A meta-analysis of five clinical trials, encompassing 2385 patients, indicates that adding adjuvant PD-1 or PD-L1 inhibitors to neoadjuvant chemoimmunotherapy does not significantly improve event-free survival (EFS) or overall survival (OS) in patients with resectable non-small cell lung cancer (NSCLC). The research, published in JAMA Network Open, also highlights an increased incidence of treatment-related adverse events (TRAEs) with the combined neoadjuvant-adjuvant approach. These findings challenge the necessity of adjuvant immunotherapy following neoadjuvant chemoimmunotherapy in this patient population.
The study, led by researchers, aimed to resolve the controversy surrounding the optimal timing of PD-1/PD-L1 inhibitor administration in resectable NSCLC. While neoadjuvant chemoimmunotherapy has demonstrated improved pathologic response and survival rates, the added benefit of adjuvant immunotherapy remained unclear. The meta-analysis compared three treatment strategies: neoadjuvant-adjuvant immunotherapy, neoadjuvant-only immunotherapy, and neoadjuvant chemotherapy alone.
Key Findings
Direct meta-analysis revealed significant improvements in EFS for both neoadjuvant-adjuvant and neoadjuvant-only immunotherapy compared to chemotherapy alone. However, indirect meta-analysis showed no significant difference in EFS (HR, 0.90; 95% CI, 0.63-1.30; P = .59) or OS (HR, 1.18; 95% CI, 0.73-1.90; P = .51) between the neoadjuvant-adjuvant and neoadjuvant-only immunotherapy groups. Furthermore, the addition of adjuvant immunotherapy significantly increased the incidence of any grade TRAEs (RR, 1.08; 95% CI, 1.00-1.17; P = .04).
"Our analysis indicates that neoadjuvant immunotherapy plus platinum-based chemotherapy might be a preferable treatment for patients with resectable NSCLC, sparing them from adjuvant immunotherapy, which increases financial burden and toxic effects while not improving survival outcomes," the authors stated.
Impact on Clinical Practice
The results suggest a potential shift in clinical practice, favoring neoadjuvant chemoimmunotherapy alone for resectable NSCLC patients. This approach could reduce the risk of TRAEs and lower healthcare costs without compromising survival outcomes. The study also underscores the importance of timing in immune checkpoint inhibitor administration, suggesting that neoadjuvant immunotherapy may elicit a more robust antitumor response when the primary tumor and tumor-draining lymph nodes are still intact.
Subgroup Analysis
Subgroup analysis revealed that patients treated with carboplatin-based chemotherapy experienced significantly inferior EFS with additional adjuvant immunotherapy (HR, 2.35; 95% CI, 1.02-5.44; P = .045). While other subgroups did not show statistically significant differences, there was a trend towards improved EFS with adjuvant therapy in patients who did not achieve pathologic complete response (pCR) from neoadjuvant therapy (HR, 0.82; 95% CI, 0.56-1.21; P = .32). These findings suggest that the extent of pathologic response at surgery could potentially guide adjuvant treatment strategies.
Safety Considerations
The meta-analysis highlighted a significant increase in TRAEs with the addition of adjuvant immunotherapy. The incidence of any grade TRAEs was significantly higher in the neoadjuvant-adjuvant group compared to the neoadjuvant-only group (RR, 1.08; 95% CI, 1.00-1.17; P = .04). This finding underscores the importance of carefully considering the potential risks and benefits of adjuvant immunotherapy in patients who have already received neoadjuvant chemoimmunotherapy.
Future Directions
While the current study discourages adjuvant immunotherapy for unselected patients who have received neoadjuvant chemoimmunotherapy plus chemotherapy, the authors emphasize the need for novel strategies to enhance the efficacy of neoadjuvant-only immunotherapy and to identify patient populations that may benefit from additional adjuvant therapy. High-dimensional multiomics investigations within the neoadjuvant treatment framework are warranted to achieve this goal. Clinical trials are also needed to assess the continuation of adjuvant immunotherapy versus observation for patients who do not achieve a pCR after neoadjuvant chemoimmunotherapy.
