PSMA-CD3 BISPECIFIC TO BE EVALUATED IN PROSTATE CANCER
Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC).
Ben Tran, MBBS, FRACP (Peter MacCallum Cancer Centre, Melbourne, VIC, Australia) outlined a phase I study that is evaluating AMG 160 in men with metastatic castration-resistant prostate cancer (mCRPC). As an immune cell engager, AMG 160 binds to both CD3 and PSMA. The primary goal of the study is to evaluate the safety and tolerability of AMG 160, defining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The preliminary efficacy and pharmacokinetics will also be explored. This is an important Phase 1 trial as one of the initial BiTE treatments for metastatic prostate cancer.
CAR-T THERAPY TARGETING PSCA EXPLORED FOR MCRPC
A phase I study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC).
A first-in-human study of a prostate stem cell antigen (PSCA)-targeted CAR T cell therapy is being led by Tanya B. Dorff, MD (City of Hope, Duarte, CA). Featuring a second-generation design with a 4-1BB co-stimulatory domain, the therapy will be tested in men with mCRPC refractory to standard therapies with tumors that express PSCA. The primary goals of the study are the evaluation of safety and treatment-related toxicities, while the persistence of CAR T cells and response will be secondarily evaluated. This phase 1 trial is important in testing the first CAR T-cell therapeutic in metastatic prostate cancer.
PEMBROLIZUMAB + ENZALUTAMIDE SHOWS ACTIVITY IN MCRPC
Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4-5
Results from the KEYNOTE-199 study of enzalutamide plus pembrolizumab in patients with mCRPC were presented by Julie Nicole Graff, MD (Oregon Health & Science University, Portland, OR). Two cohorts were discussed, including cohort 4 (RECIST-measurable disease) and cohort 5 (bone-predominant disease), all of whom were chemotherapy-naïve, and treated with the combination after progression on enzalutamide monotherapy. The overall response rate (ORR) in cohort 4 was the primary objective; secondary endpoints included disease control rate (DCR), PSA responses, and safety, among others.
After a median follow-up of over 13 months, nearly 85% of patients had discontinued the therapy, mainly due to disease progression. The ORR in cohort 4 was 12% (10/81), including 2 complete responses. In both cohorts, the DCR was 51%. Confirmed PSA responses were also noted in 13/80 (16%) of patients in cohort 4, and 4/45 (9%) in cohort 5. The overall survival rate at 12 months was 70% and 75% for cohorts 4 and 5, respectively. The safety profiles were as expected, with up to 75% of patients experiencing any adverse event, and nearly a quarter of patients with a grade 3-5 event. Given the moderate activity noted in this treatment-resistant population, further studies are ongoing, including a phase 3 trial of pembrolizumab-enzalutamide (KEYNOTE 641, NCT03834493).
COMBINATION CABOZANTINIB AND ATEZOLIZUMAB SHOWS ENCOURAGING EFFICACY IN MCRPC
Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of Cohort 6 of the COSMIC-021 Study
Given the discouraging results achieved with immune checkpoint inhibitor monotherapy in mCRPC to date, Neeraj Agarwal, MD (Huntsman Cancer Institute, Salt Lake City UT) presented a study of combination cabozantinib and atezolizumab in this population as part of the COSMIC-021 study. Eligible patients for this study had to have soft tissue progression on enzalutamide and/or abiraterone. The study aimed to evaluate the ORR.
Forty-four patients were enrolled in the study and followed for a median of 10.6 months, with a median treatment duration of 5.3 months. By RECIST 1.1, the ORR was 32% in all patients, which included two CRs and 12 PRs. Twenty-one patients also had stable disease, resulting in a DCR of 80%. Among patients with high-risk characteristics, the ORR was 33%. For all patients, the median duration of response was 8.3 months, and PSA declines of >50% were noted as well in some patients. A tolerable safety profile also accompanied these promising results: most common treatment-emergent AEs included fatigue (57%), nausea (48%), decreased appetite (45%), diarrhea (39%), PPE (32%), and vomiting (32%), with one grade 5 incidence of dehydration in an elderly patient. Given the therapeutic success achieved with this combination, further studies are ongoing, including expansion cohorts of COSMIC-021 (NCT0317096) as well as a phase 3 trial in development.
