Key Developments in Cancer Immunotherapy
Research at ESMO 2016

In line with the Society for Immunotherapy of Cancer's (SITC) mission to advance cancer immunotherapy, we monitor all news related to the field for our members. As such, SITC is pleased to present highlights of the latest advances in immunotherapy emerging from the European Society for Medical Oncology (ESMO) 2016 Congress, held in Copenhagen, Denmark, on October 7-11, 2016.

Immune checkpoint inhibitors

Latest advances in immunotherapy for non-small cell lung cancer (NSCLC)
A number of significant gains impacting immune-based treatment options for non-small cell lung cancer (NSCLC) were presented:

1. Dr. Patrick M. Forde, Johns Hopkins University, presented the first report of neoadjuvant anti-PD-1 treatment in patients with stage I-IIIA NSCLC, from a study in which post-operative chemotherapy was administered at the physician’s discretion. In this study, 12/15 patients who had tumor resections showed evidence of an anti-tumor response following treatment with nivolumab. There were no significant safety concerns or delays to surgery.
2. Three phase III trials targeting the PD-1/PD-L1 axis addressed PD-L1 expression as a biomarker to guide patient selection. The first two studies (CheckMate-026 and KEYNOTE-024) examined PD-1 blockade as a first-line treatment for advanced NSCLC. The CheckMate-026 trial, presented by Dr. Mark A. Socinski, formerly of UPMC Cancer Center, now affiliated with the Florida Hospital Cancer Institute, compared the efficacy of nivolumab to platinum-based doublet chemotherapy in patients with ≥5% PD-L1 tumor expression. Despite the favorable safety profile of nivolumab over chemotherapy, immunotherapy did not improve progression-free survival (PFS) in this setting, potentially due to the broad range of PD-L1 expression represented. The KEYNOTE-024 study, reported by Dr. Martin Reck of the Airway Research Center North in Germany, restricted enrollment to patients with ≥50% expression of PD-L1 on tumor cells. In this cohort of patients, significant improvement in PFS and overall survival (OS) were observed, along with a lower rate of treatment-related adverse events (TRAE) compared to platinum-based doublet chemotherapy. Finally, the OAK study, presented by Dr. Fabrice Barlesi, Aix Marseille University, examined the effects of the anti-PD-L1 agent atezolizumab on previously-treated NSCLC. Patients treated with atezolizumab had significant gains in OS compared to patients treated with docetaxel, and although improvements were observed regardless of PD-L1 expression levels, there were particularly pronounced benefits in patients with high expression. Together, these studies add to the broader ongoing discussion about how best to incorporate biomarkers when selecting patients for immunotherapy.

Adjuvant ipilimumab demonstrates survival benefit in melanoma
In a late-breaking abstract presentation, an update on overall survival for stage III melanoma patients treated in a randomized study of ipilimumab versus placebo was presented by Dr. Alexander Eggermont of the Institut Gustave Roussy in Villejuif, France. In this trial, EORTC 18071, 951 patients who had undergone complete resection were randomized to ipilimumab given at 10 mg/kg every three weeks for four doses and then every three months up to three years or placebo. The primary endpoint of recurrence-free survival (RFS) was significantly improved in patients who received ipilimumab. According to the updated data presented at ESMO, additional clinical benefit was seen for several secondary endpoints of the study, which included a 28% reduction in the risk of death (OS hazard ratio 0.72; 95% CI, 0.58–0.88; p=0.001) and a 24% reduction in the risk of distant metastases (HR 0.76; 95% CI, 0.64–0.92; p=0.002). The five-year overall survival rate was 65% for patients treated with ipilimumab compared to 54% for those that received placebo. Immune-related adverse events in patients receiving ipilimumab included grade 3/4 gastrointestinal (16%), hepatic (11%) and endocrine (8%) toxicities. The median follow-up for patients in this study was 5.3 years.

