Analysis of Randomized Clinical Trials Show Improved Survival with Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy for NSCLC

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An analysis of eight randomized clinical trials (RCTs) found that the use of neoadjuvant platinum-based immune checkpoint inhibitors (ICIs) combined with chemotherapy produced improvements in two-year event-free survival (EFS) and pathologic complete response (pCR) in patients with early-stage non–small cell lung cancer (NSCLC). The study, published by JAMA Network Open, noted that approximately 50% of total NSCLC cases are diagnosed at an early stage, for which surgical resection is a viable treatment option. Further, 20% of these cases have stage I or II disease, whereas 30% have stage IIIA or IIIB disease.

“Neoadjuvant (ICIs) can improve the surgical resectability of tumors and decrease the risk of distant relapse,” the study authors wrote. “(RCTs) have investigated the use of neoadjuvant ICIs in combination with platinum-based chemotherapy (ICI-chemotherapy) in resectable NSCLC, demonstrating a prolongation of event-free survival (EFS) and a significant increase in pathologic complete response (pCR). The latter is recognized as a potential surrogate for overall survival (OS).”

However, the study authors said that it is unclear whether adjuvant postoperative ICI therapy is necessary for all patients administered neoadjuvant ICI-chemotherapy. They also noted a lack of clarity regarding the required amount of preoperative ICI-chemotherapy. As such, the investigators performed a meta-analysis of RCTs evaluating neoadjuvant ICI-chemotherapy with or without adjuvant ICIs to determine the benefit of neoadjuvant ICI-chemotherapy in EFS and pCR in patients with early-stage NSCLC. They also analyzed the impact of clinical, pathologic, and treatment-related factors on the findings.

Data were extracted from full-text articles and abstracts in EMBASE, PubMed, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews through November 1, 2023, in addition to data from oncology conferences from January 1, 2008, to November 1, 2023. These included Phase II or III RCTs using neoadjuvant ICI-chemotherapy, with or without adjuvant ICIs, compared with neoadjuvant chemotherapy alone, with or without placebo or observation, in patients with previously untreated NSCLC staged IB to IIIB.

The primary outcomes were two-year EFS and pCR in the experimental arm comprised of patients administered neoadjuvant ICI-chemotherapy compared with the control arm comprised of patients administered neoadjuvant chemotherapy alone.

The analysis ultimately consisted of eight trials that included 3387 patients. The investigators found that compared with the control arm, neoadjuvant ICI-chemotherapy produced improved two-year EFS and increased the pCR rate. This finding was not significantly affected by main patient characteristics; tumor- or treatment-related factors, such as PD-L1 status; the type of platinum-compound chemotherapy administered; the number of cycles of neoadjuvant ICI-chemotherapy; or the addition of adjuvant ICIs. Notably, patients with tumor cells that were negative for PD-L1 were found to have an increased risk of relapse compared with patients with low or high PD-L1.

“We estimated and quantified a consistent association between neoadjuvant ICI-chemotherapy and 2-year EFS and pCR across the 8 RCTs so far reported,” the study authors wrote. “This association was irrespective of patients’ clinical characteristics, tumor features, main prognostic factors, and type of platinum-based chemotherapy for the neoadjuvant chemoimmunotherapy regimen, although the [hazard ratios] varied in some subgroups.”

As far as limitations to the review and meta-analysis, the authors noted that it was based on published RCTs instead of individual patient data. Further, two-year EFS was used as a benchmark and surrogate endpoint for OS, whereas findings from the IFCT-0302 trial show that 66% of disease relapse cases reported in patients with early-stage NSCLC occurred within the first two years after surgery.

“In this systematic review and meta-analysis of neoadjuvant ICI-chemotherapy RCTs in patients with early-stage NSCLC receiving neoadjuvant ICI-chemotherapy, neoadjuvant ICI-chemotherapy was associated with improved 2-year EFS and pCR,” the study authors wrote. “This association was not significantly modified by the main patient characteristics or tumor- or treatment-related factors, including high or low tumor PD-L1 status.”

Reference

Banna GL, Hassan MA, Signori A, et al. Neoadjuvant Chemo-Immunotherapy for Early-Stage Non–Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024;7(4):e246837. doi:10.1001/jamanetworkopen.2024.6837.