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Adding ramucirumab extends PFS in EGFR-mutated lung cancer

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More pathway knowledge needed

The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.

Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.

Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).



For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

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