Immuno-Oncology — The Year's News In Science

By Wayne Koberstein, Executive Editor, Life Science Leader
Follow Me On Twitter @WayneKoberstein

From The September 2015 Issue
Read the full magazine article: Combination Cancer Immunotherapy: A 2015 Update

In 2014, many of the most encouraging studies of checkpoint blockade went public at the annual ASCO (American Society of Clinical Oncology) meeting. This year, even more positive studies of new checkpoint inhibitors were reported, along with a few other cancer-immunotherapy contenders, most of them at either ASCO in May or the AACR (American Association for Cancer Research) annual meeting in April.

The following is a roundup of the key IO trials during the past year and their conclusions, including edited excerpts from the abstracts or other sources.

At AACR:

Phase 3: Improved clinical response in patients with advanced melanoma treated with nivolumab (NIVO) (BMS/Opdivo) combined with ipilimumab (IPI) (BMS/Yervoy) compared with ipilimumab alone. Conclusion: NIVO+IPI significantly improved ORR (objective response rate) and PFS (progression-free survival) compared with IPI alone in treatment-naïve patients with advanced melanoma, and had a manageable safety profile. “Most of the patients who stopped for toxicity continued to benefit,” says Fouad Namouni, VP development, lead, immuno-oncology, Bristol-Myers Squibb (head of development for Yervoy and Opdivo).

Phase 3: Pembrolizumab (Merck/Keytruda) versus ipilimumab in patients with ipilimumab-naive advanced melanoma. Conclusion: In this first randomized study comparing two immune checkpoint inhibitors, pembrolizumab prolonged PFS and OS (overall survival) and had a favorable safety profile compared with ipilimumab in advanced melanoma patients.

Phase 2: Pembrolizumab in patients with malignant mesothelioma. Conclusions: Pembrolizumab is generally well tolerated and provides robust antitumor activity in patients with advanced PD-L1 (programmed death receptor ligand) + MPM (malignant pleural mesothelioma). The 76-percent disease control rate in this previously treated MPM population is unprecedented and warrants further study.

Phase 1: Efficacy of pembrolizumab and relationship with PD-L1 expression in patients with non-small cell lung cancer (findings from KEYNOTE-001). Conclusions: Pembrolizumab provides durable antitumor efficacy and safety in patients with treatment-naive and previously treated NSCLC (non-small cell lung cancer). The data validate that membranous PD-L1 expression in greater than or equal to 50 percent of tumor cells identifies patients with advanced NSCLC who are particularly likely to obtain clinical benefit from pembrolizumab.

Phase 1/2a: IMCgp100 (immunocore/T cell-aiming peptide) for advanced melanoma. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug: T cell mobilization, activation, and tumor killing. Objective durable responses were observed, including in ocular melanoma patients.

A number of additional trials reported at AACR explored the diverse avenues of immuno-oncology, including potential combinations of checkpoint inhibitors with traditional agents such as chemotherapy and targeted therapies, and with interventions such as radiation. Mechanistic studies of checkpoint blockade, T cell activation, and tumor defenses abounded. Vaccines and co-stimulatory agents had a limited presence, however. Overall, the case for checkpoint blockade grew stronger at AACR, with much clinical data now supporting its use in more and more solid cancers, even as the debate continues over optimal combinations.

At ASCO:

Phase 3: Efficacy and safety results from a Phase 3 trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive

patients with advanced melanoma (MEL) (CheckMate 067). Conclusions: NIVO + IPI and NIVO alone had superior clinical activity vs. IPI alone. The results with NIVO + IPI and NIVO alone further suggest complementary activity of the two agents. There were no new safety signals or drug-related deaths observed with the combination.

Phase 2: PD-1 blockade in tumors with mismatch repair deficiency. Conclusion: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab.

Phase 2: Safety and efficacy study of pidilizumab in patients with metastatic melanoma. Conclusions: Despite low response rates, pidilizumab therapy results in substantial 12-month survival in heavily pretreated patients. The 12-month survival appears comparable to that of other anti-PD-1 MAbs. Treatment is very well tolerated. Further studies of pidilizumab in patients with metastatic melanoma are warranted, preferably in combination with other therapeutics.

Phase 1: First-line monotherapy with nivolumab (NIVO; anti-PD-1) in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 expression. Conclusions: First-line NIVO demonstrated durable responses, encouraging survival and a tolerable safety profile in patients with advanced NSCLC. Although response rates were higher in PD-L1+ patients, OS was encouraging in both PD-L1+ and PD-L1– patients.

Phase 1: Association of response to PD-1 blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. Conclusions: Measuring immune-related biomarkers, including T cell-specific, antigen presentation-related, and IFNγ signaling-related genes, may allow for improved selection of patients likely to respond to anti-PD-1 therapy with pembrolizumab. Results are consistent with the hypothesis that clinical responses to PD-1 blockade occur in patients with a preexisting, interferon-mediated, adaptive immune response. Further confirmation of these new signatures in melanoma is required.

Phase I: Combining anti-PD-L1 (MEDI4736/tremelimumab) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. Conclusion: Tremelimumab can be combined with trametinib ± dabrafenib at full doses with a manageable safety profile, and evidence of clinical activity in BRAF-mutant and WT (wild type) melanoma.

Phase 1b: Antitumor activity and safety of pembrolizumab in patients with PD-L1 positive advanced ovarian cancer. Conclusions: PD-1 blockade with pembrolizumab is well tolerated and has antitumor activity in patients with advanced ovarian cancer. This preliminary signal for clinical efficacy will be further investigated.

Numerous early trials of checkpoint inhibitors in various solid cancers were also presented at ASCO, further strengthening the case for broad application of the new agents. Many reported studies have investigated or are investigating possible biomarkers such as PD-L1 or details of the tumor microenvironment that affect immune activation and T cell invasion. But combinations of checkpoint inhibitors with each other or with traditional as well as new, novel agents dominated the presentations and discussions at this year’s meeting.