Expert Details Immunotherapy Developments in Lung Cancer

Charles M. Rudin, MD, PhD

The approval of durvalumab (Imfinzi) for stage III non—small cell lung cancer (NSCLC) was one of the key immunotherapy advances in the field thus far in 2018, and continues to set the stage for future immunotherapy agents and combinations, says Charles M. Rudin, MD, PhD.

Biomarker development is a critical component to further advances with anti—PD-1/PD-L1 agents, given that PD-L1 has been deemed an imperfect biomarker by many experts in the field, added Rudin. This imperfection is highlighted by results of multiple trials demonstrating that patients with low or no PD-L1 expression detected on their tumors are still responding to PD-1/PD-L1 inhibitors.

“If there's benefit in immunotherapy administration in the arm with [PD-L1] negative populations, even if the relative benefit is smaller, that may be a good rationale for use in those contexts if the patients who respond have durable responses—that is long-term progression-free survival (PFS),” said Rudin, who is chief Thoracic Oncology Service, co-director of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center.

OncLive: Please provide an overview of your presentation.

What are the data behind single-agent approaches?

After durvalumab’s success, what other immunotherapies are being explored in the stage III setting?

What combination approaches are being explored?

How reliable are biomarkers in determining response to immunotherapy?

What is an area that you would like to see addressed in this landscape?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Rudin discussed ongoing developments with immunotherapy in patients with NSCLC.Rudin: I spoke about immunotherapy for metastatic and stage III lung cancer. This is a rapidly changing area in which the indications are broadening. One of the current indications is single-agent PD-1 checkpoint inhibitor pembrolizumab (Keytruda) in the first-line setting for those patients whose tumors express at least 50% positivity for PD-L1. There is a lot of interest in pushing forward beyond single-agent immunotherapy to either combination immunotherapy or immunotherapy in combination with chemotherapy.Striking data for first-line therapy came from a trial that enrolled patients with PD-L1 expression greater than 50% to either pembrolizumab or the preexisting standard of care for that patient population, which is first-line platinum-doublet chemotherapy. That trial clearly demonstrated improvement in survival for the patients who received pembrolizumab. PACIFIC demonstrated the impact of immunotherapy after chemoradiotherapy in patients with unresectable stage III disease. We don’t have survival data for that yet, but we have PFS data which look remarkably good, suggesting a clear benefit for the use of durvalumab in that context. There is going to be additional exploration of other immunotherapies in that context. That was clearly the first benchmark. We will wait to see what the overall curve looks like, but there is always room for improvement. There are many ongoing clinical trials combining potentially synergistic combinations, such as immunotherapy with either chemotherapy or with radiation therapy. There have been preclinical data suggesting combinatorial efficacy of those approaches. Immunotherapy in combination with radiation is also an interesting approach that is being explored in multiple trials.None of the biomarkers we have for immunotherapy are perfect. They all enrich the probability of response. PD-L1 is certainly one of those factors that can enrich for the likelihood of response. Tumor mutational burden is the other one that a lot of people are now adopting as a strategy for enrichment. It's hard to know how the field will play out.Small cell lung cancer is an area where we have not had good targeted therapies or substantial advances in therapeutics over several decades. There is a real opportunity to make a lasting difference for patients with this particular form of lung cancer.