Second-line nivolumab demonstrates safety and efficacy in a phase II study in metastatic bladder cancer
The use of nivolumab in patients with metastatic urothelial cancer (mUC) who have received prior treatment was evaluated in the phase II CheckMate-275 study, presented by Dr. Matthew D. Galsky, Icahn School of Medicine at Mount Sinai. In this study, 265 patients received nivolumab (3 mg/kg) every two weeks until disease progression or unacceptable toxicity. Outcomes were evaluated by PD-L1 expression, UC subtype, and expression of an immune gene signature. Confirmed objective response rates (ORRs) were 19.6% overall (95% CI, 15.0-24.9), 16.1% in patients with low to no PD-L1 expression (95% CI, 10.5-23.1), and 28.4% in patients whose PD-L1 expression was ≥5% (95% CI, 18.9-39.5). The highest proportion of responders was seen in the basal 1 UC subtype. Response is ongoing in 76.9% of patients, and the median duration of response has not yet been reached. 18% of patients experienced grade 3/4 TRAE, of which fatigue (2%) and diarrhea (2%) predominated.

Quality of life significantly improved in patients with metastatic head and neck cancer treated with nivolumab compared to chemotherapy
Patient-reported outcomes (PRO) of the phase III CheckMate-141 randomized trial of nivolumab versus standard of care chemotherapy (investigator’s choice of methotrexate, docetaxel, or cetuximab) in patients with platinum-refractory relapsed squamous cell carcinoma of the head and neck were reported by Dr. Kevin Harrington, Institute of Cancer Research, London, UK. PRO data were obtained using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, the EORTC Head and Neck Cancer module, and EQ-5D given at baseline, week 9, and every six weeks thereafter. In all, 129/361 (35.7%) patients completed a PRO measure both at baseline and during follow-up, although low completion rates in the chemotherapy group precluded analysis of mean differences after week 15. The time to clinically relevant score deterioration was significantly longer in patients receiving nivolumab versus chemotherapy (p<0.05, 2-tailed) for several measures of symptoms and functioning, including global health, fatigue, social functioning, and pain.

Combination approaches

First-line combination immunotherapy superior to chemotherapy alone in advanced non-squamous NSCLC
Pembrolizumab in combination with standard chemotherapy was assessed in a phase II trial of treatment-naïve patients with advanced non-squamous NSCLC. Dr. Corey J. Langer, Abramson Cancer Center, presented on cohort G of the multicenter KEYNOTE-021 study, in which 123 patients were randomized to four cycles of carboplatin and pemetrexed +/- 24 months of pembrolizumab. The ORR was 55% in patients receiving combination therapy versus 29% (p=0.002) in the chemotherapy-only group, with significantly improved PFS in the combination group as well (HR 0.53, 95% CI, 0.31-0.91, p = 0.01; median PFS 13.0 vs. 8.9 months). Discontinuation due to TRAE was similar with combination therapy (10%) and chemotherapy alone (13%), despite the higher frequency of grade 3/4 TRAE seen with the addition of immunotherapy (39% vs. 26%).

T-VEC combined with ipilimumab demonstrates efficacy and safety in interim analysis of melanoma patient data
Interim results of an ongoing randomized phase II study of talimogene laherparepvec (T-VEC) in combination with ipilimumab versus ipilimumab alone, in the setting of melanoma, were presented by Dr. Jason Chesney, University of Louisville. The interim analysis was performed once in 82/173 (47.4%) patients with unresectable advanced melanoma who had ≥48 weeks of follow-up. The confirmed ORR was higher in the combination group (35.7%, 95% CI, 21.6-52.0) than for ipilimumab alone (17.5%; 95% CI, 7.3-32.8). Preliminary analyses of safety data indicated comparable incidence of TRAE between groups, with the exception of an increase in fatigue (52% vs. 39%), chills (51% vs. 3%), and pyrexia (39% vs. 8%) in the combination arm.

