FDA panel supports approval of Cyramza regimen for EGFR-mutated metastatic NSCLC
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An FDA advisory committee today voted 6-5 in favor of recommending approval of ramucirumab injection in combination with erlotinib for first-line treatment of patients with metastatic non-small cell lung cancer whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 substitution mutations.
The vote by the Oncologic Drugs Advisory Committee, or ODAC, indicates the panel believes the combination has a favorable benefit-risk profile for these patients. However, the narrow vote reflects many panelists’ concern regarding the lack of an OS improvement, despite a significant PFS benefit, reported in the phase 3 RELAY trial. Some panelists also expressed concern about toxicity and the fact that patients will have to report for infusions every 2 weeks.
“I struggled with this decision, but I ultimately came down [in favor of] approval because I believe this is safe and effective,” Philip C. Hoffman, MD, professor of medicine at University of Chicago, said after the vote. “I am a lung cancer doctor, and for many years we used bevacizumab, another VEGF inhibitor, which caused hypertension. We dealt with it through the issues and sometimes had to adjust.
“I share the concerns of many of my colleagues that patients will have to come in every 2 weeks for an infusion, which is a hassle,” he added. “I might use this regimen, but I might not. I think it’s reasonable to have it as an option.”
Results of the RELAY trial showed the addition of ramucirumab (Cyramza, Eli Lilly), a VEGFR inhibitor, to erlotinib (Tarceva; Genentech, Astellas Oncology) significantly improved the outcomes of patients with EGFR-mutated metastatic NSCLC.
Researchers randomly assigned 449 treatment-naive patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 L858R mutations to receive 150 mg erlotinib daily plus either 10 mg/kg ramucirumab or placebo every 2 weeks.
Investigator-assessed PFS served as the study’s primary endpoint, which was met based on median PFS of 19.4 months in the ramucirumab-erlotinib group compared with 12.4 months with erlotinib plus placebo (HR = 0.59; 95% CI, 0.46-0.76).
The benefit of ramucirumab was observed regardless of tumor type. Median PFS was 19.6 months among patients with exon 19 deletions and 19.4 months among those with exon 21 L858R mutations.
At the time of data cutoff in January 2019, based on 79 deaths, researchers reported an HR for OS of 0.83 (95% CI, 0.53-1.3). Eli Lilly submitted updated survival data in response to a request from the FDA, with a data cutoff of Dec. 31, 2019. Based on 125 deaths, the HR for OS was 0.92 (95% CI, 0.65-1.32).
Overall, 72% of patients who received ramucirumab plus erlotinib experienced a grade 3 or higher treatment-emergent adverse event vs. 54% of patients who received erlotinib plus placebo. The greater percentage of grade 3 or higher adverse events in the ramucirumab group was driven largely by an increase of hypertension (24% vs. 5%).
One death resulted from a treatment-emergent adverse event, which occurred in the ramucirumab group.
“This was a difficult decision, but I voted no because of the OS data,” Heidi Klepin, MD, professor of hematology and oncology at Wake Forest University, said after the vote. “That matters because we just don’t know if this is going to extend survival or actually be a detriment to survival. Because of that, I just couldn’t vote to approve this.”- by John DeRosier