described monoclonal antibodies some 44 years ago, no one has found an antibody that is absolutely unique to cancer that is not also recognizing normal cells,” he said. “And when you attack something that’s on normal cells, as well as on cancer cells, then normal cells will get destroyed just as easily as the cancer.”

Dr. Rosenberg explained that the main difference in treating hematologic malignancies with CAR T cells is that attacking CD19 or CD20, which are expressed by both cancer cells and healthy B cells, will not destroy the precursors of B cells so that patients can recover over time.

“Although you can recover from the destruction of B cells, you can’t recover from the destruction of an entire colon, the lung, or the brain,” he said. “So it’s this lack of antibodies against tumor-specific targets that’s the major problem in applying CAR T cells to solid tumors.”

A TRIAL OF ROR1-SPECIFIC CAR T CELLS IN EPITHELIAL MALIGNANCIES

Dr. Specht is trying to overcome the challenges of CAR T cells by conducting a phase I first-in-human trial of ROR1-specific CAR T cells in patients with hematologic and epithelial malignancies that have proven resistant to other advanced treatment modalities. ROR1 is uniformly expressed on the cell surface of chronic lymphocytic leukemia,1 mantle cell lymphoma,2 a subset of acute lymphoblastic leukemia, and a subset of epithelial cancers, including non–small cell lung, breast,3 and ovarian cancers. High levels of ROR1 expression are associated with poor prognosis in breast and ovarian cancers.4,5

“Targeting the ROR1 receptor is advantageous because ROR1, a receptor tyrosine-kinase, is typically expressed during early embryonic development on normal tissues but has very limited expression on adult healthy tissues,” Dr. Specht said.

Preliminary results of her trial in seven patients with triple-negative breast cancer presented at the 2018 San Antonio Breast Cancer Symposium looked encouraging.6

“Our patients ranged in age between 27 and 67 years and have all been heavily pretreated with prior metastatic therapies (range, 3-11),” she said. “We assessed patients 4 weeks after treatment and observed three patients with stable disease at this early time point. Two patients in this cohort received a second dose of CAR T cells, and one developed a prolonged partial response after the second CAR T-cell infusion.”

Dr. Specht’s team is presently treating patients at dose level 3 (up to 3.3 x 106 CAR T cells/kg), and none have experienced a dose-limiting toxicity to date.

“We have seen cytokine-release syndrome in patients treated with higher doses but have not observed neurotoxicity or high-grade off-tumor toxicity,” she said.

Although toxicity to healthy tissues is a general concern with CAR T cells, substantial toxicities have not been associated with ROR1 targeting to date. However, as a safety precaution, the engineered CAR construct used in Dr. Specht’s study has an integrated “suicide switch”—truncated EGFR—that would allow cetuximab to eliminate CAR T cells in the event of pronounced on-target, off-tumor toxicity.

PROMISING ALTERNATIVES TO CAR T CELLS

Dr. Rosenberg believes that the future of adoptive cell therapies for solid tumors resides in taking advantage of naturally occurring tumor infiltrating lymphocytes (TILs) that specifically recognize mutated cancer cells, and lymphocytes genetically engineered to express conventional T-cell receptors (TCR therapy).7 About 80% of solid gastrointestinal cancers give rise to T cells that can recognize the tumor, his team recently reported in Cancer Discovery.8

“I think that this finding represents our best hope for applying cell therapies to solid tumors,” he said.

Using TILs harvested from the patient and expanded in the laboratory, Dr. Rosenberg observed a complete response in a female patient with stage IV metastatic breast cancer and numerous liver and chest wall metastases. Four years after the treatment, she remains disease free.9

“Our latest findings published in Science and The New England Journal of Medicine have shown that T cells that recognize intracellular proteins that are the products of DNA mutations in tumors can cause these tumors to regress,” he said. “We now have long-term survivors of liver cancer, cervical cancer, and colon cancer confirming that cell therapy can work.10-12 The challenge now is how to make TILs work a lot better, but there are many ideas on how to do that.”

