'Urgent' Need to Understand Immunotherapy
De-escalation in NSCLC

Liam Davenport

September 17, 2021

A growing body of research suggests there may be an optimal duration of immunotherapy for patients with non-small cell lung cancer (NSCLC), after which it can be de-escalated or discontinued to minimize toxicity and costs while maintaining long-term efficacy.

However, the research to date does not provide a clear picture of which patients will achieve this "exceptional and durable response" and at which point patients can safely reduce or withdraw from treatment, according to Yasushi Goto, MD, PhD, a staff doctor in the Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Goto presented the latest evidence and explored the current unknowns surrounding immunotherapy de-escalation in NSCLC in a session this week at the virtual World Conference on Lung Cancer.

In addition to a toxicity and quality-of-life benefit for patients, immunotherapy de-escalation could have a significant impact on the costs of care, Goto stressed. The rising cost of new cancer treatments represents a "crisis" in terms of the affordability of healthcare, he said, and reducing these costs represents an "urgent global issue."

Evidence on Discontinuing Treatment

Goto kicked off the session by emphasizing how drastically immunotherapy has enhanced outcomes for patients with NSCLC and other cancers.

This success has brought a pressing clinical question to the forefront: How long should we treat patients with immunotherapy?

The question arose over 10 years ago when ipilimumab (Yervoy) was granted  FDA approval for patients with metastatic melanoma, but only for a total of four doses because of the drug's toxicity.

"However, some patients had very lasting efficacy with the drug, even after discontinuation," Goto said, which raised the exciting prospect that patients could achieve a functional cure with immunotherapy.

Evidence highlighting this lasting effect among patients with NSCLC soon emerged as well. A 2015 study, for instance, indicated that, despite toxicities, 50% of patients receiving nivolumab (Opdivo) continued to have a treatment effect more than 9 months after their last dose.

A 2021 analysis of patients receiving pembrolizumab (Keytruda) found that 48% of patients were disease-free after 5 years, despite having discontinued treatment after 2 years.

These investigators also found that toxicities accumulated over time — new grade ≥3 toxicities occurred in 10% of patients every 6 months — which makes it particularly important to consider limiting the duration of therapy, Goto noted.

Only one randomized study to date — the CheckMate 153 trial — has explicitly explored outcomes associated with discontinuing immunotherapy in patients with NSCLC. In this study, patients still receiving nivolumab after 1 year were randomized to continue or stop therapy. Both median progression-free survival and overall survival were significantly longer in patients who continued therapy vs those who stopped at 1 year.  

However, Goto noted that limitations in the study design, including the fact that many patients were censored at an early stage, made the results "nonconfirmatory" and he would like to see more data.

The Role of Re-treatment

Finding the optimal time to discontinue treatment is critical, but even if patients stop treatment before they achieve long-lasting benefits, they can still be retreated successfully.

Two recent studies examined the potential benefits of re-treatment. In the 2021 KEYNOTE-010 analysis, 21 patients received a second course of pembrolizumab, at a response rate of 53% and a disease control rate of 81%.

In another recent study, investigators found that among 78 patients with melanoma who had discontinued either nivolumab or pembrolizumab and were re-treated after disease progression, 15% (5 of 34) receiving a single anti-PD-1 agent responded to retreatment and 25% (11 of 44) escalated to nivolumab plus ipilimumab exhibited a response.

Goto noted that there are also ongoing randomized studies examining the optimal duration of immunotherapy in advanced melanoma. One that he is involved in, the SAVE study, is enrolling patients with advanced NSCLC who have responded to anti-PD-1 agents for over a year and will compare overall survival in those who stop therapy vs those who continue. In addition, given the "growing importance" of biomarkers as a prediction tool, Goto plans to integrate circulating tumor DNA testing to help identify patients more likely to benefit from therapy discontinuation.

If successful, such approaches could "disruptively decrease prescribing costs," by lowering doses or dose frequency, shortening the treatment duration, or by substituting therapies with fewer adverse effects, Goto said.

Discussing De-escalation in Practice

During the discussion period after his talk, session co-chair Loretta Erhunmwunsee, MD, City of Hope Comprehensive Cancer Center, in Duarte, California, asked Goto what his current practice is in regard to de-escalation.

He replied that, in Japan, physicians are allowed to continue immunotherapy beyond 2 years, but "many patients stop their immune checkpoint inhibitor due to toxicity," even if it is minor.

Exploring evidence surrounding the optimal duration of therapy, session co-chair Bishal Gyawali, MD, PhD, Queen's University, Kingston, Canada, pointed to collaborative studies in colon cancer that looked at chemotherapy duration, for example looking at 3 vs 6 months of treatment.

Gyawali wondered whether the same could be achieved in lung cancer to test the non-inferiority of shorter duration of immunotherapy vs continuing treatment until disease progression.

Goto noted that the biggest difference in the current context of NSCLC is the toxicity incurred by both the adjuvant chemotherapy and the immunotherapy, making the overall benefit to the patient "very difficult to show." Consequently, patients may not be willing to join a randomized trial in which they could experience additional toxicity for uncertain benefit.

City of Hope oncologist H. Jack West, MD, who presented at the session, said he would "love to see more trials looking at de-escalation and seeing whether we do just as well on efficacy with lower toxicity and lower costs."

Instead, "we are seeing reports of the fourth entrant into the field that just recapitulates things we already know," which is "terribly disappointing."

"I really wish we could vote with our feet more, and not participate in trials that are completely redundant compared to what we've had for years already," West said.

No funding for this study was declared. Goto disclosed relationships with AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Guardant Health, Illumina, Kyorin, MSD, Novartis, Ono Pharmaceutical, Pfizer, Shionogi Pharma, and Taiho Pharmaceutical. West disclosed relationships with AstraZeneca, EQRx, Genentech/Roche, Merck, Mirati, Regeneron, and is a regular contributor to Medscape Oncology.

IASLC World Conference on Lung Cancer 2021: Session ES13. Presented September 14, 2021.

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