A new meta-analysis has found that adding PD-1/PD-L1 inhibitors to neoadjuvant chemotherapy significantly improves outcomes for patients with resectable non-small cell lung cancer (NSCLC). The study, published in January 2024 in BMC Cancer, provides strong evidence supporting the use of immunotherapy in the neoadjuvant setting for early-stage NSCLC.
The meta-analysis included data from 7 randomized controlled trials involving a total of 2,929 patients with resectable NSCLC. The trials compared neoadjuvant immunotherapy plus chemotherapy to neoadjuvant chemotherapy alone. The primary outcomes examined were event-free survival (EFS), overall survival (OS), pathological complete response (pCR), and major pathological response (MPR).
Patients who received neoadjuvant immunotherapy plus chemotherapy had significantly higher rates of pCR (RR = 5.9, p < 0.001) and MPR (RR = 2.88, p < 0.001) compared to those who received chemotherapy alone. More importantly, the addition of immunotherapy led to substantial improvements in long-term outcomes, with significant benefits seen in both EFS (HR = 0.58, p < 0.001) and OS (HR = 0.57, p = 0.001).
Subgroup analyses revealed some interesting patterns in terms of which patients derived the most benefit from neoadjuvant immunotherapy. The EFS benefit appeared to be greater in patients from Eastern countries (HR = 0.56) compared to Western countries (HR = 0.70). There was also a trend toward increasing benefit with higher PD-L1 expression levels, with hazard ratios of 0.76, 0.56, and 0.38 for PD-L1 TPS <1%, 1-49%, and ≥50% respectively. Patients with stage III disease seemed to benefit more than those with stage I-II disease. Notably, while smokers derived significant EFS benefit from immunotherapy (HR = 0.54, p < 0.001), non-smokers did not show a statistically significant improvement (HR = 0.68, p = 0.055).
The study authors concluded that neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy can significantly improve both short-term and long-term prognosis in patients with resectable NSCLC. They noted that the efficacy appears to be affected by various clinicopathological characteristics of patients.
This meta-analysis has several strengths, including its large sample size, focus on high-quality randomized controlled trials, and comprehensive subgroup analyses. However, there are some limitations to consider. As with any meta-analysis, there was some heterogeneity between the included studies in terms of specific immunotherapy agents used, chemotherapy regimens, and patient populations. The authors attempted to account for this by using random-effects models, but some differences may remain. Additionally, longer follow-up will be needed to fully assess the impact on overall survival.
Despite these limitations, this study provides compelling evidence supporting the use of neoadjuvant immunotherapy plus chemotherapy for resectable NSCLC. The significant improvements seen in pathological response rates, event-free survival, and overall survival suggest this approach could substantially improve outcomes for patients with early-stage disease.
The potential clinical impact of these findings is substantial. If widely adopted, neoadjuvant immunotherapy could increase the number of patients achieving pathological complete responses and potentially increase cure rates for early-stage NSCLC. The subgroup analyses also provide important insights that could help guide patient selection, with those who have higher PD-L1 expression, stage III disease, and a history of smoking appearing to derive the greatest benefit.
However, several questions remain that will need to be addressed in future research. The optimal duration of neoadjuvant therapy and whether adjuvant immunotherapy is necessary after surgery are still unclear. Additionally, biomarker studies to better predict which patients will respond to immunotherapy in the neoadjuvant setting are needed. The lack of benefit seen in non-smokers is also intriguing and warrants further investigation.
It's worth noting that this meta-analysis focused solely on PD-1/PD-L1 inhibitors. As new immunotherapy agents and combinations emerge, studies examining their efficacy in the neoadjuvant setting will be important. Additionally, cost-effectiveness analyses will be crucial to determine the value of this approach from a healthcare systems perspective.
In conclusion, this meta-analysis provides strong evidence supporting the use of neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy for patients with resectable NSCLC. The significant improvements seen in both short-term and long-term outcomes suggest this approach could become a new standard of care for many patients with early-stage disease. As with any major shift in treatment paradigms, careful patient selection and continued research will be crucial to optimizing outcomes. Nonetheless, these results represent an important step forward in improving cure rates for one of the most common and deadly cancers worldwide.
References
Zhang W, Dai T, Wang D, Zhu Y, Hua W. Efficacy of neoadjuvant PD-1/PD-L1 inhibitor in resectable NSCLC: a meta-analysis based on randomized controlled trials. BMC Cancer. 2024;24(1):1522. Published 2024 Dec 18. doi:10.1186/s12885-024-13311-5
