Published: June 7, 2016
As the premier advocate and resource for cancer immunotherapy for more than 30 years, the Society for Immunotherapy of Cancer (SITC) is pleased that cancer immunotherapy has become a mainstream topic in clinical oncology, as seen at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, currently underway in Chicago, Illinois. Notable overarching themes of the cancer immunotherapy clinical trial data presented at the meeting include new immunotherapy agents in development, combination therapies, adoptive cellular therapies, and measurement of anti-tumor immunity. Some key developments are highlighted below.
Significant clinical benefit with the addition of daratumumab to the current standard of care for multiple myeloma
In a plenary session discussing the phase III CASTOR study of nearly 500 patients with relapsed or refractory multiple myeloma (RRMM), Dr. Antonio Palumbo from the University of Torino reported that the addition of daratumumab (anti-CD38) to the current standard of care, bortezomib + dexamethasone, reduced the risk of disease progression by 61%. The objective response rate (ORR) was significantly higher in the drug trio compared to bortezomib + dexamethasone alone (83% vs. 63%, p<0.0001), and the rates of complete responses (CR) and very good partial responses doubled from 9% to 19% (p=0.0012) and 29% to 59% (p<0.0001), respectively, with the addition of daratumumab. The median duration of response was 7.2 months in the bortezomib + dexamethasone group, while it had not been reached in the group treated with the drug trio. The overall toxicity for the three-drug combination was consistent with the known safety profiles for both daratumumab and bortezomib + dexamethasone therapies. In an interview following his presentation, Dr. Palumbo indicated that these data support a reevaluation of the standard of care for RRMM patients.
First-line PD-L1 blockade yields durable responses in cisplatin-ineligible bladder cancer
SITC member Dr. Arjun Vasant Balar of the Perlmutter Cancer Center in New York presented on the first cohort of the IMvigor210 study in which 119 patients with cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC) were treated with atezolizumab (anti-PD-L1) as a first-line therapy. The ORR following atezolizumab monotherapy was 24%, and a majority of responses are ongoing (21/28). Median survival was 14.8 months. Seven percent of all mUC patients achieved a CR and the partial response rate was 17% overall. Dr. Balar also noted that clinical benefit of atezolizumab was seen across all patient subgroups independent of PD-L1 expression. Although comparative studies are not yet available, these data suggest that this immunotherapy could be a well-tolerated alternative to traditional chemotherapy. Watch more on the study here.
Novel dual immunotherapy combination of 4-1BB agonist and anti-PD-1 well tolerated in advanced solid tumors
The combination therapy using utomilumab (CD137/4-1BB agonist) and pembrolizumab (anti-PD-1) was assessed in a phase Ib trial of patients representing a broad range of advanced solid tumors. Dr. Anthony Tolcher of START San Antonio presented findings illustrating that this combination immunotherapy was well tolerated with no reported dose-limiting toxicities. The majority of treatment-related adverse events (AEs) were grade I/II, and there was no association between the frequency or severity of AEs and the dose of utomilumab. Twenty-six percent of patients experienced a complete (2/23) or a partial (4/23) response, and the majority of these confirmed responses (4/6) have lasted 6 months or longer. Treatment was ongoing in 5 patients at the time of analysis; thus, the safety and efficacy of this drug combination will continue to be monitored.
Combination of nivolumab and ipilimumab increased overall survival in small cell lung cancer (SCLC)
An arm of the phase I/II Checkmate 032 study investigating the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in patients with advanced SCLC following first-line platinum-based chemotherapy was presented by Dr. Scott Antonia of the Moffitt Cancer Center. In this trial, 216 patients were randomized into treatment groups receiving either nivolumab monotherapy or the combination of nivolumab + ipilimumab at one of two different doses (1mg/kg nivolumab + 3mg/kg ipilimumab [N1/I3] or 3mg/kg nivolumab + 1mg/kg ipilimumab [N3/I1]). The ORR for nivolumab alone was 10% (95% CI, 5-18%) compared with 23% for N1/I3 (95% CI, 13-36%) and 19% for N3/I1 (95% CI, 9-31%). The 1-year OS rate was 33% (95% CI, 22-45%) in the monotherapy group, 35% (95% CI, 22-48%) for N1/I3, and 43% (95% CI, 30-56%) for N3/I1. AEs were more frequent in both the N1/I3 and N3/I1 (74% and 79%) versus 53% in the single-agent group; however, only 11% of patients overall came off treatment due to toxicity.