ADC + PEMBROLIZUMAB COMBINATION SHOWS PROMISE
Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma
Initial durability results for metastatic urothelial cancer treated with first-line enfortumab vedotin plus pembrolizumab were presented by Jonathan E. Rosenberg, MD (Memorial Sloan Kettering Cancer Center, New York, NY). Initial results had been reported at ESMO 2019, wherein patients treated with a median of 7 cycles of therapy demonstrated an ORR of 71% (13% CR). In this report, patients had received a median of 9 cycles of therapy, and the goal of the study was the safety/tolerability of the combination, followed by determination of recommended dose and responses.
After a median of 11.5 months follow-up, the ORR for this study was 73.3%, including 15.6% CRs. Median progression free survival was 12.3 months, and median OS was not reached. Over half of the responders have ongoing responses, with 11 patients experiencing responses of longer than 10 months. An ORR of 53.3% was noted in patients with liver metastases, while patients with PD-L1 high or low disease exhibited ORRs of 78.6% and 63.2%, respectively. The most common adverse events included fatigue (58%), alopecia (53%), and peripheral sensory neuropathy (53%). One treatment-related death was reported, due to multiple organ failure. These preliminary durability results demonstrate the promise of this combination, warranting continued investigation.
NOVEL INTRAVESICAL THERAPY INVESTIGATED FOR BCG-UNRESPONSIVE NMIBC
Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): Results from a phase III trial
Given the difficultly of managing BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), Stephen A. Boorjian, MD (Mayo Clinic, Rochester, MN) and colleagues investigated treatment with an adenovirus-based therapy, nadofaragene firadenovec, in this population. Intravesical administration of nadofaragene results in delivery of the human IFNα2b gene. Patients were administered nadofaragene every 3 months for 12 months (additional doses discretionary), with the primary endpoint of complete response rate in patients with carcinoma in situ (CIS).
At month 3 after treatment, 55/103 patients with CIS experienced a complete response, and 45.5% of these did not experience biopsy-confirmed high-grade recurrence after 12 months. In patients without CIS (high-grade Ta/T1 alone), 72.9% were free of recurrence at 3 months, and 43.8% remained without recurrence at 12 months. Those adverse events that were observed were largely temporary, including instillation site discharge, fatigue, bladder spasms, micturition urgency, and hematuria. No treatment-related grade 4-5 events occurred.
Notably, the FDA recently approved pembrolizumab for the same indication. In the KEYNOTE-057 study, a complete response rate of 41% was observed, with 46% of patients experiencing a complete response of at least 12 months, and median duration of response of 16.2 months. Durability of response will therefore be an important outcome of this study of nadofaragene firadenovec in the future, to compare with the newly-approved regimen.
NEOADJUVANT APPROACH FOR MIBC TO IMPROVE PATHOLOGIC RESPONSE RATES
Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy
A neoadjuvant therapy approach for muscle-invasive bladder cancer (MIBC) consisting of nivolumab, gemcitabine, and cisplatin was discussed by Shilpa Gupta, MD (Masonic Cancer Center, University of Minnesota, Minneapolis, MN). Radical cystectomy-eligible patients received 4 cycles of therapy followed by cystectomy within 8 weeks. Since pathologic response at the time of cystectomy correlates with survival, the primary goal of this phase II study was the pathologic response rate. Safety, progression-free survival, and correlative investigations were among secondary goals.
