Charu Aggarwal, MD, MPH

Charu Aggarwal, MD, MPH, discussant of the CHOICE-01 trial, underscored the “tremendous progress” that’s been made over the past 2 decades in the management of metastatic non–small cell lung cancer, with overall survival increasing from less than 1 year with the use of combination chemotherapy to more than 2 years with the integration of immunotherapy.

“Long-term outcomes confirm that we are making a meaningful difference in overall survival,” said Dr. Aggarwal, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Associate Director of Penn Center for Precision Medicine, Abramson Cancer Center, University of Pennsylvania. “The 5-year survival rates are greater than 30% now for patients diagnosed with stage IV disease, and multiple trials confirm our current practice of integrating chemotherapy with immunotherapy.”

According to Dr. Aggarwal, several clinical trials have formally established the practice of using chemoimmunotherapy, including quadruplet regimens, since the initial success of immunotherapy in 2016. Thus, additional trials incorporating new PD-1 or PD-L1 agents and comparing them with the standard chemotherapy doublet do not provide an incremental benefit and do not move the field forward, she explained.

Should Progression-Free Survival Be a Primary Endpoint?

Dr. Aggarwal also questioned the role of progression-free survival as a primary endpoint, given a weak correlation with overall survival hazard ratios.

“In a recent perspective piece in The Lancet,¹ Gyawali et al asked us to critically think about whether the term progression-free survival may affect patient choices,” said Dr. Aggarwal. “After all, patients with advanced cancer want a treatment to improve survival to meaningfully impact quality of life. The authors propose replacing the phrase ‘progression-free survival’ with ‘progression-free interval,’ so we may better dissociate survival from this endpoint.”

What Next?

Given the abundance of PD-1 and PD-L1 agents available, Dr. Aggarwal said that head-to-head trials are needed to demonstrate improved efficacy or tolerability of one immune checkpoint inhibitor. With respect to safety, however, Dr. Aggarwal noted that immune-related adverse events are a class effect and that many agents have similar adverse-event profiles.

“We must focus on innovation that moves the needle in terms of efficacy, tolerability, and cost,” she said. “If a drug has a cost advantage, for example, it will drive up competition and drive down health-care costs, which may be meaningful to the society as a whole.”

Dr. Aggarwal also emphasized the need to ensure equitable access to novel agents. Although PD-1 and PD-L1 monoclonal antibodies have spread globally since their initial introduction, important gaps in utilization exist. “One of the ways to ensure [equitable access] is by using multiregional clinical trials with diverse populations and coordinated worldwide regulatory submissions to ease this inequity,” said Dr. Aggarwal.

The Role of Biomarkers

Finally, Dr. Aggarwal highlighted the role of biomarkers in identifying patients who may benefit from immunotherapy—or potentially be harmed by it. The combination of tumor mutational burden (TMB) and T-cell–inflamed gene-expression profile (GEP), for example, may help categorize patients and stratify treatment.

“Patients with low GEP and low TMB tumors have almost a 0% response rate to immunotherapy,” said Dr. Aggarwal. “Armed with this knowledge, we can better design clinical trials to help these patients achieve a higher response rate, which may translate into improved survival outcomes.”

Biomarkers such as circulating tumor DNA serial monitoring may also correlate with radiographic outcomes and overall survival, said Dr. Aggarwal, enabling providers to escalate or de-escalate treatment depending on response.

“Now that we’ve established a good standard of care [with chemoimmunotherapy], we must strive to use this as the control arm and build upon this standard for our patients without actionable mutations,” Dr. Aggarwal concluded. “We must also integrate biomarkers in the future to better inform both trial design and how we follow patients.” 

DISCLOSURE: Dr. Aggarwal reported financial relationships with Genentech, Lilly, Celgene, Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo/AstraZeneca, Regeneron/Sanofi, Eisai, BeiGene, Turning Point Therapeutics, Pfizer, Janssen, and Boehringer Ingelheim.

REFERENCE

1. Gyawali B, Eisenhauer E, Tregear M, et al: Progression-free survival: It is time for a new name. Lancet Oncol 23:328-330, 2022.