Comparative effectiveness of carboplatin/pemetrexed with versus without bevacizumab for advanced nonsquamous non-small cell lung cancer

Background

For patients with advanced non–small cell lung cancer (NSCLC) whose tumors do not harbor an actionable genomic alteration or have PD-L1 expression (tumor proportion score ≥50%), a platinum-based chemotherapy doublet remains a standard component of first-line therapy.^1,2 Multiple cytotoxic agents are recommended as partners for platinum based on clinical trial data and expert opinion,³ and the choice is often based on histology.³ Use of pemetrexed for nonsquamous tumors is supported by subgroup analysis of a 2008 randomized trial, which demonstrated superior overall survival (OS) in patients with nonsquamous histology who received cisplatin/pemetrexed compared with cisplatin/gemcitabine.⁴ Despite debate regarding interpretation of this trial,⁵ carboplatin/pemetrexed is the most commonly used first-line chemotherapy regimen in the United States for advanced nonsquamous NSCLC.^6,7

Although recent data have established that the addition of the immune checkpoint inhibitor pembrolizumab to first-line carboplatin/pemetrexed improves OS in advanced nonsquamous NSCLC regardless of PD-L1 expression,⁸ some patients are unable to receive PD-1 inhibitors because of preexisting autoimmune disease⁹ or lack of access.¹⁰ When these patients lack a targetable mutation, carboplatin/pemetrexed alone or with the antiangiogenic monoclonal antibody bevacizumab remains a relevant systemic regimen. Bevacizumab was initially approved for nonsquamous NSCLC in 2006 based on results of the randomized phase III ECOG 4599 trial, which demonstrated an OS advantage associated with addition of bevacizumab to carboplatin/paclitaxel.¹¹ Although results of the PointBreak trial showed that carboplatin/pemetrexed/bevacizumab yielded similar OS compared with carboplatin/paclitaxel/bevacizumab, but with less toxicity,¹² there has never been a randomized controlled trial (RCT) to demonstrate that OS is improved by adding bevacizumab to carboplatin/pemetrexed. Thus, despite frequent use of this regimen in clinical practice, current ASCO clinical practice guidelines state that there is insufficient evidence to recommend bevacizumab in combination with pemetrexed/carboplatin.² Because of this significant gap in the literature, we used nationally representative electronic health record (EHR) data from Flatiron Health to compare the effectiveness of first-line carboplatin/pemetrexed ± bevacizumab in patients with metastatic nonsquamous NSCLC. We also supplemented these data with our institutional experience to account for confounding clinical variables not captured in the Flatiron database.