Combinations, Better Biomarkers Key to Advancing Immunotherapy in NSCLC

Scott J. Antonia, MD, PhD

Beyond the strong efficacy outcomes observed with single-agent immunotherapies in non—small cell lung cancer (NSCLC)—including pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq)—the field is now awaiting the next phase: combination regimens.

This next step was seen in early pooled findings from the phase Ib CheckMate-012 study, which were presented at the 2016 ASCO Annual Meeting. In the trial, frontline treatment with the combination of nivolumab and ipilimumab (Yervoy) demonstrated a 57% objective response rate (ORR) in patients with PD-L1—positive advanced NSCLC.

Patients received nivolumab alone or in combination with ipilimumab every 6 weeks (Q6W) or every 12 weeks (Q12W). Across the full study population, which was not selected based on PD-L1 expression, nivolumab had an ORR of 23%. In the combination arms, the ORRs were 47% and 39% in the Q12W and Q6W arms, respectively.

“Immunotherapy is a modality that has emerged over the last 4 or 5 years as being very important and has now become the standard of care for the treatment of patients with lung cancer, and in a variety of different clinical settings,” said Scott J. Antonia, MD, PhD, chair of the Department of Thoracic Oncology at Moffit Cancer Center.

OncLive: What immunotherapies are available in NSCLC?

In an interview during the 2016 OncLive State of the Science Summit on Advanced Non—Small Cell Lung Cancer, Antonia discussed the immunotherapeutic advances in NSCLC and novel agents and regimens on the horizon.Antonia: Right now in lung cancer, the drugs—which are monoclonal antibodies—that are blocking the checkpoint protein and inhibiting monoclonal antibodies are directed at the PD-1/PD-L1 system. Therefore, either they bind to PD-1 that is the immune checkpoint protein on the surface of the lymphocytes that do the killing of the tumor cells, or they are PD-L1, which is the ligand, and can be produced by tumor cells and produces that immune suppression with the tumor microenvironment. Those are the drugs available now.

What other immunotherapies are emerging?

There are 3 now commercially available and FDA-approved agents that are indicated for the treatment of lung cancer. They are pembrolizumab, nivolumab, and atezolizumab.There are a large number of them. Probably the most advanced are in combination—anti—PD-1 agents with anti–CTLA-4 inhibitors. There are 2 of those—tremelimumab and ipilimumab (Yervoy)—and each of them are being combined with a PD-1 or PD-L1 inhibitor. The randomized trials are ongoing now, so it’s not proven yet that the combinations will be producing any more efficacy than monotherapy. However, the early trials, which were fairly large expanded cohort trials with the combinations, look very promising.

Beyond that, there is a whole pipeline of different immunotherapeutics that are being tested alone or in combination. Therein lies also the challenge. There is also the large number of immunotherapies out there and, there is such heterogeneity among patients and across different cancers, and there is an extremely large number of these combinations.

What role will immunotherapy have in NSCLC treatment 5 years from now?

The question becomes, “How do you test all of the combinations?” Well, it is just not possible. There needs to be development of better biomarkers that allow for more rational and logical development of these combinations. [We need to improve] the selection of the patients who would properly receive the drugs that they would derive the benefit from.There is no question that this is the tip of the iceberg. There has been a fairly dramatic impact on the field of lung cancer just with the single class of agents of anti—PD-1/PD-L1. There is no telling just how far we can go with this but, certainly, there is going to be a wide variety of immunotherapeutics that come onto the scene.

What other challenges are present in the field?

What do you hope that community oncologists took away from your lecture?

This includes adoptive T-cell therapy, the resurrection of vaccines to increase the number of tumor reactive T cells in patients, agents designed to drive more T cells into the tumors and, of course, agents designed to block or thwart the immune suppressive mechanisms present within the tumor microenvironment. There are many of those. There is really no predicting what will really come to the forefront as being the next leap that can be made with this. There are lots of possibilities.We still need to be able to better predict who will develop toxicities. Even though toxicities are relatively uncommon, they can be severe in some patients. We need better ways of predicting in which patients and when these toxicities arise, so that they can be treated as well.Clearly, we have the utility and the settings in which to do the PD-L1 biomarker testing. PD-L1 is the best biomarker that we have right now. It is a fairly good marker for selecting patients who should be treated [with immunotherapy] in the frontline setting. Of course, we are understanding the toxicities that are involved with these, the early recognition of these toxicities, and how to treat them. It is so important to catch these autoimmune toxicities early to keep people out of trouble. If that can be the case, then these drugs can be given very safely.

Hellmann MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 2016;34 (suppl; abstr 3001).