Meta-Analysis Supports Immune Checkpoint Inhibitors in Frontline NSCLC Treatment

A systematic review and meta-analysis of 19 randomized controlled trials (RCTs) evaluated and ranked frontline immune checkpoint inhibitor (ICI)-based regimens for non–oncogene-addicted non–small cell lung cancer (NSCLC).

NSCLC is the most common type of lung cancer worldwide, and the advent of immunotherapy significantly expanded a treatment landscape that was previously centered on traditional chemotherapy. Personalizing therapy based on relevant biomarkers is now recommended in current treatment guidelines, and there are several targeted options that may improve outcomes for certain patients.

“First-line ICI regimen in non–oncogene-addicted NSCLC has been evaluated in various RCTs. However, the optimal treatment strategy is yet to be established,” the authors wrote. Their meta-analysis pooled data from 19 RTCs of 17 therapy regimens with a goal of determining the safety and efficacy of first-line ICIs when given alone and when paired with other ICIs or chemotherapy. The accompanying rankings may help guide clinical trial design and clinical decision-making.

The primary end points in the analysis were overall survival (OS) and progression-free survival (PFS), which were assessed via comparison between estimated HRs determined by stratified Cox proportional hazards models. Overall response rate (ORR) and treatment-related adverse events served as secondary end points.

ICI-based therapy, either alone or in combination with chemotherapy, was associated with better OS, PFS, and ORR outcomes in the all-comers NSCLC population. One exception was OS in patients with liver metastases. Specifically, combination pembrolizumab plus chemotherapy as well as cemiplimab monotherapy were ranked the highest overall among the regimens. In most subgroups, combination atezolizumab, chemotherapy, and bevacizumab ranked highest for PFS benefits but had a worse safety profile.

Patients with a programmed death-ligand 1 (PD-L1) expression of less than 1% experienced the best estimated OS when treated with nivolumab plus ipilimumab with or without chemotherapy. For those whose disease had 1% to 49% PD-L1 expression, pembrolizumab plus chemotherapy appeared to be the best option for OS. The best treatment for patients with a PD-L1 expression greater than 50% seemed to be cemiplimab when it came to OS.

Pembrolizumab with or without chemotherapy was ranked first for OS in nonsquamous (NSQ) NSCLC, similar to the all-comers cohort. However, patients with NSQ disease on cemiplimab showed less OS and PFS improvement than patients in the all-comers cohort showed on cemiplimab.

For patients with squamous disease, more research is needed to provide insight into the best treatment regimen. However, one takeaway from the meta-analysis is that a regimen of nivolumab plus ipilimumab with or without chemotherapy showed better OS and PFS results in the population with squamous than the same ICI combination in the all-comers population. Therefore, nivolumab plus ipilimumab may hold potential in this subset of patients.

Compared with chemotherapy, all of the ICI regimens showed improvements in OS and PFS in patients who had brain metastases. In NSCLC, brain metastases are a common metastatic site and are associated with poor outcomes and significant morbidity. Still, data on patients with non–oncogene-addicted NSCLC with brain metastases is limited. In the analysis, combination nivolumab, ipilimumab, and chemotherapy ranked higher than in the overall population, which aligns with findings in the melanoma setting. Cemiplimab appeared to impact OS most significantly in the context of brain metastases.

Overall, the meta-analysis confirms that ICIs could potentially play a key role in frontline NSCLC treatment and identifies multiple combinations that hold promise is more specific settings. The findings also emphasize the importance of tailoring treatment to the individual, as ICI regimens ranked differently depending on the NSCLC cohort.

“In the absence of head-to-head RCTs, these findings define the current scenario and therefore could be of help to provide recommendations for clinical practice in selecting the optimal first-line strategy in different conditions and offer valuable information for the design of future research,” the authors concluded.

Reference

Siciliano MA, Caridà G, Ciliberto D, et al. Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer: a systematic review and meta-analysis. ESMO Open. Published online April 12, 2022. doi:10.1016/j.esmoop.2022.100465