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Immunotherapy Revolutionizes NSCLC, But Unanswered Questions Remain

Gina Columbus
Published: Monday, Apr 24, 2017

Edward B. Garon, MD

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.

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.

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

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.


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