Immunotherapy Arrives in Stage III NSCLC, But Questions Remain

Thomas A. Hensing, MD

Although an optimal treatment approach has yet to be identified for patients with stage III non—small cell lung cancer (NSCLC), Thomas Hensing, MD, explained that significant progress has been made with the introduction of immunotherapy agents to the field.

“More recently, we’ve made a big step forward in terms of what we can offer patients,” said Hensing, co-director of the Thoracic Oncology Program at NorthShore University HealthSystem. “We’re seeing that translates not only into longer survival, but an increase in the number of patients with stage III disease who are being cured. It is definitely a very promising time in terms of having new treatments to offer patients.”

One of the landmark studies that opened the door to the use of immunotherapy is the PACIFIC trial, which served as proof of principle that the PD-L1 inhibitor durvalumab (Imfinzi) can benefit unresectable patients with stage III disease. This study was the basis for the February 2018 FDA approval of durvalumab for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy.

In PACIFIC, patients treated with durvalumab following chemoradiotherapy demonstrated a 24-month overall survival (OS) rate of 66.3% (95% CI, 61.7%-70.4%) versus 55.6% (95% CI, 48.9-61.8) in those who received placebo (two-sided P = .005).^1,2

The standard treatment approach for these patients with cancer that cannot be surgically removed is chemoradiation; however, only a small number of patients have been cured using this therapy. Up to 89% of patients will progress to metastatic disease after chemoradiation, and so, having a new treatment option available to prolong time without disease progression is a significant step in the right direction, Hensing added.

OncLive: What are the currently available treatment options for patients with stage IIIa NSCLC?

What trials have evaluated the use of immune checkpoint inhibitors in this population?

In an interview with OncLive during the 2018 State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Hensing discussed the emergence of immunotherapy in the stage III NSCLC armamentarium, and questions that must be answered to build on this initial success.Hensing: For most patients who come in with stage III disease—a disease that’s locally advanced within the chest—we treat it with a combination of modalities. Most patients will likely be treated with some kind of chemotherapy and radiation. The biggest new addition to that is now—at least for some patients—immune checkpoint inhibitors that have recently been shown to significantly improve OS.A significant landmark study that was just published was the PACIFIC trial. In that study, they randomized patients who came in with stage III disease that was not operable; these patients had received chemotherapy and radiation and were randomized to 1 year of durvalumab versus placebo. What they showed last year was that the progression free survival (PFS) rate in patients improved significantly by more than 11 months.

Is there knowledge about which patients do not respond to durvalumab?

What investigators presented at the 19th World Conference on Lung Cancer and was published in the New England Journal of Medicine was the OS data, which were significantly in favor of durvalumab.One of the common biomarkers that we test for is called PD-L1, and that testing was done on the majority of patients on the study, but it was not required. Therefore, for about one-third of patients who were on the study, we don’t have information pertaining to their PD-L1 status. The authors did go back and look at the benefit based on expression of PD-L1, but the trial itself was designed as an all-comers study, and the benefit was seen across the board.

What are the next steps with immunotherapy research in this setting?

Based on some post-hoc analyses, the question came up about whether patients whose tumors don’t express PD-L1 truly benefit from this approach. That would be one area that we’re going to need to know that about our patients, and that’s definitely one subset for whom we really need to continue to put on clinical trials to decide on the best approach. For those patients who don’t have tumors with PD-L1 expression, should we be doing something different?We will all look at the PACIFIC trial as the landmark study that served as proof of principle that this strategy can help patients. As beneficial as it was, we’re still not curing everybody, so there’s still room for improvement and a lot of questions that remain to be answered. This is step one, but it is definitely a significant step in the right direction.

Are there any other factors that need to be considered with this approach?

We need to find out: what else can we do for those patients who are not benefiting from this approach? Do we need to combine different types of immunotherapy? Can we give immunotherapy differently? Can we give it before or during radiation—will that be helpful? There are a lot of questions that are out there, and a significant amount of research is happening, so my sense is, we are going to see these answers pretty quickly.Not so much specific to durvalumab, but any time you add a medication, you need to consider toxicity. What are the added adverse events (AEs)? For the most part, they were manageable for the majority of patients. One of the key things, when you add an immune checkpoint inhibitor, is it opens the door to AEs that are unique to that class of agents.

On the one hand, they’re very beneficial; on the other, it’s incumbent upon those who are treating patients that they really understand how to manage those AEs. The key to management is early diagnosis and appreciating what can happen with these agents. As long as people are comfortable at managing those AEs, they are manageable, but the key is early diagnosis.

Moving forward, what challenges need to be addressed?

It’s not [just the responsibility of the] oncologist; these patients are seeing their primary care physicians. Perhaps they’re seeing other specialists, and we really need to train all of our colleagues in our health systems about how to recognize AEs that come from this class of agents. We are going to see [the use of these agents] more and more and we’re going to ask our colleagues, help us manage these patients, and identify if they have one of these AEs early.The key thing is that the PACIFIC trial was clearly a significant step forward. We got here because of the PACIFIC trial. We had patients participating in a study, we made it available to them, and there are a number of trials that are happening. We need to work to get these patients on trials and make these studies readily available no matter where patients live; this is so they can participate in the next generation of studies that are following up on lessons learned from PACIFIC, but are also starting to explore some other questions. We are all excited about what we saw on PACIFIC, but I don’t think we should stop or rest there. We need to continue to make trials available to our patients.

References

1. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: updated results from PACIFIC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.01.
2. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online ahead of print September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809697.