Bottom Line: A subset of patients with non-small cell lung cancer (NSCLC) who discontinued immune checkpoint inhibitor (ICI) therapy due to immune-related adverse events (irAEs) continued to experience long-term disease control.
Journal in Which the Study was Published: Clinical Cancer Research , a journal of the American Association for Cancer Research (AACR)
Authors: Senior author Mark Awad, MD, PhD , chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, and first author Federica Pecci, MD, a research fellow at Dana-Farber Cancer Institute
Background: Immune checkpoint inhibitors have revolutionized the treatment landscape for NSCLC, offering significant survival benefits in both early-stage and advanced disease. However, by stimulating the immune system, ICIs can cause irAEs, such as pneumonitis, colitis, and hepatitis, which can also lead to permanent treatment discontinuation.
"When immunotherapy activates the immune system, the goal is to selectively target cancer cells. But this activation can also cause inflammation in other organs," Awad said. "Whenever we see these side effects, we question whether we should keep giving immunotherapy or if we need to stop treatment temporarily or permanently."
Between 3% and 12% of patients treated with a single ICI and up to 25% of patients treated with dual ICI combination therapy may need to discontinue treatment due to irAEs, Awad explained. Many of these patients face concerns about whether their cancer will progress or recur if they stop treatment.
How the Study was Conducted: Awad and colleagues sought to characterize the outcomes of patients with NSCLC who discontinued ICIs. They also evaluated clinical and pathological characteristics that were associated with longer PFS and OS after discontinuation.
Results: In a multi-institutional cohort of 2,794 patients who were treated with ICIs alone or in combination with other therapies, approximately 10% discontinued treatment due to irAEs; among these patients, the median post-discontinuation progression-free survival (PFS) was 12.7 months, and the median post-discontinuation overall survival (OS) was 43.7 months.
"These outcomes suggest that patients can experience prolonged disease control and survival after stopping treatment due to toxicity or if side effects are impacting their quality of life," Pecci said.
Among patients who received treatment before discontinuing for less than three months, between three and six months, and more than six months, the median PFS after discontinuation was 6.2 months, 13.9 months, and 25.8 months, respectively; the median OS after discontinuation was 21.7 months, 42.7 months, and 86.9 months, respectively.
In a multivariable analysis, predictors of longer post-discontinuation PFS included high PD-L1 expression, a complete or partial response (CR/PR) to treatment, and a treatment duration of either three to six months or more than six months before discontinuation. Furthermore, factors associated with prolonged post-discontinuation OS were nonsquamous histology, CR/PR to treatment, and a treatment duration exceeding six months.
The use of steroids or other immunosuppressants to treat irAEs was not associated with a difference in PFS or OS after discontinuation in the study, suggesting that such treatments may not jeopardize the anticancer response.
Author's Comments: "We identified clinical and pathological features that can help physicians to better understand which patients can benefit longer without any additional treatment after discontinuing for toxicity," Pecci said. "Our study can serve as a valuable resource to support clinicians in the complex considerations of treatment discontinuation for irAEs."
While discontinuation is clearly warranted in cases of severe irAEs, the management of grade 2 irAEs often presents a more nuanced challenge for clinicians. These findings may help physicians provide patients with a clearer, more individualized assessment of their risk of disease progression, Pecci said, taking into account factors such as treatment duration before discontinuation, response to therapy, and other clinicopathologic characteristics.
Study Limitations: Limitations of this study include its retrospective design, which could be hindered by missing or inaccurate data annotations. Additionally, comparisons based on treatment duration before discontinuation may be confounded by an overrepresentation of long-term responders in the longer-duration groups. To mitigate this, landmark analyses and multivariable Cox regression models were used to help reduce potential biases and enhance the reliability of the findings.
Funding & Disclosures: Funding for this study was provided by the National Institutes of Health. Awad has served as a consultant for Merck, Bristol Myers Squibb, Genentech, AstraZeneca, Blueprint Medicines, Synthekine, AbbVie, Gritstone bio, Mirati Therapeutics, Regeneron, Affini-T Therapeutics, and EMD Serono and has received institutional funding from Bristol Myers Squibb, Eli Lilly and Company, Genentech, AstraZeneca, and Amgen. Pecci reports no conflicts of interest.
