Eli Lilly Reports Positive Phase 3 Results for VEGFR2 Inhibitor Cyramza in First-Line Treatment of EGFR-Mutated Non-Small Cell Lung Cancer

Recently, Eli Lilly announced that the combination therapy of its anti-angiogenic monoclonal antibody drug Cyramza (ramucirumab) and Roche’s tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) achieved positive results in a pivotal Phase 3 trial for the first-line treatment of previously untreated patients with metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations. These findings were recently published in The Lancet Oncology.

Lung cancer is the leading cause of cancer-related deaths, accounting for one-quarter of all cancer fatalities. Approximately 10%–20% of Western lung cancer patients and 40%–60% of Asian lung cancer patients harbor activating EGFR gene mutations. As a member of the receptor tyrosine kinase family, EGFR is a transmembrane growth factor receptor protein that promotes cell growth and division. Under healthy conditions, the extracellular domain of EGFR is tightly regulated by ligands such as growth factors; binding to these ligands induces receptor dimerization, thereby activating downstream signaling pathways. However, mutations in the tyrosine kinase domain of the intracellular portion of EGFR may lead to its constitutive activation without ligand binding, resulting in abnormal cell proliferation and the transformation of healthy tissue into cancer. Patients with EGFR gene mutations are highly sensitive to tyrosine kinase inhibitor (TKI) therapy, and combination therapies involving TKIs and other treatments have the potential to delay disease progression and the emergence of TKI resistance.

Cyramza, a vascular endothelial growth factor (VEGF) receptor 2 antagonist, is an anti-angiogenic therapy. Cyramza blocks the activation of this signaling pathway by inhibiting the specific binding of VEGF receptor 2 to VEGF-A, VEGF-C, and VEGF-D. Blocking the interaction between VEGF proteins and blood vessels helps suppress tumor growth by slowing angiogenesis and reducing tumor blood supply. Cyramza has received FDA approval as a second-line treatment for gastric cancer, non-small cell lung cancer (NSCLC), colorectal cancer, and hepatocellular carcinoma (HCC).

▲Schematic diagram of the mechanism of action of Cyramza (Image source: Cyramza official website)

A total of 449 patients with metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) were enrolled in the Phase 3 RELAY trial. They were randomized to receive either Cyramza in combination with erlotinib or placebo plus erlotinib. The combination therapy group achieved a progression-free survival (PFS) of 19.4 months, compared with 12.4 months in the erlotinib monotherapy group, thereby meeting the primary endpoint of significantly prolonging PFS. Improvements were also observed in the combination therapy group for secondary or exploratory endpoints, including duration of response, time to second progression or death (PFS2), and time on targeted therapy.

Dr. Maura Dickler, Vice President of Late-Stage Oncology Development at Eli Lilly, stated, “To date, the positive data from the RELAY trial represent the most robust clinical evidence supporting the simultaneous targeting of EGFR and VEGFR pathways for the treatment of NSCLC, and Eli Lilly is excited by these findings. The RELAY trial suggests that this combination therapy has the potential to provide new treatment options for patients with metastatic NSCLC harboring EGFR mutations.”

References:

[1] Lilly's CYRAMZA® (ramucirumab) Phase 3 Data in First-Line EGFR-Mutated Non-Small Cell Lung Cancer Published in The Lancet Oncology. Retrieved Oct. 8, 2019, from https://investor.lilly.com/news-releases/news-release-details/lillys-cyramzar-ramucirumab-phase-3-data-first-line-egfr-mutated

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