OVERALL SURVIVAL SIGNIFICANTLY INCREASED WITH MAINTENANCE AVELUMAB IN UROTHELIAL CARCINOMA
LBA1: Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis
Thomas Powles, MBBS, MRCP, MD (Barts Cancer Institute) discussed the JAVELIN Bladder 100 trial, which investigated maintenance avelumab in patients with advanced urothelial carcinoma who had at least stable disease on induction chemotherapy, compared to best supportive care alone. The co-primary endpoints of the trial were overall survival in all-comers and in those with PD-L1-positive disease. The results of the planned interim analysis were discussed.
After a median follow-up of 19 months, a significant increase in overall survival was noted with avelumab maintenance, at 21.4 vs 14.3 months (HR 0.69, p<0.001). In the PD-L1+ subpopulation, median OS was not reached with avelumab, and 17.1 months with BSC alone (HR 0.56, p<0.001). Notably, in this population with the selected PD-L1 assay, patients with PD-L1+ tumors had improved survival regardless of treatment. Any-grade treatment-emergent adverse events occurred in 98% of patients on avelumab treatment and 77.7% with BSC. Two treatment-related deaths occurred in the experimental arm, though there were no grade 4 or 5 immune-related adverse events (irAEs). The most common irAE was hypothyroidism in nearly 25% of patients. This study represents the longest OS ever reported in a phase 3 trial in this urothelial cancer population, and therefore has potential to impact the clinical management of these patients in the near future.
Given the potential for immune checkpoint inhibitors to play an even larger role in the management of urothelial carcinoma, click here to read an article from the Journal for ImmunoTherapy of Cancer (JITC) on the toxicities that may be expected in these patients.
LACK OF BENEFIT SEEN WITH ADJUVANT ATEZOLIZUMAB IN MIUC
5000: IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC)
Maha H. A. Hussain, MD, FACP, FASCO (Northwestern University) discussed the primary analysis of IMvigor010, investigating adjuvant atezolizumab in patients with resected high-risk muscle-invasive urothelial carcinoma. In this trial, patients were randomized to receive either adjuvant atezolizumab at 1200 mg Q3W or to observation, with the primary endpoint of disease-free survival (DFS).
A total of 809 patients were included in the intent-to-treat population and were followed for a median of 21.9 months. Characteristics were well-balanced between the two arms, including previous neoadjuvant chemotherapy treatment and lymph node positive disease. The median DFS in the entire study population was 19.4 months with atezolizumab and 16.6 months with observation (HR: 0.89, p= 0.2446), a difference that did not reach statistical significance. DFS was not influenced by baseline clinical or prognostic factors, including PD-L1 status: the DFS HR for IC0/1 patients was 0.81 and 1.01 for IC2/3. Notably, PD-L1 expression seemed to have a prognostic impact in this study, as those patients with IC2/3 demonstrated enhanced outcomes over those with IC0/1, regardless of treatment. As may be expected, a higher rate of adverse event incidence was noted in the atezolizumab arm, including more treatment discontinuation due to adverse events. There was one grade 5 event attributed to atezolizumab. Overall, this study does not indicate benefit of adjuvant atezolizumab monotherapy for prevention of disease recurrence in high-risk muscle-invasive urothelial carcinoma.
EFFICACY SIGNALS SEEN FOR LENVATINIB + PEMBROLIZUMAB IN ICI-REFRACTORY MCCRCC
5008: Phase II trial lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC)
The phase 2 KEYNOTE-146 study was presented by Chung-Han Lee, MD, PhD (Memorial Sloan Kettering Cancer Center). This trial investigated the combination of lenvatinib and pembrolizumab in patients with metastatic clear cell renal cell carcinoma who progressed on previous PD-1/PD-L1-directed immune checkpoint inhibitor therapy with the primary endpoint of objective response rate at 24 weeks.