Forty-one patients were enrolled and treated in this study. At the time of cystectomy, a pathologic response was observed in 65.8% of these patients, with 49% of patients achieving pathologic complete responses. PD-L1 status did not correlate with responses. Of note, molecular subtyping showed a patient with claudin-low subtype had high immune infiltration and had complete response. Another patient with luminal infiltrated subtype had high stromal infiltration and did not respond (pathologic stage T3N2 at time of cystectomy). The majority of adverse events were attributed to gemcitabine/cisplatin, including neutropenia, thrombocytopenia, and renal insufficiency. Three patients experienced an immune-related adverse event, but none of these required steroid treatment. Cystectomies were performed in all patients without unexpected surgical complications or delays.
ACTIVITY OBSERVED WITH COMBINATION REGIMEN IN CLEAR CELL RCC
A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy
Pavlos Msaouel, MD, PhD (MD Anderson Cancer Center, Houston, TX) reported on a phase I/II trial testing combination sitravatinib and nivolumab in patients with advanced clear cell renal cell carcinoma. Patients were eligible for the study if they had previously progressed on up to two VEGF-targeted therapies. A late-onset Bayesian EffTox design was employed to determine the optimal dose of sitravatinib, and secondary goals included investigation of survival times and correlative biomarkers.
40 patients were enrolled and treated with sitravatinib and nivolumab. The majority of patients (85%) had IMDC intermediate risk disease; another 12.5% had IMDC favorable risk, and 2.5% had IMDC poor risk disease. Most patients (92.5%) had received either sunitinib or pazopanib, and 15% of patients had received prior axitinib. The ORR was 39% (15/38), and disease control rate was 92% (35/38), showing significant disease activity for this combination. With a median follow up of 17.7 months, median PFS was 10.3 months and median OS was not reached.
RADIOTHERAPY AND IMMUNE CHECKPOINT INHIBITION COMBOS SHOW PROMISE FOR MRCC
Given the synergy that has been indicated in preclinical studies of radiotherapy and immune checkpoint inhibition, two studies explored the combination of stereotactic body radiotherapy (SBRT) and immunotherapy.
Nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in pretreated patients (pts) with metastatic renal cell carcinoma (mRCC): First results of phase II NIVES study
Cristina Masini, MD (Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy) and colleagues investigated treatment of metastatic renal cell carcinoma with stereotactic body radiotherapy (SBRT) and nivolumab. Patients with mRCC that progressed after two or fewer anti-angiogenic therapies were eligible for the study. SBRT was performed on one metastatic lesion to a total dose of 10 Gy in 3 fractions, seven days after the first nivolumab dose, and patients were evaluated for the overall response rate.
Sixty-nine patients were enrolled in the study, and followed for a median of 15 months. The median number of nivolumab doses was 12, resulting in an overall response rate of 19% and a disease control rate of 63.5%. Although the site of metastatic SBRT varied (including the lung, bone, and lymph nodes), no correlation was found between the irradiated tissue and outcomes; however, the best outcomes were noted in clear cell mRCC. The median PFS and OS in this study were 4 and 22.1 months, respectively. Grade 3-4 nivolumab-related toxicities occurred in nearly a quarter of patients, with no grade 3-4 toxicities related to radiotherapy.
Combination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC)
Similarly, Hans J. Hammers, MD, PhD (University of Texas Southwestern Medical Center, Dallas, TX) presented a study of combination nivolumab/ipilimumab with SBRT. In this investigation, patients were eligible if they had received prior TKI and/or IL-2, and were treated with standard-of-care ipilimumab/nivolumab followed by nivolumab monotherapy. SBRT to 50 Gy in 5 fractions was administered to 1-2 lesions between the first two doses of ipi/nivo. Safety, tolerability, and ORR in non-irradiated lesions were then assessed.
At the time of analysis, with a median follow up of 24 months, 14 of the 25 patients enrolled in the study had experienced a partial response, resulting in an ORR of 56% and median PFS of 8.2 months. The median duration of response and median overall survival were not reached at the time of this analysis. The use of combination nivolumab/ipilimumab resulted in 40% of patients experiencing immune-related adverse events requiring prednisone management, and no adverse events over grade 2 were noted due to radiotherapy.
