On May 29, 2020, the U.S. Food and Drug Administration (FDA) approved two combination regimens: ramucirumab (Cyramza) was approved in combination with erlotinib for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. The second approval was atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.
NSCLC: Relay Trial
Ramucirumab plus erlotinib is the first and only FDA-approved anti–vascular endothelial growth factor (VEGF) receptor/EGFR tyrosine kinase inhibitor combination therapy for metastatic EGFR-mutated NSCLC. This approval is based on efficacy and safety data from the global, randomized, placebo-controlled phase III RELAY trial. Initiated in 2015, the study randomly assigned 449 patients across North America, Europe, and Asia. The primary endpoint of the RELAY trial is progression-free survival; key secondary endpoints include safety, overall response rate, duration of response, and overall survival.
In the RELAY study, treatment with ramucirumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with placebo in combination with erlotinib (19.4 months in the ramucirumab-containing arm vs 12.4 months in the placebo-containing arm [hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.46–0.76, P < .0001]). The progression-free survival treatment effect was consistent across exon 19 and exon 21 subgroups.
At the time of the final analysis of progression-free survival, overall survival data were not mature, as just 26% of planned events for the final analysis had occurred (HR = 0.83, 95% CI = 0.53–1.30). A final overall survival analysis is planned when at least 300 events have occurred.
The overall safety profile observed in the RELAY study was consistent with that of its individual components.
IMbrave150: Metastatic HCC
Atezolizumab in combination with bevacizumab received FDA approval for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy. The approval was based on results from the phase III IMbrave150 study, a global, multicenter, open-label study of 501 patients with unresectable or metastatic HCC who had not received prior systemic therapy. Patients were randomly assigned 2:1 to receive atezolizumab/bevacizumab or sorafenib.
Atezolizumab was administered intravenously (IV) at 1,200 mg on day 1 of each 21-day cycle, and IV bevacizumab was administered at 15 mg/kg on day 1 of each 21-day cycle. Sorafenib was administered orally at 400 mg twice daily on days 1 through 21 of each 21-day cycle. Patients received the combination or the control arm treatment until disease progression or unacceptable toxicity.
The two primary endpoints were overall survival and independent review facility–assessed progression-free survival per Response Evaluation Criteria in Solid Tumors, version 1.1. Additional study endpoints were independent review facility–assessed overall response rate.
The trial demonstrated that treatment with atezolizumab plus bevacizumab improved overall survival by 42% (HR = 0.58, 95% CI = 0.42–0.79, P = .0006) and improved progression-free survival by 41% (HR = 0.59, 95% CI = 0.47–0.76, P < .0001) compared with sorafenib.
Serious adverse reactions (grade 3 or 4) occurred in 38% of people in the combination arm. The most frequent serious adverse reactions (≥ 2%) were bleeding in the gastrointestinal tract, infections, and fever.
IMbrave150 is the first phase III cancer immunotherapy study to show an improvement in overall and progression-free survival in people with unresectable or metastatic HCC compared with sorafenib.
The review of this application was conducted under the FDA’s Project Orbis initiative, which provides a framework for concurrent submission and review of oncology medicines among international partners. Simultaneous applications were submitted to regulators in the United States, Australia, Canada and Singapore, under Project Orbis. Additionally, the FDA rapidly reviewed and approved the application under its Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. For additional information, visit FDA.gov.