The second approach his team is vigorously pursuing involves TCR-based therapies, where T cells are primed to selectively attack the products of the very mutations that caused the cancer.

“By definition those mutations are not present in normal cells, so when we use conventional T-cell receptors, we don’t see normal cell toxicity at all,” he said.

Although cytokine-release syndrome has been reported in patients undergoing adoptive cell therapies, Dr. Rosenberg explained that these side effects are relatively rare and usually aren’t life-threating.

“Most patients will experience fever and some malaise, but T-cell therapies are overall very well tolerated,” he said. “Approximately one out of every 30 patients will be treated in an intensive care unit, while 95% are treated on the regular ward and are out of the hospital in 10 days.”

His team is currently conducting a clinical trial that aims to investigate the safety and efficacy of CAR TCR immunotherapy targeting mesothelin in patients with common epithelial cancers including cervical, pancreatic, ovarian, and lung (ClinicalTrials.gov identifier: NCT01583686).

“The beauty [of TCR therapy] is that it is not cancer type–specific—by attacking the mutations you can attack any cancer,” he said. “Generally, this treatment is working in our hands about 15% of the time, but we are getting better and there are many ideas on how to improve it.”

Dr. Specht noted that TCR-based therapies are advantageous with regard to targeting tumor antigens expressed intracellularly but that they also come with their own challenges and limitations—for a TCR therapy to work, the patient’s HLA genotype must be matched to treatment, which can limit its broad application.

“CAR T-cell therapy is different in that CARs recognize their antigen directly and can be used for the treatment of all malignancies bearing the relevant tumor antigen regardless of the patient’s HLA genetics,” she said.

PERFECTING THE THERAPY

More than 550,000 Americans died of epithelial tumors in the last year alone, and finding a treatment that works reproducibly is a major challenge, Dr. Rosenberg said.

“Virtually nobody is cured of the solid epithelial cancer once it has metastasized,” he added. “The worry now is finding a treatment that works reproducibly…. If we find something that works, the geniuses of industry will find ways to make it available.”

Dr. Specht agrees that numerous challenges still need to be overcome but remains optimistic about the overall outlook for cellular therapies.

“Advances in reshaping the suppressive solid tumor microenvironment and more elegant CAR T-cell design to prevent T-cell exhaustion are all under intense study and suggest a bright future for cellular immunotherapy in solid tumors,” she concluded.

— Jasenka Piljac Žegarac, PhD

REFERENCES

  1. Baskar S, Kwong KY, Hofer T, et al. Unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia. Clin Cancer Res. 2008;14:396-404.
  2. Bicocca VT, Chang BH, Masouleh BK, et al. Crosstalk between ROR1 and the Pre-B cell receptor promotes survival of t(1;19) acute lymphoblastic leukemia. Cancer Cell. 2012;22:656-667.
  3. Zhang S, Chen L, Cui B, et al. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS One. 2012;7:e31127.
  4. Cui B, Zhang S, Chen L, et al. Targeting ROR1 Inhibits Epithelial-Mesenchymal Transition and Metastasis. Cancer Res. 2013;73:3649-3660.
  5. Zhang H, Qiu J, Ye C, et al. ROR1 expression correlated with poor clinical outcome in human ovarian cancer. Sci Rep. 2014;4:5811.
  6. Specht JM, Lee SM, Turtle C, et al. A phase I study of adoptive immunotherapy for ROR1+ advanced triple negative breast cancer (TNBC) with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR). Cancer Res. 2018;79:P2-09-13.
  7. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62-68.
  8. Parkhurst MR, Robbins PF, Tran E, et al. Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers. Cancer Discov. 2019;9:1022-1035.
  9. Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nature Med. 2018;24:724-730.
  10. Stevanović S, Pasetto A, Helman SR, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017;356:200-205.
  11. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344:641-644.
  12. Tran E, Robbins, PF, Lu Y-C, et al. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016;375:2255-2262.

