In most comprehensive meta-analysis to date comparing neoadjuvant chemoimmunotherapy and chemotherapy using randomised clinical trials data, neoadjuvant chemoimmunotherapy was associated with improved overall survival (OS), event-free survival (EFS), major pathological response (MPR), and pathological complete response (pCR) compared with neoadjuvant chemotherapy. In addition, chemoimmunotherapy was associated with improved resectability and an increased rate of R0 resections, with a similar rate of adverse events.
This meta-analysis showed an improvement in EFS with neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy across age, sex, and histology (squamous versus non-squamous) groups of non-small cell lung cancer (NSCLC). There was an improvement for patients with stage II and stage III disease. Chemoimmunotherapy was associated with a benefit in EFS for all 3 categories for PD-L1 level although the OS benefit was restricted to the subgroup with a PD-L1 level of 1% or greater according to Dr. Jonathan D. Spicer of the Department of Surgery, McGill University in Montreal, Canada, and colleagues who published the findings on 21 March 2024 in the JAMA Oncology.
The authors wrote in the background that that the US Food and Drug Administration (FDA) approved in 2022 neoadjuvant nivolumab with platinum-doublet chemotherapy for patients with resectable NSCLC based on results of the phase III CheckMate 816 study. In 2023, the FDA approved neoadjuvant pembrolizumab in combination with platinum-containing chemotherapy for resectable NSCLC followed by single-agent pembrolizumab in the adjuvant setting across all PD-L1 strata after OS results were available from KEYNOTE-671.
However, the European Medicines Agency (EMA) approved nivolumab in combination with platinum-based chemotherapy in the neoadjuvant setting only in patients at high risk of recurrence and with tumour cell PD-L1 expression levels greater than 1%. This was based on an analysis showing no difference in EFS between neoadjuvant chemoimmunotherapy and chemotherapy in patients with PD-L1 levels less than 1% in CheckMate 816, with a decision still pending regarding results of KEYNOTE-671.
Existing meta-analyses of non-randomised clinical trials have described inconsistent results when comparing neoadjuvant chemoimmunotherapy with studies assessing other neoadjuvant treatment regimens. This highlights that the inclusion of single-arm studies results in indirect comparisons that are prone to high levels of bias due to interstudy heterogeneity in stage, sex, age, and histology. Recent randomised clinical trials of neoadjuvant chemoimmunotherapy are not captured by existing systematic reviews which prompted the authors of the article published in the JAMA Oncology to compare neoadjuvant chemoimmunotherapy and neoadjuvant chemotherapy in terms of adverse events and surgical, pathological, and efficacy outcomes in a larger number of patients through a meta-analysis of randomised and non-randomised clinical trials.
The authors systematically searched MEDLINE and Embase from 1 January 2013 to 25 October 2023 for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients. Study selection excluded observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy. Surgical, pathological, and efficacy endpoints and adverse events were pooled using a random-effects meta-analysis.
Among 43 eligible trials comprising 5431 patients of whom 4020 males [74.0%] and median age range of 55 to 70 years, there were 8 randomised clinical trials with 3387 patients. For randomised clinical trials, pooled OS (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.54-0.79; I2 = 0%), EFS (HR 0.59, 95% CI 0.52-0.67; I2 = 14.9%), MPR (risk ratio 3.42, 95% CI, 2.83-4.15; I2 = 31.2%), and pCR (risk ratio 5.52, 95% CI 4.25-7.15; I2 = 27.4%) favoured neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy.
For patients with baseline tumour PD-L1 levels less than 1%, there was a significant benefit in EFS for neoadjuvant chemoimmunotherapy compared with chemotherapy (HR 0.74; 95% CI 0.62-0.89; I2 = 0%). This finding has increased importance given the recent restriction by the EMA of neoadjuvant chemoimmunotherapy to patients with PD-L1 levels of 1% or greater.
Future studies should continue to assess the benefit associated with neoadjuvant chemoimmunotherapy by subgroup as OS matures. In addition, future studies may be able to assess whether the specific type of chemotherapy or immunotherapy is associated with outcomes for patients treated with neoadjuvant chemoimmunotherapy according to the authors.
In an accompanied editorial article, Drs. Christian Rolfo of the Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY, US and Alessandro Russo of the Department of Onco-Hematology, Papardo Hospital in Messina, Italy wrote that the results of the present meta-analysis show that the relative risk for both MPR and pCR was significantly increased for neoadjuvant chemoimmunotherapy in randomised clinical trials. Whether patients with pCR and/or MPR could benefit from deintensified regimens compared with those not reaching a pCR/MPR still remains unclear. Recently, liquid biopsy has emerged as a potential novel biomarker for minimal residual disease detection, identifying patients at higher risk of relapse after surgery and might be used for selecting patients to escalating or de-escalating therapeutic strategies.
References
- Sorin M, Prosty C, Ghaleb L, et al. Neoadjuvant Chemoimmunotherapy for NSCLC A Systematic Review and Meta-Analysis. JAMA Oncology; Published online 21 March 2024. doi:10.1001/jamaoncol.2024.0057
- Rolfo C, Russo A. The Chemoimmunotherapy Revolution in Resectable NSCLC—The Times They Are A-Changin’. JAMA Oncology; Published online 21 March 2024. doi:10.1001/jamaoncol.2024.0043