A total of 104 patients were enrolled in the study and were treated for a median of 7 months. By irRECIST, the ORR at 24 weeks was 51%, with best overall responses of partial response in 55% and stable disease in an additional 36% of patients. Responses were typically seen at the first assessment. OS at 12 months was 77%, with the median not yet reached. Previous treatments with anti-CTLA-4 or VEGF inhibitors did not seem to impact outcomes in this study. Treatment-related adverse events of any grade were experienced by 99% of patients, leading to discontinuation in 15%, and the dose of lenvatinib was decreased in 43% of patients at 3 months. The most common adverse events leading to lenvatinib dose reduction were fatigue, diarrhea, and proteinuria. Future work with this combination regimen is continuing, with a phase 3 trial in the front-line setting ongoing.
Click here to read an article from JITC outlining some potential biomarkers for application to renal cell carcinoma patients undergoing immune checkpoint inhibitor treatment.
SIGNIFICANT BENEFIT FOR PEMBROLIZUMAB TREATMENT IN MSI-HIGH COLORECTAL CANCER
LBA4: Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study
The phase 3 KEYNOTE-177 study was presented by Thierry Andre, MD (Sorbonne University and Saint-Antoine Hospital), which investigated pembrolizumab for the management of MSI-H metastatic CRC as a first-line treatment. Primary endpoints of the study were PFS and OS, with PFS results discussed in this presentation. OS data are not yet mature.
A total of 307 patients were included in the ITT population and followed for a median of 32 months. Progression-free survival was significantly enhanced in the pembrolizumab arm, reaching a median of 16.5 months compared to 8.2 months in the control arm of chemotherapy +/- bevacizumab or cetuximab. This led to a hazard ratio of 0.60 with p = 0.002. Interestingly, the PFS curves favored chemotherapy for the first six months of treatment; however, by month 24, the PFS rate was 48% with pembrolizumab and 19% with control. Compete responses were noted in 11.1% and 3.9% of patients treated with pembrolizumab and chemotherapy, respectively. A higher rate of progressive disease was, however, also noted in the pembrolizumab arm, at 29.4% compared to 12.3% with chemotherapy, indicating a sizable portion of patients with primary immunotherapy refractory disease. The safety profile of the pembrolizumab treatment was more favorable than chemotherapy, reducing grade 3+ adverse events by 44%. Overall, this study indicates a potential new standard-of-care for MSI-high CRC management, although OS results are still outstanding.
A recent article in JITC discussed harmonization of tumor mutational burden measurements, to help better identify potential immune checkpoint inhibitor responders.
EARLY RESULTS INDICATE ACTIVITY FOR COMBINATION THERAPY IN RAS-MUTATED, MSS COLORECTAL CANCER
3006: Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated, microsatellite-stable, previously untreated metastatic colorectal cancer (MCRC): Results of the first intermediate analysis of the phase Ib/II MEDETREME trial
François Ghiringhelli, MD (Center Georges François Leclerc) and colleagues investigated the potential of FOLFOX combined with durvalumab and tremelimumab for the first-line treatment of microsatellite-stable, RAS-mutated, metastatic colorectal cancer. The phase 1b/2 study aimed to primarily evaluate safety and progression-free survival at six months. Biomarker investigations were also presented.
At the time of intermediate efficacy analysis, 55 patients were enrolled in the MEDITREME trial and treated with the combination regimen. Sixteen patients had at least one year of follow-up in this analysis. The PFS rates were 62.5% and 50% at 6 and 12 months, respectively. The safety profile was largely as-expected for the combination, with many of the events attributed to the chemotherapy component. Notable grade 3/4 events included neutropenia in 50% of patients, elevated blood pressure in 25% of patients, asthenia in 18.75%, and diarrhea in 12.5%. Correlative studies indicated lower levels of myeloid-derived suppressor cells at baseline in responding patients, and there was evidence of tumor-specific T cell clones induced in responders as well. The study is awaiting final analysis to confirm the promising results.