Suboptimally Primed CD8 T Cells Identified As Major Contributors to Anti–PD-1 Therapeutic Resistance

In a study published in Nature Immunology, a team of investigators led by Samir N. Khleif, MD, of Georgetown Lombardi Comprehensive Cancer Center, found that the condition of T cells before anti–PD-1 therapy is a critical factor that determines patients’ ability to respond to this treatment.1

“We found that if the CD8 T cells are not properly primed by antigens and we block the PD-1/PD-L1 pathway, then those cells will morph into completely dysfunctional, unprogrammable, and unresponsive T cells,” Dr. Khleif said in an interview with ASCO Daily News.

“Treatment with anti–PD-1 therapy under those conditions is adversary and will lead to induction of resistance, and those T cells will not respond to further treatment with anti–PD-1 therapy or to further activation with vaccines,” he said.

The majority of patients, Dr. Khleif explained, have tumors that suboptimally prime T cells, either because they have a low mutational burden or because of the lack of T-cell infiltration (i.e., cold tumors). These latest findings could have a broad impact on the efforts aimed at overcoming resistance to anti–PD-1 therapy as well as on the selection of patients suitable for this type of treatment.

UNRAVELING NOVEL MECHANISMS OF THERAPEUTIC RESISTANCE TO ANTI–PD-1 THERAPY

Despite remarkable individual responses to anti–PD-1 therapy observed in a range of tumors to date and the growing number of approved indications for anti–PD-1 therapy in recent years, most patients with cancer do not experience a response to this type of therapy.

“There is a major gap in knowledge related to the reasons why almost 85% of [tumors] do not respond to anti–PD-1 therapy and/or how to reverse it,” Dr. Khleif said. “The two things that we do know from an immunologic point-of-view is that a [tumor] is more likely to respond if [it] is T-cell infiltrated and if it has a high mutational burden. However, these two criteria apply to a minority of patients with cancer.”

Understanding the mechanisms governing therapeutic resistance is critical to overcoming the barrier that greatly impairs the efficacy of anti–PD-1 therapy. With this in mind, Dr. Khleif and his collaborators conducted a series of animal model experiments and found that, in animals with suboptimally primed T cells, PD-1 blockade abolished the therapeutic benefit and rendered these animals resistant to anti–PD-1 therapy, whereas simultaneous anti–PD-1 and vaccine therapies led to resistance reversal. Furthermore, treatment with anti–PD-1 therapy before proper antigen priming rendered these mice resistant to additional vaccine therapy.

In trying to understand the reasons behind these findings, they discovered that PD-1 blockade in suboptimally primed CD8 cells induces dysfunctional PD-1+CD38hiCD8+ cells, which results in erroneous T-cell receptor signaling and lack of response to antigenic stimulation.

“Since most of our patients have cold, uninfiltrated tumors with low tumor mutational burden, based on these data, we believe that, when we treat these patients with anti–PD-1 therapy, the PD-1+CD38hiCD8+ cells are induced. These cells are very unresponsive to therapy and eventually die,” Dr. Khleif said.

REVERSING RESISTANCE

Dr. Khleif’s team used the combination of vaccine therapy before anti–PD-1 therapy to prime mouse T cells in their experiments, which resulted in antigen activation of T cells and resistance reversal. In addition, they demonstrated that depleting PD-1+CD38hiCD8+ cells in an adoptive-cell therapy experiment led to improved therapeutic outcomes.

“Reversing resistance can potentially be achieved either by activating T cells prior to treatment with anti–PD-1 therapy using cancer vaccines, chemotherapy, or other priming modalities or by depleting dysfunctional PD-1+CD38hiCD8+ cells,” he said, stressing that priming the patient’s tumor with a cancer vaccine first is probably critical to achieving an optimal therapeutic response.

“The majority of clinical trials that combine vaccines with anti–PD-1 therapy treat the patients with anti–PD-1 therapy first because it takes time to make neoantigen vaccines,” he said. “But this may not be the proper way because, based on the data, that approach may potentially incur resistance and, as a result, the [disease] would fail to respond. This is why we believe that such findings may have major implications on immune therapeutic strategies.”

He also noted that, “until we do prospective clinical trials, we won’t know the exact effect or percentage of patients in which this could make a difference.”

