Highlights
• Among advanced NSCLC patients completing 2 years of pembrolizumab therapy, the 48-month overall survival rate reached 76.9%, demonstrating durable treatment benefits.
• Only 26.1% of patients required subsequent therapy after discontinuation, with chemotherapy and radiotherapy being the most common approaches.
• Immunotherapy rechallenge was exceptionally rare, occurring in just 0.1% of patients, suggesting that ongoing immunotherapy may not be necessary for all long-term responders.
• Radiotherapy as first subsequent treatment showed the highest 12-month survival rate at 87.0%.
Background
Immunotherapy has fundamentally transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), offering unprecedented survival benefits for a subset of patients. Pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor, has become a cornerstone of first-line treatment for patients whose tumors express programmed death-ligand 1 (PD-L1). Current standard practice recommends approximately 2 years of immunotherapy treatment for patients who achieve disease control and tolerate therapy well.
However, a critical knowledge gap exists regarding the optimal management strategy after completing the recommended 2-year immunotherapy course. While clinical trials have established the efficacy of pembrolizumab during the active treatment phase, little is understood about post-immunotherapy therapeutic strategies and long-term outcomes once treatment is discontinued. Questions remain about whether treatment-free intervals are safe, what proportion of patients will require subsequent therapy, and which treatment modalities offer the best outcomes when progression occurs.
Study Design
This nationwide, population-based, retrospective cohort study utilized administrative health data from the French National Health Insurance database. The study population included patients diagnosed with incident lung cancer between January 1, 2015, and December 31, 2022, who met specific treatment criteria.
Population and Treatment Criteria:
Patients were required to have received pembrolizumab for 22 to 26 months (approximately 2 years) and survived at least 29 months from treatment initiation. This landmark approach ensured adequate follow-up to assess outcomes after the planned immunotherapy duration. The data cutoff was October 31, 2024, with analysis performed in October 2025.
Key Endpoints:
The primary endpoint was overall survival (OS), defined as the time between the landmark (29 months) and death from any cause. Secondary endpoints included time to next treatment or death, calculated from the last pembrolizumab infusion to initiation of new treatment or death. The study specifically examined subsequent therapeutic management patterns following pembrolizumab discontinuation.
Statistical Analysis:
Survival analyses employed standard epidemiological methods, with median follow-up calculated using the reverse Kaplan-Meier method. All confidence intervals were reported at the 95% level.
Key Findings
Patient Population
From an initial cohort of 41,498 patients who received frontline pembrolizumab for advanced disease, 5,293 patients were alive at the landmark time and had completed 2 years of treatment. Of these, 1,555 patients discontinued pembrolizumab at the 2-year timepoint. The final study population comprised 1,480 patients who had at least 6 months of follow-up after discontinuation.
The patient characteristics demonstrated a relatively balanced distribution: median age was 63.0 years (range, 32.0-90.0), 537 patients (36.3%) were female, and 943 patients (63.7%) were male. Regarding initial treatment, 616 patients (41.6%) had received pembrolizumab monotherapy, while the remainder had received combination therapy.
Overall Survival Outcomes
After a median follow-up of 16 months (95% CI, 15.2-16.8) from the landmark timepoint, the study revealed remarkably favorable survival outcomes. The overall survival rate at 48 months was 76.9% (95% CI, 72.7%-81.3%), indicating that approximately three-quarters of patients who completed 2 years of pembrolizumab remained alive nearly 4 years from their initial treatment milestone.
This finding holds significant clinical importance, as it suggests that the benefits of pembrolizumab may extend well beyond the active treatment period. The sustained survival advantage likely reflects the establishment of durable immunological memory and potential immune-mediated tumor control even after treatment cessation.
Time to Next Treatment or Death
The time to next treatment or death at 48 months after pembrolizumab discontinuation was 49.9% (95% CI, 45.3%-55.0%). This metric captures the proportion of patients who either required subsequent therapy or experienced death, providing insight into the durability of treatment-free intervals. The finding that approximately half of patients remained treatment-free at 4 years demonstrates that many long-term responders can enjoy extended periods without systemic therapy, avoiding the cumulative toxicities associated with continued treatment.
Subsequent Treatment Patterns
Overall, 387 patients (26.1%) received subsequent therapy following pembrolizumab discontinuation. This relatively low proportion of patients requiring additional treatment aligns with the favorable survival outcomes observed in the study.
First Subsequent Treatments:
The distribution of first subsequent treatments revealed distinct patterns:
- Chemotherapy: 200 patients (51.7%)
- Radiotherapy: 183 patients (47.3%)
- Immunotherapy: 4 patients (1.0%)
Notably, chemotherapy and radiotherapy dominated the landscape of subsequent treatments, while immunotherapy-based approaches were rarely employed. This pattern likely reflects clinical awareness of potential reduced efficacy with rechallenge and concerns regarding cumulative toxicity.