MANY STUDIES HIGHLIGHT PROMISE OF ICIS IN SCLC
9000: Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161
9001: KEYNOTE-604: Pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC)
9002: Durvalumab +/- tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated results from the phase III CASPIAN study
Ticiana Leal, MD (University of Wisconsin-Madison) presented the phase 2 ECOG-ACRIN EA5161 trial, comparing etoposide and platinum (EP) to nivolumab and EP. With 160 patients in the intent-to-treat population, the median PFS was significantly extended with the use of nivolumab in this study to 5.5 months, compared to 4.6 months for EP alone (p=0.047). Median OS was also longer for the nivolumab arm, at 11.3 vs. 8.5 months (p=0.038). No new safety signals were noted, with grade 3/4 adverse events occurring in 77% of the nivolumab-treated patients and 62% of the chemotherapy-alone arm.
A phase 3 study comparing pembrolizumab plus EP to EP alone in 453 patients was discussed by Charles M. Rudin, MD, PhD (Memorial Sloan Kettering Cancer Center). At final analysis, the median PFS was 4.8 months in the pembrolizumab arm, and 4.3 months with placebo, with a HR of 0.75 (p=0.0023). Medians are similar due to overlap during the chemotherapy treatment period but then divergence favors immunotherapy. Likewise, the OS was extended in patients receiving pembrolizumab, though not significantly so, with median OS of 10.8 vs 9.7 months (HR: 0.8, p = 0.0164). Any-cause grade 3/4 adverse events occurred in 77% of patients in the pembrolizumab arm and 75% in the EP-alone arm.
The CASPIAN study was presented by Luis G. Paz-Ares, MD, PhD (Hospital Universitario 12 de Octubre), with three treatment arms: EP alone, durvalumab plus EP (D+EP), and durvalumab, tremelimumab and EP (D+T+EP), enrolling 805 patients. An updated analysis comparing D+EP to EP as well as the first results for D+T+EP vs EP were discussed. Significantly longer median OS was experienced by patients receiving D+EP compared to EP (12.9 vs 10.5 mo, HR: 0.75, p= 0.0032). The median OS for patients treated with D+T+EP was 10.4 months, which did not amount to a statistical improvement in OS (HR: 0.82, p=0.0451). Across most other metrics, outcomes were also similar between the D+T+EP and D+EP arms. Grade 3/4 adverse events were noted in 62.3%, 70.3% and 62.8% of patients in the D+EP, D+T+EP and EP arms. As a whole, this study indicates no benefit from the addition of tremelimumab to durvalumab and chemotherapy.
Overall, these studies all point to the promise of immune checkpoint inhibitors in first-line regimens for ES-SCLC; however, the optimal regimen is yet to be determined.
ANTI-TIGIT ANTIBODY ADDED TO ATEZOLIZUMAB SHOWS POTENTIAL IN FRONT-LINE PD-L1+ NSCLC
9503 - Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE)
Melissa L. Johnson, MD (Sarah Cannon Research Institute) presented the CITYSCAPE study, investigating the anti-TIGIT antibody tiragolumab in combination with atezolizumab compared to placebo and atezolizumab. This phase 2 trial enrolled patients with NSCLC tumors expressing PD-L1 (TPS >= 1%) with the primary endpoints of ORR and PFS.
Primary analysis occurred in June 2019; at this time, a benefit was seen for the addition of tiragolumab to atezolizumab, improving both ORR and median PFS in the ITT population (ORR: 31.3% vs 16.2%; median PFS: 5.4 vs 3.6 months). With another six months of follow-up, these improvements were maintained, with ORR of 37.3% vs 20.6% and median PFS of 5.6 vs 3.9 months. For PD-L1 >= 50% patients, the ORR was greatly increased with the tiragolumab regimen, at 66% compared to 24%, whereas for tumors with PD-L1 from 1 to 49%, tiragolumab did not increase ORR over atezolizumab (16% vs 18%). The safety profiles were largely similar between the two arms, with grade 3+ events occurring in 48% of the tiragolumab arm and 44% with placebo. Therefore, the enhanced outcomes and reasonable safety of combination tiragolumab and atezolizumab may warrant future investigation as a chemotherapy-free option for front-line management of NSCLC, particularly for those tumors with high PD-L1 expression.
