RELAY: Ramucirumab, erlotinib combination improves PFS in EGFR-mutated metastatic NSCLC

CHICAGO — The addition of ramucirumab to erlotinib significantly improved the outcomes of patients with EGFR-mutated metastatic non-small cell lung cancer compared with erlotinib alone, according to phase 3 data from the RELAY trial.

During a presentation at the ASCO Annual Meeting, Kazuhiko Nakagawa, MD, PhD, professor of medicine at Kindai University in Osaka, Japan, said the findings will likely have a “strong impact” on clinical practice.

Previously, data from the phase 3 FLAURA study showed that first-line treatment with osimertinib (Tagrisso, AstraZeneca) was superior to first-line treatment with other tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC. However, widespread use of osimertinib — a third-generation tyrosine kinase inhibitor — has led to a clinical problem of acquired resistance. Since other EGFR TKIs have limited efficacy compared with osimertinib, novel treatment approaches combining these agents with other targeted therapies are needed “to intensify the clinical potential,” according to Nakagawa.

“I believe VEGFR inhibitor is one of the most optimal targeted therapies to combine with EGFR TKI, because your blockade of two receptor signaling pathways, VEGFR and EGFR, are strongly supported by preclinical and clinical data,” he said. “Ramucirumab is a human IgG1 monoclonal antibody which targets VEGFR-2 directly. In the RELAY study, we combined ramucirumab with a first-generation EGFR TKI, erlotinib.”

Nakagawa and colleagues randomly assigned 449 treatment-naive patients (77% Asian) with metastatic NSCLC whose tumors had EGFR exon 19 deletion or exon 21 L858R mutations in a 1:1 ratio to receive 150 mg of erlotinib (Tarceva; Genentech, Astellas Oncology) daily plus 10 mg/kg of ramucirumab (Cyramza, Eli Lilly) every 2 weeks or 150 mg of erlotinib daily plus placebo every 2 weeks. The patients were enrolled at 100 different sites across 13 countries. The primary endpoint was investigator-assessed PFS.

At the time the data were presented, 29% of patients in the ramucirumab arm and 19% in the placebo arm were still receiving the study treatment.

Median PFS in the ramucirumab arm was 19.4 months, which was significantly longer than in the placebo arm (median PFS, 12.4 months; HR = 0.59; 95% CI, 0.46-0.76) and “comparable to the median PFS of osimertinib in [the] FLAURA [trial],” Nakagawa said.

The benefit of ramucirumab was observed regardless of tumor type. The median PFS was 19.6 months among patients with the exon 19 deletion and 19.4 months among those with the exon 21 L858R mutation.

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Overall response rates were similar between the ramucirumab group (ORR = 76%; 95% CI, 71-82) and placebo group (ORR = 75%; 95% CI, 69-80), but the duration of response was longer in the ramucirumab group (18 months vs. 11.1 months; HR = 0.62; 95% CI, 0.48-0.81).

OS data were not mature enough to be presented and the median time to the second disease progression (PFS2) was not yet reached, according to Nakagawa. However, interim results indicate that PFS2 was longer in the ramucirumab group vs. placebo group (HR = 0.69; 95% CI, 0.49-0.97).

“These RELAY data show that the PFS benefits shown with ramucirumab [are] preserved beyond first progression, indicating that possibility of OS benefit,” Nakagawa said.

The researchers assessed patients for T790M resistance mutations after progression. They detected T790M in 43% of patients who received ramucirumab and in 47% of patients who received placebo.

The safety profiles of ramucirumab and erlotinib were consistent with established data in this patient population. Overall, 72% of patients who received ramucirumab plus erlotinib had a grade 3 or higher treatment-emergent adverse event vs. 54% of patients who received erlotinib plus placebo. The greater percentage of grade three or higher adverse events in the ramucirumab arm was largely driven by an increase in hypertension in this group (24% vs. 5%, respectively), according to the researchers. There was one death caused by a treatment-emergent adverse event, which occurred in the ramucirumab group.

“In conclusion, RELAY met the primary endpoint, with a remarkable median PFS of 19.4 months,” Nakagawa said. “According to these results, I believe now that ramucirumab [plus] erlotinib combination therapy is a new, exciting additional treatment option for EGFR-mutated metastatic NSCLC.” – by Stephanie Viguers

Reference:

Nakagawa K. Abstract 9000. Presented at: ASCO Annual Meeting; May 31- June 4, 2019; Chicago.

Disclosure: Nakagawa reports receiving honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, CareNet Inc., Chugai Pharma, Clinical Trial Co. Ltd, Daiichi Sankyo, Eli Lilly, Hisamitsu Pharmaceutical, Kyorin Pharmaceutical, Medical Review Co. Ltd., Medicus Shuppan, Publishers Co. Ltd., Merck, Nanzando Co. Ltd., Nichi-Iko Pharmaceutical Co. Ltd., Nikkei Business Publications, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Pfizer, Reno Medical K.K., SymBio Pharmaceuticals, Taiho Pharmaceutical, Takeda Pharmaceutical, Thermo Fisher Scientific K.K., Yodosha Co. Ltd. and Yomiuri Telecasting Corporation; speakers' bureau fees from Astellas Pharma, Ono Pharmaceutical and Takeda Pharmaceutical; and research funding on behalf of his institution from A2 Healthcare Corporation, Abbvie, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharma, CMIC Shift Zero K.K., Daiichi Sankyo, Eisai, EP-CRSU Co. Ltd., Eli Lilly, EPS Corporation, Gritsone Oncology Inc., ICON Japan K.K., inVentiv Health Japan, IQVIA Services JAPAN K.K., Kissei Pharmaceutical, Kyowa Hakko Kirin, Linical Co. Ltd., Merck, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Parexel International Corporation, Pfizer, Quintiles Inc., SymBio Pharmaceuticals, Taiho Pharmaceutical and Takeda.