These two studies point to the potential for multimodality treatment of patients with mRCC. Although they cannot be directly compared, the eventual durability of responses with these two regimens will provide useful insight for future management of mRCC. These trials were single-cohort studies, and future prospective randomized trials will be necessary to further evaluate the utility of radiation in augmenting the systemic response of immunotherapies.
LONG-TERM BENEFITS OBSERVED FOR NIVOLUMAB/IPILIMUMAB COMBINATION IN RCC
Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC)
An extended 42-month follow-up of patients with advanced RCC (aRCC) treated with either nivolumab/ipilimumab or sunitinib was presented by Nizar M. Tannir, MD, FACP (MD Anderson Cancer Center, Houston, TX). The overall survival and response outcomes per independent radiology review committee were presented for patients with clear cell aRCC, with primary endpoints of OS, ORR, and PFS in intermediate/poor risk (I/P) patients. The entire intent-to-treat (ITT) population was explored in secondary analyses.
Overall survival hazard ratios remained favorable for patients treated with ipilimumab/nivolumab in both the ITT and I/P groups, at 0.72 (0.61-0.86) and 0.66 (0.55-0.80), respectively. In the I/P cohort, the ORR was also higher in the ipilimumab/nivolumab cohort, with 42% objective responses, including 10% complete responses. In patients with complete responses, median duration of response was not reached, and median duration of treatment free intervals in patients with complete responses and no subsequent therapies was 34.6 months. After 42 months follow up, the PFS HR was 0.76, with 35% of patients treated with ipilimumab/nivolumab without progression versus 13% for patients treated with sunitinib. In the ITT population, the ORRs were 39% for ipilimumab/nivolumab and 33% for sunitinib (p=0.02). Across all cohorts in this study, the plateau of PFS and OS curves after long-term follow-up points to the promise of lasting, durable responses with this combination immunotherapy approach for aRCC. This marks the longest follow up for any immunotherapy combination phase 3 trial in first-line treatment of aRCC.
NIVOLUMAB MONOTHERAPY SHOWS 5-YEAR BENEFITS
Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with >5 years of follow-up in patients with advanced renal cell carcinoma (aRCC)
The final analysis of CheckMate 025 was discussed by Robert J. Motzer, MD (Memorial Sloan Kettering Cancer Center, New York, NY). After a minimum follow-up of 64 months, the overall survival was compared for patients with aRCC treated with either nivolumab or everolimus as a primary endpoint.
Across all long-term evaluations, nivolumab was favored over everolimus. At 60 months, the OS rate was 26% vs 18% (HR 0.73, p<0.0001), and the PFS rates were 5% vs 1% (HR 0.84, p=0.03). At the extended follow-up, 28% and 18% of nivolumab- or everolimus-treated patients had ongoing responses. The ORR was statistically significantly higher with nivolumab, with an odds ratio of 6.86 (4.01-11.74). The safety profile was also improved with nivolumab, as 21% of nivolumab-treated patients experienced a grade 3-4 adverse event compared to 37% treated with everolimus. Nivolumab monotherapy is an established treatment option for patients with previously-treated aRCC, and these long-term survival outcomes show the durability of long-lasting responses.
RCC BIOMARKERS’ IMPORTANCE VERIFIED WITH IMMUNOTHERAPY TREATMENTS
NIVOREN GETUG-AFU 26 translational study: Association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N)
A correlative biomarker analysis of the NIVOREN GETUG-AFU 26 study was discussed by Yann-Alexandre Vano, MD (Georges Pompidou Hospital, University Paris Descartes, Paris, France). Patients with metastatic clear cell RCC were treated with nivolumab, and tumor tissues were analyzed via immunohistochemistry for various immune- and tumor-related markers.
