Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab. METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response. CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

Pemetrexed use in the adjuvant setting for completely resectable non-small-cell lung cancer.

Supported by evidence from the LACE (Lung Adjuvant Cisplatin Evaluation) metaanalysis, cisplatin-based adjuvant chemotherapy is now recommended as the standard of care for patients with surgically resected early-stage non-small-cell lung cancer (NSCLC) per American Society of Clinical Oncology and European Society for Medical Oncology clinical practice guidelines. These standard regimens, which principally include cisplatin-etoposide and cisplatin-vinorelbine, are associated with long- and short-term toxicities. Hence, cisplatin-based regimens with an improved therapeutic index and optimal safety and tolerability profile are still needed. Pemetrexed, an antifolate, is currently indicated for first-line, maintenance, and second-line therapy for advanced nonsquamous NSCLC. Pemetrexed-platinum, with or without targeted agents, has proven to be efficacious with an acceptable toxicity profile when given in the first-line metastatic setting. Therefore, it is reasonable that pemetrexed be investigated in the adjuvant setting. This review collates data from January 2000 through August 2012 on the use of pemetrexed-platinum regimens in the adjuvant setting either alone or in combination with targeted agents. To date, more than 1000 patients with early stage NSCLC have been enrolled in adjuvant therapy studies evaluating various pemetrexed-containing treatment regimens, and additional patients are being enrolled in ongoing studies. Current evidence appears to favor the combination with cisplatin over that with carboplatin. We await more robust safety and efficacy data from these ongoing adjuvant trials to define with clarity the role of pemetrexed-containing regimens in this setting.