TREATMENT OPTIONS FOR PD-1-RESISTANT MELANOMA EXPLORED
10005: Ipilimumab (IPI) alone or in combination with anti-PD-1 (IPI+PD1) in patients (pts) with metastatic melanoma (MM) resistant to PD1 monotherapy
Given the uncertainty in managing patients with PD-1-resistant melanoma, Ines Pires Da Silva, MD, PhD (Melanoma Institute Australia) discussed a multicenter, retrospective trial of either ipilimumab monotherapy or ipilimumab in combination with anti-PD-1 (IPI+PD1) in this patient population. The investigators aimed to determine the response, survival, and toxicity rates of patients managed with these two regimens, as well as to identify clinical predictors of response.
The analyzed patients were approximately treated 1:1 with the two regimens, with largely similar characteristics between the two groups aside from more brain metastases in the group treated with IPI+PD1. With a median follow up of 22.2 months from the start of the ipilimumab regimen, a higher response rate was seen with IPI+PD1 over IPI alone, at 32% vs 13%. PFS and OS were also improved with the combination treatment: at one year, PFS rates were 25% and 13%, and OS rates were 58% and 38%, for the IPI+PD1 and IPI arms, respectively. Among analyzed subgroups, only patients with BRAF-mutated tumors experienced similar response rates with the two therapies (19% with IPI+PD1 and 24% with IPI). Grade 3+ adverse events occurred at similar rates with the two treatments. Several factors were combined to create a prediction of OS, incorporating tumor stage, LDH level, treatment option, sex, performance status, BRAF mutations, metastatic sites, and time to recurrence on original therapy. This study favors IPI+PD1 treatment for melanoma after progression on PD-1 monotherapy with improved efficacy and similar rates of toxicity to ipilimumab monotherapy.
The SITC Immunotherapy Resistance Taskforce recently published recommendations for defining resistance to PD-1 blockade, which may be read here at JITC.
INTRATHECAL AND INTRAVENOUS NIVOLUMAB SHOWS EFFICACY IN MELANOMA LEPTOMENINGEAL DISEASE
10008: Single-center phase I/Ib study of concurrent intrathecal (IT) and intravenous (IV) nivolumab (N) for metastatic melanoma (MM) patients (pts) with leptomeningeal disease (LMD)
A study of intrathecal and intravenous nivolumab in patients with leptomeningeal disease from metastatic melanoma was discussed by Isabella Claudia Glitza, MD (MD Anderson Cancer Center). Intrathecal administration of other therapies, like IL-2, has shown some promise for LMD; however, the toxicity profile of IT nivolumab was expected to be more desirable than that of IL-2. Therefore, this study evaluated the safety and recommended dose of combined IT and IV nivolumab.
Of the 18 patients treated on the study to date, the majority had previous treatments, including radiotherapy, checkpoint inhibitors, or BRAF/MEK inhibitors. After receiving a median of four doses of IT nivolumab, eight adverse events were attributed to IT nivolumab, and all were grade 1. No grade 4 or 5 toxicities were observed. After a median follow-up of nearly 14 weeks, the median OS in this population was 19.4 weeks. Five patients remain on treatment. The investigators are planning to expand this trial to include more patients and patients with LMD from cancers other than melanoma, including lung cancer, given the encouraging safety profile and potential efficacy observed in this trial.
STUDY INDICATES TOTAL LYMPH NODE DISSECTION MAY BE AVOIDED IN SOME PATIENTS WITH MELANOMA
10002: First safety and efficacy results of PRADO: A phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma
Response-driven treatment options for stage III melanoma were discussed by Christian U. Blank, MD, PhD (Netherlands Cancer Institute). In this trial, patients received two cycles of neoadjuvant ipilimumab 1 mg/kg + nivolumab 3 mg/kg, after which responses were assessed in the index lymph node (ILN). Patients with a major pathologic response (MPR, <10% viable tumor remaining) in the ILN did not have to undergo therapeutic lymph node dissection, while those with a partial pathologic response (pPR, 11-49% viable tumor remaining) did. Patients with no response (pNR) underwent TLND and also received systemic adjuvant therapy for one year with or without radiation therapy. The primary endpoints were pathologic response rates in the ILN and 2-year relapse-free survival.