Combination of IDO1 inhibitor and pembrolizumab well tolerated in select solid tumors
Dr. Tara C. Gangadhar, Abramson Cancer Center, provided updated results from the phase I ECHO-202/KEYNOTE-037 trial. A total of 62 patients with advanced melanoma and select solid tumors were treated with the indoleamine 2,3-dioxygenase 1 (IDO) inhibitor, epacadostat (25, 50, 100 or 300mg BID during dose escalation/expansion), together with pembrolizumab, to assess the safety and efficacy of this combination therapy. All dose cohorts of epacadostat ≥50 mg twice daily yielded ongoing response with a median follow-up of 42 weeks (min, max; 31.7, 75.9) and median PFS has not yet been reached. Of the grade ≥3 TRAEs, which occurred in 18% of patients, the most common were rash (8%) and increased lipase (3%) with no treatment-related deaths. Enrollment is ongoing for phase II and phase III studies based on these data.

Biomarkers

Baseline measures of T cells in the tumor microenvironment correlate with response to sequential nivolumab and ipilimumab in melanoma
Dr. Jeffrey S. Weber of the NYU Langone Medical Center in New York presented data from a phase II clinical trial comparing sequential nivolumab and ipilimumab (arm A) vs. the reciprocal regimen (ipilimumab followed by nivolumab; arm B) in 140 patients with unresectable metastatic melanoma. Patients in arm A demonstrated superior ORR and OS compared with arm B, and responders in arm A were shown to have higher T cell infiltrates and T cell clonality in pre-treatment tumor samples than non-responders (p=0.002). Analysis of these T cell parameters using pre- and post-treatment samples revealed that increase in T cell infiltration and clonality correlated with response to treatment in both arms (p=0.002, odds ratio=30). These determinants of treatment response appeared to be specific to the tumor microenvironment, as T cell analyses using peripheral blood samples did not correlate with treatment response in either arm.

Serum IL-8 levels predict response to treatment with anti-PD-1 in metastatic melanoma and NSCLC
Dr. Miguel F. Sanmamed, Yale School of Medicine, investigated serum IL-8 levels as a potential biomarker of anti-PD-1 treatment response in patients with metastatic melanoma or NSCLC. Blood from 63 patients with advanced melanoma or NSCLC was drawn at four time points: baseline, 2-4 weeks after treatment with anti-PD-1 monotherapy or anti-PD-1 in combination with anti-CTLA-4, time at best response, and time at disease progression. Serum IL-8 levels in responders were significantly lower at time of best response [melanoma validation set: 49 pg/mL(Q1-Q3: 20-78); NSCLC: 6 pg/ml (Q1-Q3: 0-17)] compared to baseline melanoma validation set: 110 pg/mL(Q1-Q3: 40-521); NSCLC: 16 pg/ml (Q1-Q3: 6-32)] in all cohorts examined (p<0.05). IL-8 levels increased significantly upon disease progression in patients with melanoma [validation set: 249 pg/mL (Q1-Q3: 57-535; p<0.05 for best response vs. disease progression). Changes in serum IL-8 levels 2-4 weeks after treatment initiation strongly correlated with response to anti-PD-1.

Clinical management

Suboptimal reporting of adverse events in clinical trials involving immunotherapies
Dr. Paolo Bossi, Fondazione IRCCS – Instituto Nazionale dei Tumori, presented a systematic review of TRAE reporting in clinical trials of targeted therapies and immunotherapies that led to drug approval by the U.S. Food and Drug Administration (FDA). Utilizing a 24-point score based on the Consolidated Standards of Reporting Trials (CONSORT) guidance, 81 trials conducted between 2000 and 2015 and including > 45,000 adults with solid malignancies, were identified for review. Reporting of recurrent and late toxicities was found to be inadequate in 90% of the trials, with insufficient explanation of the time of occurrence of TRAE in 86% of trials and limited descriptions of toxicities that led to treatment discontinuation in 50% of trials. Additionally, 1 in 3 trials failed to report dose reductions due to TRAE. These data indicate a need to re-examine how TRAE data are collected and reported.

Society for Immunotherapy of Cancer (SITC)
555 East Wells Street, Suite 1100 | Milwaukee, Wisconsin 53202-3823 USA
Phone: +1 414 271 2456 | Email: info@sitcancer.org

© 2016 Society for Immunotherapy of Cancer

Join us on:

       

If you do not wish to be included in our mailing list, please forward this message to info@sitcancer.org with the word "Remove" in the subject line.

Please add info@sitcancer.org to your safe senders list.