A subset of non-small cell lung cancer (NSCLC) patients who discontinued immune checkpoint inhibitor (ICI) therapy due to immune-related adverse events (irAEs) continued to experience long-term disease control, according to a new study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
The multi-institutional research, led by senior author Dr. Mark Awad, chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, and first author Dr. Federica Pecci, a research fellow at Dana-Farber Cancer Institute, provides valuable insights for clinicians managing treatment-related toxicities.
Sustained Benefits After Treatment Discontinuation
In a cohort of 2,794 NSCLC patients treated with ICIs alone or in combination with other therapies, approximately 10% discontinued treatment due to immune-related adverse events. Among these patients, the median progression-free survival (PFS) after discontinuation was 12.7 months, while the median overall survival (OS) reached 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," explained Dr. Pecci.
The findings address a significant clinical dilemma in immunotherapy management. Between 3% and 12% of patients treated with a single ICI and up to 25% of patients on dual ICI combination therapy may need to discontinue treatment due to adverse events.
"When immunotherapy activates the immune system, the goal is to selectively target cancer cells. But this activation can also cause inflammation in other organs," said Dr. Awad. "Whenever we see these side effects, we question whether we should keep giving immunotherapy or if we need to stop treatment temporarily or permanently."
Treatment Duration Correlates with Outcomes
The researchers identified several factors associated with better outcomes after treatment discontinuation. Treatment duration before discontinuation emerged as a particularly important predictor:
- Patients treated for less than three months: median PFS of 6.2 months and OS of 21.7 months after discontinuation
- Patients treated for three to six months: median PFS of 13.9 months and OS of 42.7 months after discontinuation
- Patients treated for more than six months: median PFS of 25.8 months and OS of 86.9 months after discontinuation
Predictors of Prolonged Response
In multivariable analysis, the researchers identified several factors associated with longer post-discontinuation progression-free survival:
- High PD-L1 expression
- Complete or partial response (CR/PR) to treatment
- Treatment duration of either three to six months or more than six months before discontinuation
Factors associated with prolonged overall survival included:
- Nonsquamous histology
- Complete or partial response to treatment
- Treatment duration exceeding six months
Notably, the use of steroids or other immunosuppressants to treat immune-related adverse events did not negatively impact PFS or OS after discontinuation, suggesting these treatments do not compromise the anticancer response.
Clinical Implications for Treatment Decisions
"We identified clinical and pathological features that can help physicians better understand which patients can benefit longer without any additional treatment after discontinuing for toxicity," said Dr. Pecci. "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 adverse events, the management of moderate (grade 2) immune-related adverse events often presents a more nuanced challenge. The findings may help physicians provide patients with a clearer, more individualized assessment of their risk of disease progression after discontinuation.
The study had some limitations, including its retrospective design and potential biases related to treatment duration comparisons. The researchers employed landmark analyses and multivariable Cox regression models to mitigate these limitations and enhance the reliability of their findings.
The research was funded by the National Institutes of Health, with Dr. Awad disclosing consulting relationships with several pharmaceutical companies including Merck, Bristol Myers Squibb, Genentech, AstraZeneca, and others. Dr. Pecci reported no conflicts of interest.
Implications for Immunotherapy Management
This study provides reassurance to both clinicians and patients that discontinuing immunotherapy due to adverse events does not necessarily mean losing cancer control benefits. For many patients, especially those who have already responded to treatment and received therapy for longer periods, the immune system may continue to control the cancer even after treatment stops.
The findings could potentially influence treatment guidelines and clinical decision-making, particularly in cases where patients experience quality-of-life-impacting side effects but are concerned about stopping therapy. The predictive factors identified may help stratify patients according to their risk of progression after discontinuation, allowing for more personalized treatment plans.