Half of patients on this trial experienced a pathologic complete response after the two cycles of therapy, 11% a near-complete response, and 10% had a partial pathologic response. MPR rate was 61%. Pathologic response was underestimated by radiological response assessment, which indicated an ORR of 45% and complete response rate of 14%. Within 12 weeks of therapy, 97% of patients experienced any adverse event, including 22% grade 3 or higher. As may be expected, higher incidence of surgery-related adverse events was seen with the full TLND procedure over the ILN resection alone. This also led to higher quality of life scores in patients who avoided TLND. The survival data is not yet mature for this study, but results to date suggest potential for reduced morbidity by avoiding surgery for patients with initial responses to immune checkpoint inhibitors.
Click here to read a recent study in JITC lending support to the evaluation of pathologic responses for determining treatment outcomes for patients on immune checkpoint inhibitors.
BENEFIT OF NIVOLUMAB + IPILIMUMAB MAINTAINED EVEN WITH FEWER COMBINATION DOSES
10003: A phase II study to evaluate the need for > two doses of nivolumab + ipilimumab combination (combo) immunotherapy
While combination nivolumab/ipilimumab is typically given for four doses for metastatic melanoma, a study conducted by Michael A. Postow, MD (Memorial Sloan Kettering Cancer Institute) and colleagues investigated the efficacy of a lower number of combination doses. In this trial, patients were evaluated via CT after two combination doses and allocated to further treatment based on their response: those with a CR, PR, or stable disease without an increase >4% in total tumor burden (favorable anti-tumor effects, FATE) were transitioned to maintenance nivolumab, while patients without these responses continued on to the remaining two combination doses. The primary endpoint of the study was response rate at week 12.
Among the 60 enrolled patients, 18%, 58%, 12% and 10% received 1, 2, 3 or 4 combination doses, respectively. At 12 weeks, the ORR was 48%, while the best ORR at any time thereafter was 57%. After six weeks, 68% of patients experienced no tumor burden growth; notably, no patients experienced a response with continued ongoing combination dosing if they had not already achieved a response after two doses. All patients on this study experienced some degree of treatment-related adverse event, with three treatment-related deaths on-study (2 myocarditis, 1 possible adrenal insufficiency). Lending support to the importance of early response on combination therapy, favorable changes in immunologic blood markers were only noted after one combination therapy dose and did not further improve with continued dosing. This study points to the importance of early imaging to determine whether a patient will benefit from combination immune checkpoint inhibition, while also giving support to the use of shorter combination immunotherapy dosing regimens in the management of melanoma.
The importance of quality of life for patients with melanoma treated with immune checkpoint inhibitors is discussed in this recent JITC article.
DUAL-TARGETED CD19/CD22 CAR T THERAPY INVESTIGATED IN DLBCL
8001: Phase I Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL
Aravind Ramakrishnan, MD (St. David’s South Austin Medical Center) outlined the Phase I Alexander study, which is evaluating a CD19/22 dual-targeted CAR T therapy for patients with relapsed/refractory DLBCL. The CAR product was manufactured using a bicistronic retroviral vector, encoding anti-CD19 (OX40 co-stimulation) and anti-CD22 (4-1BB co-stimulation); prior to administration, patients received Flu/Cy lymphodepletion and then underwent transfusion of 50, 150, or 450 x 106 CAR T (AUTO3) cells. Once the safety of the CAR dose levels was established, patients were also allocated to one of three regimens: AUTO3 alone, with pembrolizumab Q3W for three doses, or with a single dose of pembrolizumab on day 1. The study aimed to evaluate the safety profile of these treatments, along with responses and biomarkers.
