Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer

Abstract

Purpose Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non‐small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first‐line treatment for advanced NSCLC. Materials and Methods Published and presented literature was searched using the key search terms “non‐small cell lung cancer” AND “checkpoint‐inhibitors” (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first‐line advanced NSCLC were identified. Results Four first‐line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab‐chemotherapy, atezolizumab‐chemotherapy, and atezolizumab‐bevacizumab‐chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor‐negative (EGFR−)/ anaplastic lymphoma kinase gene (ALK)− NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab‐chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab‐ipilimumab in all‐comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab‐chemotherapy administered based on PD‐L1 status and histology is a preferred treatment option. Outcomes for atezolizumab‐bevacizumab‐chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. Conclusion First‐line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR−/ALK− and squamous advanced NSCLC. Implications for Practice Single‐agent immune checkpoint inhibitors are now standard of care for advanced non‐small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE‐189 and IMPower‐130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE‐407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first‐line NSCLC. Programmed death ligand‐1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

Does Pemetrexed Work in Targetable, Nonsquamous Non-Small-Cell Lung Cancer? A Narrative Review

“…However, inconsistent results have been obtained with these agents when given as monotherapy for second-line treatment in patients with EGFR-positive disease [61][62][63][64], and it therefore remains to be determined whether they are appropriate for use in patients with driver mutations. Combining immune checkpoint inhibitors with pemetrexed could improve outcomes [65], providing a potential therapeutic option following the development of TKI resistance. Indeed, several ongoing clinical studies are assessing the benefits of such combination treatment in patients with EGFR-positive advanced nonsquamous NSCLC who progressed after TKI therapy [66][67][68].…”

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

“…Conventional cytotoxic chemotherapies promote anticancer immunity through the release of tumor-associated antigens and/or depletion of immunosuppressive cells ( 26 , 27 ). Chemotherapy regimens in tandem with ICIs have been extensively studied and have become treatment options for NSCLC, triple-negative breast cancer and urothelial carcinoma ( 28 – 31 ). Similar to chemotherapy, radiation treatment can augment the anticancer immune response through the release of tumor antigens and modulation of the TME ( 21 , 32 ).…”

Digital Pathology Analysis Quantifies Spatial Heterogeneity of CD3, CD4, CD8, CD20, and FoxP3 Immune Markers in Triple-Negative Breast Cancer

“…Recently, the Impassion130 study demonstrated that first-line treatment with atezolizumab and nab-paclitaxel resulted in an overall survival benefit in patients with advanced programmed death-ligand 1 (PD-L1) positive TNBC, and this is a new standard of care (Schmid et al, 2020). Meanwhile, immune checkpoint blockade also advances the treatment outcomes for other cancer types including melanoma (Long et al, 2016), non-small cell lung cancer (Melosky et al, 2020), and renal-cell carcinoma (Motzer et al, 2019). However, not all patients experience therapeutic benefit from immunotherapy.…”