PD-1+CD38HICD8+ CELLS AS BIOMARKERS OF RESPONSE TO ANTI–PD-1 THERAPY

In the next step, in collaboration with several clinical and academic centers across the United States, the investigators assessed the levels of PD-1+CD38hiCD8+ cells from the tumor biopsies of patients with metastatic melanoma treated with either anti–PD-1 alone or in combination with anti–CTLA-4 antibodies. They found that the number of PD-1+CD38hiCD8+ cells was much higher in nonresponding compared with responding tumor lesions: 100% of patients with no tumor response had more than 4% of PD-1+CD38hiCD8+ cells in the CD8+ population analyzed in the tumor microenvironment compared with only 25% of patients with responding tumors.

“This could be a biomarker that helps us separate responders from nonresponders, but these findings still need to be prospectively confirmed,” Dr. Khleif said.

“Also, we found that, in patients [whose disease] responded, PD-1+CD38hiCD8+ levels went down during anti–PD-1 therapy within 6 to 9 weeks, whereas in patients who did not [experience a response], PD-1+CD38hiCD8+ levels continued to be high or further increased. So this is another potential strategy of following up and knowing whether the disease will or will not respond before we even need to do a CT scan.”

As a follow-up to this research, Dr. Khleif’s team is currently in the planning stages for a couple of clinical trials that will investigate the use of a tumor-specific cancer vaccine in reversing resistance to anti–PD-1 therapy and depletion of dysfunctional T cells.

“We’re also looking at some ongoing clinical trials and doing prospective analyses of PD-1+CD38hiCD8+ cells as biomarkers,” he said.

— Jasenka Piljac Žegarac, PhD

REFERENCE

  1. Verma V, Shrimali RK, Ahmad S, et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti–PD-1 resistance. Nature Immunol. 2019;20:1231-1243.

Re-exploring Neoadjuvant Therapy for Resectable Non–small Cell Lung Cancer in the Immunotherapy Era

For many years, the standard-of-care treatment of early-stage (I-IIIA) non–small cell lung cancer (NSCLC) was surgical resection of the primary tumor. Surgery offers potential cure; however, only a minority of patients remain disease free at 5 years.1 Most patients have postsurgical recurrent disease and most of the recurrences are at distant sites. Starting systemic therapy at the earliest time can potentially eradicate micrometastases and prevent future recurrences. Therefore, neoadjuvant therapy is an attractive option.

Neoadjuvant therapies provide opportunities to evaluate tumor response to treatment at resection. Residual tumor and the surrounding microenvironment can be used to evaluate reasons for lack of response and elucidate molecular pathways contributing to tumor resistance to therapy. Neoadjuvant therapy also offers oncologists the opportunity to switch to a different regimen if lack of response is discovered during resection.

There are, however, some pitfalls with this approach. Neoadjuvant therapy can delay surgery, which is the main curative treatment of early-stage NSCLC. Localized disease can potentially become metastatic while the patient is receiving neoadjuvant therapy and, therefore, becomes ineligible for curative surgery. There is also concern for increased surgical complications related to neoadjuvant treatment. There is potential for overtreatment in a subset of patients who have early pathologic stage cancer with minimal risk for recurrence.

Previous studies of neoadjuvant platinum-based chemotherapy with or without radiation have shown mixed results. A 2014 meta-analysis of 15 randomized trials including 2,385 patients showed that neoadjuvant therapy in early-stage NSCLC provides 6% absolute recurrence-free survival (RFS) and 5% absolute overall survival (OS) at 5 years when compared with surgery alone.2 The magnitude of OS benefit of neoadjuvant chemotherapy was similar to adjuvant chemotherapy. There are few head-to-head trials comparing the two systemic therapy approaches. One randomized trial showed that there was no significant difference in 5-year disease free survival (DFS) between neoadjuvant and adjuvant therapy.3 Current National Comprehensive Cancer Network guidelines recommend either neoadjuvant or adjuvant cisplatin doublet chemotherapy for stage IB-IIIA NSCLC.