Twenty-three patients have been treated thus far, including dose escalation from 50 to 450 x 106 cells with both pembrolizumab-containing regimens. Across these patients, no dose-limiting toxicities or treatment-related deaths have been observed to date. No cases of severe cytokine release syndrome and only one incidence of neurotoxicity (which later resolved) were noted, and four patients (17%) received tocilizumab. Common grade 3+ treatment-emergent adverse events included neutropenia, thrombocytopenia, and anemia. Preliminary efficacy results indicate an overall response rate of 69% across all evaluable patients who received doses of at least 150 x 106 cells (the recommended phase 2 dose), including 56% complete responses. In those patients allotted to the AUTO3 + single pembrolizumab dose, the ORR was 75%, with 63% CR also. Given the therapeutic success and reasonable safety observed to date with these regimens, future investigations are ongoing.
MANY ONGOING TRIALS OF BCMA-DIRECTED CAR T THERAPIES DEMONSTRATE SUCCESS
8503: Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results
8504: Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011)
8505: Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma
Several studies were presented during the 2020 ASCO Virtual Scientific Program discussing the use of BCMA-directed CAR T therapies for multiple myeloma, all in various stages of clinical development and using different constructs. All these trials tested the CAR constructs in patients with highly pre-treated multiple myeloma after Cy/Flu lymphodepletion.
Nikhil C. Munshi, MD (Dana-Farber Cancer Institute) presented the phase 2 KarMMa study, investigating idecabtagene vicleucel in 128 patients. Dose levels from 150- 450 x 106 CAR T cells were investigated. After a median follow-up of 13.3 months, the overall response rate across all doses was 73%, with higher doses leading to higher response rates (82% at 450 x 106 cells). CRR was 33%. The median PFS across all patients was 8.8 months. Cytopenias of any grade occurred in almost all patients, while cytokine release syndrome was observed in 84% of patients as well, mostly grade 1-2 (5 pts grade 3, 1 grade 4, 1 grade 5). Two-thirds of patients at higher dose levels required tocilizumab. Neurotoxicity occurred in 18% of patients, and most were low-grade.
The phase 1/2 EVOLVE study was discussed by Sham Mailankody, MBBS (Memorial Sloan Kettering Cancer Center), which tested orvacabtagene autoleucel in 62 patients. This presentation highlighted the higher dose levels in the study: 300, 450, and 600 x 106 CAR T cells. Across all doses, the ORR was 92% and the median PFS was only reached for the 300 x 106 cells dose level, at 9.3 months, with 9.5 months follow-up for patients in that dose level cohort. The other dose levels had shorter follow-up times. Two dose-limiting toxicities were observed, including a long-lasting grade 3 neurologic event and grade 4 neutropenia. One patient died due to grade 5 macrophage activation syndrome. Cytokine release syndrome of any grade was noted in 89% of patients, and neurotoxicity was found in 13%. 76% of patients received tocilizumab.
Extended follow-up from the phase 1b/2 CARTITUDE-1 study was presented by Jesus G. Berdeja, MD (Sarah Cannon Research Institute), wherein patients were treated with JNJ-68284528 at a median dose of 0.73 x 106 CAR cells/kg. Twenty-nine patients have been enrolled and followed for a median of 11.5 months. The ORR in this study was 100%, which included 86% stringent complete remission. The 9-month PFS in this study was 86%. Any-grade adverse events resulting from the therapy included neutropenia in 100% of patients (all grade 3+), cytokine release syndrome in 93% (1 pt grade 3, 1 pt grade 5), and neurotoxicity in four patients (1 grade 3). 79% of patients received tocilizumab.
Given the promising results achieved in these studies, BCMA-directed CAR T therapies are poised to have clinical impact for patients with multiple myeloma in the near future.
HIGH PATHOLOGIC RESPONSE RATES WITH NEOADJUVANT CHECKPOINT BLOCKADE IN UNDIFFERENTIATED PLEOMORPHIC SARCOMA
11505: Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS)
Christina Lynn Roland, MD (MD Anderson Cancer Center) highlighted a trial of neoadjuvant nivolumab or combination ipilimumab/nivolumab in patients with undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma (DDLPS). Patients with UPS also received 50 Gy radiation. This study aimed to evaluate the pathologic response rate (pRR, assessed by hyalinization), as well as safety, other response metrics, and exploratory correlative analyses.
