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Immunotherapy Arrives in Stage III NSCLC, But Questions Remain

Kristi Rosa
Published: Monday, Nov 26, 2018

Thomas A. Hensing, MD
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.

In an interview with OncLive during the 2018 State of the Science SummitTM 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.

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

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.

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

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.

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.

Is there knowledge about which patients do not respond to 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.

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?

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

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.

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