Recent advances in treatment of advanced-stage NSCLC using immunotherapies have significantly improved DFS and OS. Given their favorable tolerability profile, using these agents neoadjuvantly in early-stage NSCLC is an alternative to chemotherapy.

In a small pilot study from 2018, Forde et al.4 showed that neoadjuvant PD-1 blockade with nivolumab in early-stage resectable NSCLC achieved major pathologic response (MPR; defined as less than 10% viable tumor cells in resected specimen) rate of 45% in a cohort of 20 patients. Similarly, Shu et al.5 presented a study during the 2018 World Conference on Lung Cancer in which 11 patients were given two cycles of neoadjuvant atezolizumab (PD-L1 inhibitor), carboplatin, and nab-paclitaxel combination. It showed an MPR rate of 64% and an overall response rate (ORR) of 73%. The encouraging results of these studies prompted subsequent immunotherapy-based neoadjuvant studies in early-stage NSCLC, including NEOSTAR and LCMC3, which were presented during the 2019 ASCO Annual Meeting. Both studies support further investigation of use of immunotherapy in early-stage NSCLC.

NEOSTAR

NEOSTAR6 is a phase II trial in which 44 patients with early-stage (I-IIIA) NSCLC were randomly selected to receive nivolumab (N) or nivolumab plus ipilimumab (NI) prior to surgery. Patients in group N received nivolumab 3mg/kg on days 1, 15, and 29. In group NI, nivolumab and ipilimumab were given on day 1 followed by nivolumab monotherapy on days 15 and 29. Patients underwent surgery 3 to 6 weeks after the last dose of immunotherapy. Standard-of-care postoperative therapy was given to both arms. The primary endpoint was MPR rate. Secondary endpoints included toxicity, perioperative morbidity/mortality, ORR, RFS, OS, R0 resection rate, pathologic complete response (pCR) rates, and CD8+ tissue infiltrating lymphocytes (TILs) in resected tumors. In the intent-to-treat population, 41 patients completed neoadjuvant immunotherapy and 39 underwent surgery. Seven of 21 patients and three of 23 patients achieved MPR in the NI and N arms, respectively. NI induced a 44% MPR rate in patients who underwent resection and met the trial prespecified efficacy boundary in the intent-to-treat population. There were six patients in NI arm and two patients in N arm who experienced pCR.

The study showed that elevated baseline PD-L1 expression is associated with pathologic responses. Radiographic responses based on RECIST criteria were also positively associated with MPR. However, there were 12% of patients who had stable disease or progression on imaging who had MPR at resection. Pathologic examinations in these patients showed granulomas without any trace of tumor cells. The investigators termed this phenomenon nodal immune flare (NIF) and noted that it is of critical importance to biopsy the nodes if there is high suspicious for NIF. Otherwise, these patients can be mistakenly excluded from potentially curative surgery. Both NI and N arms showed increased tissue infiltrating lymphocytes (TIL) with higher frequencies, diversity and reactivity seen in NI arm..

The most common treatment-related adverse events (TRAEs) were rash (52%) and fatigue (35%) in the NI and N groups, respectively. Grade 3 to 5 hypermagnesemia (4%), hypoxia (4%), and pneumonitis (4%) were seen in the N group; diarrhea (4%) and hyponatremia (4%) were seen in the NI group.

Overall, no unacceptable toxicity or increased perioperative morbidity/mortality were noted and the results were encouraging.

LCMC3

In LCMC3,7 patients were given two cycles of neoadjuvant atezolizumab, a PD-L1 inhibitor, on days 1 and 22. Imaging with CT, PET/CT, and brain MRI were obtained at baseline and again after completion neoadjuvant treatment prior to resection. Surgery was followed by standard-of-care chemotherapy. The primary endpoint was MPR rate at surgical resection. Secondary endpoints were DFS, ORR, OS, biomarkers, and adverse events.

The study planned to enroll 180 patients. A large portion of the cohort had stage IIIA/B disease (46%). At the interim analysis, 101 patients completed two cycles of neoadjuvant atezolizumab. Eleven patients did not receive surgery due to non-treatment related complications. Ninety patients underwent surgical resection and 84 patients had MPR assessment. Seven patients with EGFR/ALK mutations were excluded from primary efficacy population (77 patients).