Twenty-three patients were evaluable, including 14 DDLPS and 9 UPS. One patient developed metastasis during neoadjuvant therapy and one patient experienced surgical delay. The highest pRR was seen in patients with UPS at a median of 95% (notably higher than historical controls), while the median pRR in the DDLPS cohort was 22.5%. The additional of CTLA-4 blockade did not increase response in either group. There was no correlation between pRR and radiologic responses in this trial – median radiographic tumor size changes were -4% in the UPS cohort and +9% for DDLPS, pointing to the need for better clinical markers of response. After therapy, median hyalinization was 8.75% in the DDLPS cohort, and 93% for UPS. While sarcomas continue to be difficult to treat with immune checkpoint therapy, this study indicates potential efficacy of neoadjuvant blockade with anti-PD-1 therapy in UPS.
Click here to read a recent study in JITC investigating pembrolizumab in other rare cancers.
MODEST ACTIVITY OF PEMBROLIZUMAB MONOTHERAPY FOUND IN RECURRENT OVARIAN CANCER
6005: Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer
Ursula A. Matulonis, MD (Dana-Farber Cancer Institute) presented the final analysis of the KEYNOTE-100 study, investigating pembrolizumab monotherapy in advanced ovarian cancer. Two patient cohorts were included: A) no more than two previous therapies and B) 3-5 prior chemotherapies. Primary endpoints included ORR in both cohorts and ORR by tumor PD-L1 expression using CPS.
Cohort A treated 285 patients, and 91 patients were in cohort B. Median follow up was 37.8 months. In cohort A, the ORR was 8.1% in the total population, 6.9% if PD-L1 CPS was >= 1 and increased to 11.6% with CPS >=10. For cohort B, the ORR overall was 9.9%, 10.2% with PD-L1 CPS >=1, and 18.2% with PD-L1 CPS >=10. The median duration of response was longer in cohort B, at 23.6 months, compared to 8.3 months in A. Median overall survival was 18.7 months in A and 17.6 months in B; however, this was extended in both cohorts with increased PD-L1 expression, reaching 21.9 and 24.0 months for patients in cohorts A and B, respectively, with PD-L1 CPS >=10. Two-thirds of responses lasted at least six months. Immune-related adverse events occurred in 23.7% of all patients, and two treatment-related deaths were noted, due to Stevens-Johnson syndrome and hypoaldosteronism. Overall, this study noted modest activity with pembrolizumab monotherapy in patients with PD-L1-expressing ovarian cancer, indicating potential for further development of other treatment strategies incorporating immune checkpoint inhibition.
DUAL INHIBITION OF PD-1 AND LAG-3 SHOWS POTENTIAL
3004: A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms
An early investigation of MGD013, a bispecific DART molecule binding both PD-1 and LAG-3, was presented by Jason J. Luke, MD, FACP (University of Pittsburgh). This dose escalation and expansion study evaluated the safety and dosing properties in patients with advanced solid tumors or hematologic malignancies, with doses from 1-1200 mg Q2W.
Full, sustained receptor binding for PD-1 was found for doses >120 mg. The recommended phase 2 dose of 600 mg every two weeks was used for the expansion cohorts. A total of 258 patients were enrolled between the escalation and expansion arms. Any-grade treatment-related adverse events occurred in 57.6% of patients, with 18% being grade 3+ and, as a result, no maximum tolerated dose was identified. Confirmed partial responses were observed in 3/41 escalation patients (including 2 patients who had prior immune checkpoint inhibitor therapy), while 18 patients in this cohort had stable disease. In the expansion cohorts, an ORR of 4.3% was seen for TNBC, 8.7% for epithelial ovarian cancer, and 14.3% for checkpoint inhibitor-naïve NSCLC. No responses were seen in post-checkpoint inhibitor NSCLC. MGD013 was also tested in combination with an anti-HER2 antibody, margetuximab, resulting in an ORR of 42.9% in HER2-amplified cancers. Throughout the study, responses were correlated with LAG-3 expression and IFN-gamma score. Therefore, this early-phase study indicates a reasonably safe and potentially efficacious therapy for advanced cancers, targeting multiple mechanisms of immune evasion.