Safe to Stop Immunotherapy at 2 Years in Stable Lung Cancer

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression-free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression-free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online on June 4 in JAMA Oncology to coincide with a presentation at the American Society of Clinical Oncology annual meeting.

Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders vs ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at the City of Hope outside of Los Angeles, California, noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our healthcare system,” he said.

Study Details

For their review, Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with upfront ICIs for 700 to 760 days (ie, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression-free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs] possible undertreatment,” as West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

Two-year overall survival from the 760-day mark was 79% in the fixed-duration group vs 81% with indefinite treatment, with no difference on either univariate (HR 1.26, P = .36) or multivariable (HR 1.33, P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well-balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend towards being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. West has a regular column on Medscape.com and reported personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

JAMA Oncol. Published online June 4, 2023. Full text; editorial.

ASCO Annual Meeting Abstract 9101. Presented June 4, 2023. Abstract.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected].

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