The results showed that 15 of 77 (19%) patients experienced MPR and four of 77 (5%) had pCR. Thirty-eight of 77 (49%) experienced greater than 50% pathologic regression. It was noted that pathologic regression did correlate with change in tumor lesion size radiographically per RECIST criteria. However, PD-L1 expression and tumor mutational burden (TMB) did not correlate with pathologic regression and MPR. The most common TRAEs were fatigue (20%), infusion-related reaction (11%), and pyrexia (10%). Grade 3 to 5 TRAEs were pneumonitis (three patients), nasal congestions (two patients), decreased lymphocyte counts (two patients), and anemia (one patient).

The study showed that atezolizumab monotherapy in the neoadjuvant setting was well tolerated and no new safety signals were detected. pCR (5%) and MPR (19%) rates were encouraging. Efficacy interim analysis passed its futility boundary and study enrollment continues.

ANALYSES OF NEOSTAR AND LCMC3

Both NEOSTAR and LCMC3 studies demonstrated that immunotherapy showed activity against early-stage NSCLC measured by MPR (Table). Both studies resulted in relatively low TRAEs with grade 3 toxicities in 6% to 11% of patients. Progression rates during treatment were low, and high proportion of patients (about 89%) received curative surgical resection. PD-L1 showed positive correlation with MPR in NEOSTAR, but both PD-L1 and TMB did not seem to correlate with MPR in LCMC3. Radiographic response had positive correlation to MPR in both studies.

That said, both studies are relatively small with wide confidence intervals. MPR rates are comparable to the rates achieved by historical neoadjuvant chemotherapy and had tolerable TRAEs. The MPR rates with immunotherapy alone are lower than that of combination immunotherapies and immunotherapy plus chemotherapy. MPR, commonly in neoadjuvant studies, has been shown to have positive correlation with OS, but it has not been fully validated and cannot be used as surrogate marker for drug approval.8 Longer follow-up and larger studies are needed to answer these questions.

Currently, there are four larger phase III trials of immunotherapy in combination with chemotherapy in the neoadjuvant setting; IMpower030 (NCT03456063), CheckMate 816 (NCT02998528), KEYNOTE-671 (NCT03425643), and AEGEAN (NCT03800134) are underway to better define the roles of checkpoint inhibitors in early-stage NSCLC. With the use of neoadjuvant immunotherapy, the role of chemotherapy, radiation, and concurrent chemoradiation remains unanswered. The roles of biomarkers PD-L1 and TMB remain to be determined, as the markers have not been shown to consistently predict tumor response. T-cell expansion and ctDNA are emerging biomarkers that may prove useful in the future. Nevertheless, the studies showed us that immunotherapy as a viable treatment option and a potential major step forward in achieving long-term cures in the early-stage NSCLC.

– Jeffrey Chi, MD, and Nagashree Seetharamu, MD, MBBS

REFERENCES

  1. Lackey A, Donington JS. Surgical management of lung cancer. Semin Intervent Radiol . 2013;30:133-140.
  2. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet . 2014;383:1561-1571.
  3. Yang XN, Cheng G, Ben XS, et al. Survival study of neoadjuvant versus adjuvant chemotherapy with docetaxel combined carboplatin in resectable stage IB to IIIA non-small lung cancer. J Clin Oncol . 2013;31(15_suppl):7537-7537.
  4. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med . 2018;378:1976-1986.
  5. Shu CA, Grigg C, Chiuzan C, et al. Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC). J Clin Oncol . 2018;36(15_suppl):8532-8532.
  6. Cascone T, Nassib William W, Weissferdt A, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. Presented at: 2019 ASCO Annual Meeting. May 31-June 4; Chicago, IL.
  7. Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). Presented at: 2019 ASCO Annual Meeting. May 31-June 4; Chicago, IL.
  8. Hellmann MD, Chaft JE, William WN Jr., et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol . 2014;15:e42-e50.
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