Lilly's Cyramza in Combination with Erlotinib Receives CHMP Positive Opinion for First-Line Treatment of EGFR-Mutated Metastatic NSCLC in Europe

Recently, Eli Lilly announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended EU approval for its anti-angiogenic monoclonal antibody drug.Cyramza (ramucirumab) in combination with the tyrosine kinase inhibitor (TKI) erlotinib as first-line treatment for adult patients with metastatic non-small cell lung cancer (NSCLC) harboring EGFR gene mutations. Previously, Eli Lilly had already submitted regulatory applications to the drug regulatory authorities in the United States and Japan, with regulatory actions from both parties expected in 2020.

Lung cancer is the leading cause of cancer-related deaths. According to statistics released in a press release, 1.8 million people die from lung cancer annually worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 80%–85% of all lung cancer cases. Among these, about 10%–35% of NSCLC patients harbor EGFR mutations.

Epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family, is a transmembrane growth factor receptor protein that promotes cell growth and division. Under physiological conditions, the extracellular domain of EGFR is tightly regulated by ligands such as growth factors; binding of these ligands induces receptor dimerization, thereby activating downstream signaling pathways. However, mutations in the intracellular tyrosine kinase domain of EGFR may lead to constitutive activation of the receptor independent of ligand binding, resulting in abnormal cell proliferation and the transformation of healthy tissue into cancer. Patients harboring EGFR gene mutations are highly sensitive to tyrosine kinase inhibitor (TKI) therapy, and combination regimens comprising TKIs and other therapeutic agents 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 inhibit tumor growth by slowing angiogenesis and reducing tumor blood supply. Previously, Cyramza has been approved by the U.S. FDA 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)

The CHMP’s opinion is based on the positive results of the RELAY study, a randomized, double-blind, Phase 3 clinical trial involving 449 patients with metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations). The trial results demonstrated that the combination therapy of Cyramza and erlotinib significantly improved progression-free survival (PFS) to 19.4 months, compared with 12.4 months in the active control group receiving placebo plus erlotinib, thereby meeting the primary endpoint of the study. Furthermore, patients in the combination therapy group showed improvements in secondary or exploratory endpoints, including duration of response, time to second progression or death (PFS2), and time on targeted therapy.

“Based on data from the RELAY study, the CHMP issued a positive recommendation. This demonstrates the potential of simultaneously targeting the EGFR and VEGFR pathways for the treatment of patients with NSCLC,” said Ms. Anne White, President of Lilly Oncology. “The positive opinion from the CHMP is an important step toward making this therapy available to patients with metastatic lung cancer harboring EGFR mutations.”

References:

[1] CHMP Issues Positive Opinion to Expand CYRAMZA® (ramucirumab) Label to Include Results from RELAY Study in Patients with Metastatic EGFR-Mutated Non-Small Cell Lung Cancer, Retrieved December 13， 2019, from https://www.prnewswire.com/news-releases/chmp-issues-positive-opinion-to-expand-cyramza-ramucirumab-label-to-include-results-from-relay-study-in-patients-with-metastatic-egfr-mutated-non-small-cell-lung-cancer-300974577.html

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