Immunotherapy Revolutionizes NSCLC, But Unanswered Questions Remain

Edward B. Garon, MD

Immunotherapy has had a milestone impact in the field of non—small cell lung cancer (NSCLC). However, as more research unravels, investigators are unsure which set of combinations will likely have the most positive effect on their patients with advanced disease.

For example, pembrolizumab (Keytruda) plus combination chemotherapy with carboplatin/pemetrexed led to a priority review designation by the FDA in January 2017. Results of cohort G of the KEYNOTE-021 trial showed that the pembrolizumab triplet elicited an objective response rate of 55% versus 29% with the chemotherapy regimen alone (P = .0016). The median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy (HR, 0.53; 95% CI, 0.31-0.91; P = .010).

However, some physicians are skeptical, as this was a phase II trial with a smaller study size of 123 patients and the initial overall survival data, though immature, did not indicate a benefit for either arm.

Moreover, immunotherapy combinations—specifically PD-1 plus CTLA-4 inhibitors—are also on hold. In January 2017, Bristol-Myers Squibb announced a delay in the development of its nivolumab (Opdivo) and ipilimumab (Yervoy) combination until findings from the CheckMate-227 trial are available—a set of data oncologists are eagerly awaiting.

Within the same week, AstraZeneca announced modifications to its clinical development program for its regimen combining the PD-1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab, which has been adapted to included OS and PFS. PFS and OS findings are to be expected in mid-2017 and 2018, respectively.

OncLive: What is the current role of immunotherapy in NSCLC?

Reflecting on these announcements, Edward B. Garon, MD, director of Thoracic Oncology at the Jonsson Comprehensive Cancer Center at University of California, Los Angeles, discussed the challenges researchers are currently facing with immunotherapy in NSCLC and what the future likely holds for the pivotal agents. Garon lectured on immunotherapy in NSCLC during the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer.Garon: Obviously, this is an area that has evolved very rapidly and we finally have sort of hit a point where things are stable. However, now it looks like things may change again on some level. Of course, we are awaiting future data. For the last couple of years, we have had approved agents directed against PD-1 and a PD-L1 inhibitor, atezolizumab (Tecentriq).

The other big change is that we have spent a great deal of time over the last couple of years debating the value of PD-L1 as a biomarker. Although there is still much controversy, it has become clear that it is a biomarker that is here to stay. Now, we sort of have a clear paradigm, which is that patients who have staining for PD-L1 on at least half of their cells using the immunohistochemistry (IHC) 22C3 assay will be treated with pembrolizumab as their initial therapy.

In some ways, it is exciting that after much debate, we now have a clear paradigm. But, of course, as soon as that happens we have things looming on the horizon. The nearest term is the potential approval of combinations looking at chemotherapy plus a PD-1 inhibitor—in this case, pembrolizumab.

There is some controversy related to that data. At this point, it is clear that when one adds pembrolizumab to a chemotherapy backbone—in this case, carboplatin and pemetrexed—that the PFS is improved. The data on OS are immature but does not, at least to this point, indicate a survival benefit. That is going to be something that the field is going to grapple with over time: whether to look at the combination of chemotherapy and a PD-1 inhibitor or, whether to look at sequential therapy.

The other big, looming question, which we don’t have answers to yet, is what will happen to the immunotherapy plus immunotherapy combinations? The leading combination, at this point, is PD-1/PD-L1 plus a CTLA-4 inhibitor. There are a lot of data that have been generated to date. That data has not really been randomized and has been subject to several biases. However, we will soon be having randomized data that will help guide us as to whether this is going to be a treatment option.

What is the status of the clinical trial investigating durvalumab plus tremelimumab?

Last summer, we saw the disappointment with the CheckMate-026 findings on frontline nivolumab. What are your thoughts?

It would certainly be exciting if we are at the point where we can carefully manipulate the immune system—to a point where we can have therapies that can be combined in a way that is safe to enhance targeting of the tumor. Again, we need to see data before we have confidence that that will be the way to move forward.There are the 2 leading combinations that are soonest to give us the data: they are durvalumab plus tremelimumab and nivolumab and ipilimumab. Those are both combinations that have been evaluated in large studies, randomized data will become available but is not yet. There had been a raging debate in the field—the value of the PD-L1 biomarker—and in many respects, that was reflected in the 2 frontline studies. The frontline pembrolizumab study was focused on patients with PD-L1 staining on at least half of their cells. That ended up as a target marker of around one-quarter of patients with lung cancer. The enhancement strategy for the CheckMate-026 study looked at a much broader population of patients with at least a 5% PD-L1 cut point. Enrollment was based on the 1% cut point for PD-L1; the primary analysis was based on the 5% cut point, and that ended up encompassing the majority of patients with lung cancer.

What does the future of immunotherapy in NSCLC look like to you?

There was not success seen from combination chemotherapy; in some respects, that is the easy part of the story. As part of that study, using the complimentary diagnostic for nivolumab IHC 28-8, the group of patients with high levels of PD-L1 staining at that 50% cut point using that antibody also did not appear to have a benefit in PFS using nivolumab. The reasons for that are still somewhat unclear. In my estimation, there is a lot left to learn about the future of immunotherapy. This is a question that people ask me all the time: where do I think things will be? There is a range of things we could see.

On the optimistic side, we could see that the understanding of the immune system has greatly enhanced, that we are able to devise clever combinations that are able to deliver greater efficacy while minimizing toxicity. And, that we can find subsets of people who will benefit from different immune-oncology—based approaches. That would be the most positive.

The most negative [thing to see] would be to say that, regarding the PD-1/PD-L1 inhibitor experience, we will look 5 years down the road much like the erlotinib (Tarceva) experience did over 5 years. Here, there were many studies trying to add to erlotinib that were not successful. I certainly hope that is not the outcome. However, we sort of have to, as a field, be prepared for anything—between the most optimistic as well as the most pessimistic of the potential outcomes.

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.