Excellent safety profile of OX40 agonist/atezolizumab combination for solid tumors
A dose escalation phase Ib study to evaluate the safety and pharmacokinetics of MOXR0916 (OX40 agonist) and atezolizumab in 51 patients with a variety of advanced solid tumors was presented by Dr. Jeffrey Infante from the Sarah Cannon Research Institute. In this study, no dose-limiting toxicities occurred, and a maximum-tolerated dose was not reached. Moreover, no grade 4 AEs or treatment-related deaths resulted from this drug combination. The pharmacokinetics of the dual treatment were similar to those seen in each monotherapy. The assessment of efficacy is ongoing. However, partial responses were reported in 2 out of 51 patients at the time of analysis, and early evidence of immune activation following treatment was shown in paired tumor biopsies.
Durable complete responses achieved with CD19 CAR-T cells in B cell malignancies
Dr. Cameron Turtle of the Fred Hutchinson Cancer Research Center reported on a phase I/II adoptive therapy trial in which patients with relapsed or refractory CD19+ B cell malignancies (ALL, NHL, and CLL) received a 1:1 ratio of CD8+ and CD4+ chimeric antigen receptor (CAR) T cells following lymphodepletion with either cyclophosphamide (Cy) + fludarabine (Flu) or Cy alone. Improved clinical outcomes were noted in patients who received Cy+Flu lymphodepletion and are associated with superior CAR T cell persistence. CRs were achieved by 94% (32/34) of patients with ALL, 50% (10/20) of the NHL patients receiving the preferred dosing regimen of 2 x 105 cells/kg CAR T cells with Cy+Flu lymphodepletion, and 45% (5/11) of CLL patients who underwent Cy+Flu lymphodepletion. Disease-free survival rate was 60% among ALL patients who received Cy+Flu lymphodepletion versus less than 10% for ALL patients who received Cy alone (p=0.0005), but OS was not yet significant between those two groups. The median PFS and OS was not reached for the NHL or CLL groups.
Mismatch repair deficiency in colon cancer predictive of response to PD-1 blockade
Updated results for the expanded trial of pembrolizumab (anti-PD-1) in mismatch repair deficient (dMMR, n=28) versus proficient (pMMR, n=25) colon cancer were presented by Dr. Luis A. Diaz of Johns Hopkins University School of Medicine. Of the 21 dMMR patients that remain in the study, the rates of PFS and OS at 24 months were 61% and 66%, respectively. Median PFS was 2.4 months in the pMMR group with a median OS of 6 months, whereas neither had been reached in the dMMR cohort. In an interview on this study, contributing author Dr. Dung T. Le suggests that mismatch repair deficiency could be used as a biomarker to predict response to immunotherapy.
Systematic evaluation of biomarkers in mUC patients treated with atezolizumab
The outcome of an exploratory analysis of immune and genetic predictors of clinical response to anti-PD-L1 therapy was reported by Dr. Jonathan Rosenberg of Memorial Sloan Kettering Cancer Center. Archival tumor specimens from patients with mUC were assayed for PD-L1 expression by IHC, gene expression by RNA-sequencing with molecular subtypes assigned per The Cancer Genome Atlas (TCGA), and mutational load by genomic profiling. Expression of PD-L1 by immune cells (p=0.0109), TCGA subtype (p=0.0384), and mutational load (p< 0.0001) were all found to be predictors of response to atezolizumab. In addition, the combinations of these biomarkers had an additive predictive value.
Mutational load in melanoma predictive of response to anti-PD-1 therapy
Hybrid capture-based next-generation sequencing (HC NGS) was used to determine whether the number and type of mutations in melanoma correlated with response to anti-PD-1 immunotherapy. Presented by Dr. Douglas Buckner Johnson of Vanderbilt University, archival samples were stratified into high (>23.1 mut/megabase [MB]), intermediate (3.2-23.1 mut/MB), and low (<3.2 mut/MB) genomic mutational load (ML) groups. Patients who responded to anti-PD-1 therapy were found to have a higher ML compared to non-responders in both discovery (median 45.6 vs. 3.9 mut/MB; p=0.003, n=32) and validation cohorts (37.1 vs. 12.8 mut/MB; p=0.002, n=33). OS was increased in patients with a high ML (median OS not reached) compared to those with intermediate (300 days) or low ML (375 days). TCR clonality and PD-L1 gene amplification were also assayed in these samples but did not correlate with response.