Immunotherapy Rechallenge:
Perhaps the most striking finding was the rarity of immunotherapy rechallenge. Considering all subsequent treatment lines, only 19 patients (0.1%) received an immunotherapy rechallenge. This extremely low rate suggests that clinicians may be appropriately reserving immunotherapy rechallenge for selected cases where the potential benefits are perceived to outweigh the risks, or that evidence supporting rechallenge efficacy remains limited.
Outcomes by Subsequent Treatment Modality
Twelve months after initiation of new treatment following pembrolizumab discontinuation, survival rates varied substantially by treatment modality:
- Radiotherapy: 87.0% (95% CI, 81.6%-92.7%)
- Chemotherapy: 69.9% (95% CI, 61.1%-80.0%)
- Immunotherapy: 61.4% (95% CI, 41.3%-91.4%)
These findings should be interpreted cautiously due to potential selection biases inherent in observational data. Patients selected for radiotherapy may have had more favorable disease characteristics, such as localized progression amenable to focal treatment, while those requiring systemic chemotherapy or immunotherapy rechallenge may have had more aggressive or widespread disease. Nevertheless, the data provide valuable real-world insights into outcomes associated with different subsequent treatment strategies.
Expert Commentary
This retrospective cohort study provides crucial real-world evidence addressing a clinically relevant question: what happens to advanced NSCLC patients after they complete the standard 2-year course of pembrolizumab? The findings carry significant implications for clinical practice and future research directions.
Clinical Implications:
The high survival rates observed in this study support the current practice of limiting pembrolizumab treatment to approximately 2 years for patients who achieve disease control. The 76.9% 48-month survival rate demonstrates that discontinuing immunotherapy does not compromise long-term outcomes for most patients. This observation aligns with emerging understanding that the immunological effects of checkpoint inhibitors may persist well beyond the treatment period, potentially through mechanisms including establishment of immunological memory and ongoing immune surveillance.
The low rate of immunotherapy rechallenge (0.1%) reflects appropriate clinical caution in the absence of robust evidence supporting efficacy. This finding underscores the need for prospective studies evaluating optimal strategies for patients who progress after completing initial immunotherapy, including biomarker-driven approaches to identify candidates who might benefit from rechallenge.
Limitations and Considerations:
Several limitations merit consideration when interpreting these findings. The retrospective, observational design introduces potential confounding by indication, as patients selected for different subsequent treatments may have had inherently different prognoses. The study lacked detailed information on PD-L1 expression levels, tumor histology, and specific progression patterns, which could influence treatment decisions and outcomes. Additionally, the French healthcare system context may limit generalizability to other healthcare settings with different treatment patterns and access to therapies.
The variation in survival outcomes by treatment modality should not be interpreted as indicating superiority of radiotherapy over chemotherapy, given the likely selection biases. Patients with oligoprogressive disease may be ideal candidates for radiotherapy, while those requiring systemic therapy may have more advanced or aggressive disease requiring chemotherapy or immunotherapy approaches.
Future Directions:
This study highlights several important research gaps. Prospective trials are needed to establish optimal duration of immunotherapy, criteria for treatment discontinuation, and evidence-based strategies for managing progression after completing planned immunotherapy. Biomarker studies investigating predictors of durable response and progression patterns could enable personalized treatment duration decisions. Additionally, research into the immunological mechanisms underlying sustained treatment-free intervals may inform next-generation immunotherapy approaches.
Conclusion
This nationwide cohort study provides valuable real-world evidence regarding outcomes and treatment patterns among advanced NSCLC patients who completed 2 years of pembrolizumab therapy. The findings demonstrate that long-term survivors maintain favorable prognosis after immunotherapy discontinuation, with approximately three-quarters surviving at 48 months and fewer than one-third requiring subsequent treatment.
The rarity of immunotherapy rechallenge and the predominance of chemotherapy and radiotherapy as subsequent treatments suggest that current clinical practice appropriately limits repeated immunotherapy exposure. The differential survival outcomes by treatment modality highlight the need for careful patient selection and underscore the importance of individualizing subsequent treatment decisions based on disease characteristics, patient preferences, and available evidence.
These findings support continued use of fixed-duration immunotherapy for appropriate patients with advanced NSCLC while emphasizing the importance of shared decision-making and ongoing monitoring for signs of progression. As the population of NSCLC survivors completing immunotherapy continues to grow, optimizing post-immunotherapy management strategies will become increasingly important for maximizing long-term outcomes while minimizing treatment-related toxicities.
Funding and Disclosures
Study data were obtained from the French National Health Insurance database. The authors declare no conflicts of interest relevant to this study. No specific funding information was provided in the original publication.
References
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