Immune cell populations, immune checkpoints, and AXL, PBRM1, and BAP1 expression were all evaluated from archival tissue specimens. Overall survival was significantly longer in patients whose tumors demonstrated PBRM1 loss (HR: 0.59, p = 0.05), consistent with previous reports in RCC. PBRM1 loss was also associated with higher CD8+ T cell density, more CD163-macrophages in the central tumor, and higher expression of both LAG-3 and PD-1. Extended PFS was observed for patients whose tumors did not express the receptor tyrosine kinase AXL (HR: 1.29, p = 0.04), as well as for patients with a high level of PD-1-positive cells at the invasive margin of their tumors (HR: 0.67, p = 0.04). This study served to evaluate these biomarkers in the setting of immune checkpoint inhibition, and supports the growing evidence that many of these biomarkers are prognostic but not predictive of treatment efficacy.
PAPILLARY RCC MAY BENEFIT FROM MET AND PD-L1 INHIBITION
Overall survival results for durvalumab and savolitinib in metastatic papillary renal cancer
Thomas Powles, MBBS, MRCP, MD (Barts Cancer Institute, London, United Kingdom) presented overall survival results at 12 months for patients with metastatic papillary renal cancer treated with combination savolitinib (inhibiting MET) and durvalumab (inhibiting PD-L1). The single-arm phase I/II study enrolled previously treated or untreated patients to receive durvalumab and savolitinib in order to evaluate response rates, PFS, OS, and tolerability.
Forty-one patients were treated with at least one dose of the study regimen and followed for a median of 14.3 months. In the entire patient population, the ORR was 27%, while in treatment-naïve patients (n=27) the ORR was 33%. The median OS in the entire cohort, as well as in treatment-naïve patients, was 12.3 months. No new safety signals were noted, with 34% of patients experiencing a grade 3/4 adverse event related to the treatments. Exploratory biomarker studies (PD-L1 and MET expression) did not identify any characteristics associated with improved outcomes.
Cristina Suarez Rodriguez, MD (Vall d’Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain) was first author of this study but was giving birth to her child at time of the conference. Dr. Powles gave particular tribute to her role as primary PI of this study.
CYTOREDUCTIVE NEPHRECTOMY DEMONSTRATES SURVIVAL BENEFIT AFTER TARGETED- AND IMMUNOTHERAPIES
Cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or targeted therapy (TT): A propensity score-based analysis
Ziad Bakouny, MD, MSc (Dana-Farber Cancer Institute, Boston, MA) and colleagues evaluated the impact of cytoreductive nephrectomy (CN) on survival of patients treated with targeted and immunotherapies. While CN has traditionally played a major role in the management of mRCC, the efficacy and disease control with immunotherapy in this population may impact the utility of CN. This retrospective analysis therefore evaluated outcomes for patients receiving targeted therapies or immune checkpoint inhibitors over the last ten years in relation to CN.
Targeted therapies were employed in 3856 patients, 64% of whom received CN, while 198 patients were treated with ICIs, and 72.2% also underwent CN. Inverse probability of treatment weighting of propensity scores was employed to account for treatment selection bias in this analysis. For both groups of patients, CN was associated with improved 2-year survival rates. For ICI-treated patients, those undergoing CN demonstrated a 69.1% 2-year OS rate, compared to 41.4% without CN. Likewise, when used in combination with targeted therapies, CN resulted in an improvement in 2-year OS rates from 25.8% to 54.1%. The authors therefore suggest that CN still has a major role to play in the current landscape of ICI-treated mRCC. Retrospective analyses of surgery has significant selection bias, even in large populations. However, this study forms the basis of the PROBE trial, a phase 3 prospective trial being developed in the cooperative groups, which will enroll patients with mRCC, treat with ipilimumab-nivolumab, and randomize to nephrectomy versus no nephrectomy.