Immunotherapy Agents, Combinations to Compete for Frontline NSCLC

Sukhmani Padda, MD

Immunotherapy agents, both as monotherapy and in combination, are emerging in the pipeline of non—small cell lung cancer (NSCLC) and could end up competing as frontline treatment for patients, explains Sukhmani Padda, MD.

For example, the PD-1 inhibitor pembrolizumab (Keytruda) is the sole immunotherapy agent approved in the first-line setting for patients with NSCLC; however, many other immunotherapy agents and combination regimens are in development that are aimed at this line of therapy.

In a presentation during the 4th Annual Miami Lung Cancer Conference^®, Padda, assistant professor of medicine, Stanford University Medical Center, addressed the optimal immunotherapy choices for select patients versus standard platinum-based chemotherapy, as well as ongoing clinical trials of agents looking to join pembrolizumab in the frontline setting.

OncLive: What are the latest developments in immunotherapy in the frontline setting in lung cancer?

Following her presentation, Padda sat down for an interview with OncLive to discuss the status of ongoing trials participating in this race to the frontline in lung cancer.Padda: It’s been a really exciting time in lung cancer because we finally have something for patients who don’t have a molecular driver mutation, other than chemotherapy. Just last year, pembrolizumab, which is a PD-1 checkpoint inhibitor, was approved for a subgroup of patients with NSCLC. We should go through the eligibility because it’s really important: these are patients who have no evidence of EGFR mutations in their tumor or ALK rearrangements, and a high level of PD-L1 expression, which was defined as ≥50%.

Are there any other immunotherapy-based regimens in the pipeline that are promising?

In that specific population, looking at a primary endpoint of progression-free survival [PFS], pembrolizumab beat chemotherapy with a hazard ratio of 0.5. That was a really nice development, as it is nice to have something else to offer our patients with lung cancer.As you can imagine, there is a lot of excitement right now around immunotherapy. Essentially, every permutation and combination you can imagine is being tested. We know that there are a variety of PD-1 and PD-L1 immune checkpoint inhibitors, there are also many other checkpoint inhibitors, and even checkpoint agonists, that are all being targeted. We’ll have to see who, in the end, wins the race.

The furthest along in development is the combination of chemotherapy plus immunotherapy in the first-line setting. This was part of the KEYNOTE-021 study, specifically cohort G. This was a randomized phase II study that looked at the combination of

carboplatin/pemetrexed plus pembrolizumab versus carboplatin/pemetrexed alone. The trial did allow for crossover to the combination arm. The primary endpoint for that study was overall response rate, and so they did see an enhanced overall response rate with the combination of immunotherapy and chemotherapy in that setting, around 55% versus 30% with chemotherapy alone.

If you look at the waterfall plots overall, though, there does seem to be deeper responses when you give the combination of chemotherapy and immunotherapy and overall less patients progress. I think it’s promising in that setting that potentially you could get a deeper response and perhaps in a shorter timeframe.

Any other ongoing trials that you’re excited to see the results of?

How reliable is PD-L1 as a biomarker?

What would you like community oncologists to understand about treatment with immunotherapy for patients with lung cancer?

They also looked at PD-L1 expression; it wasn’t required to enroll in the study but it was used as a stratification factor. Even when they looked at PD-L1-positive, 1% versus <1%, they didn’t see a huge difference in response rate although potentially if you have very high levels of PD-L1 expression you may garner an even higher response rate. There was also progression-free survival benefit, but there’s been no overall survival benefit, at least yet, shown. So it’ll be interesting to see where this lands, it’s been brought to the FDA to examine based on this randomized phase II study, but a bigger phase III study is ongoing.In addition to the combination of chemotherapy and immunotherapy, there are a lot of exciting combinations ongoing, but the one furthest along in development is the combination of PD-1 checkpoint inhibitors plus our old-school CTLA-4 checkpoint inhibitors. For example, nivolumab [Opdivo] plus ipilimumab [Yervoy] is a combination that’s been tested in the first-line setting. We always worry about toxicity when we put 2 checkpoints together, particularly drugs like ipilimumab. But when we give ipilimumab at a lower dose and frequency, it seems to be better tolerated and there is a signal there for enhanced response rates. This is exciting preliminary data, but we’ll have to see where it actually falls out in the landscape of lung cancer treatment.It’s what we have. There’s a variety of immunohistochemistry antibodies and platforms for PD-L1 testing. Essentially, every PD-1 or PD-L1 checkpoint on the market has its own companion or complimentary diagnostic. So far the one that is really coupled with use of the drug is pembrolizumab (the 22c3 antibody). For patients in the first-line setting, they had to have ≥50% of PD-L1 expression with that particular antibody. Even in the second-line setting, and beyond, that drug is tied to positive expression, so they have to at least express a threshold of 1%, whereas other immune checkpoint inhibitors like nivolumab and atezolizumab [Tecentriq] aren’t necessarily coupled to a companion diagnostic. It’s what we have, it’s not perfect. There are other things being examined, such as tumor mutation burden, but I think PD-L1 will probably evolve.I think there is a lot of excitement about immunotherapy, but I still think we always need to proceed with caution. It’s important to recall for first-line treatment with immunotherapy, the only drug we have available in that line is pembrolizumab. In that setting it’s a good first-line treatment for those patients that meet the eligibility criteria. We also have to be cautious with patients who have a history of autoimmune disease—whether that’s from arthritis, lupus, or ulcerative colitis—to make sure that we engage with those specialists who are managing the patients for their autoimmune diseases because we are giving them immune checkpoint inhibitors that rev up the immune system and could exacerbate those autoimmune disease. It’s not an absolute contraindication to use these drugs for patients with these comorbid conditions, but we need to proceed with caution.

Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.