The U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 6-5 that ramucirumab (Cyramza®; Eli Lilly), in combination with erlotinib (Tarceva®; Genentech/Roche) demonstrated a favorable benefit/risk profile for patients with untreated metastatic EGFR-positive non-small cell lung cancer (NSCLC).
Previously known as LY3009806, ramucirumab is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that binds specifically to VEGFR-2, thereby blocking the binding of the receptor ligands (VEGF-A, VEGF-C, and VEGF-D) – which may slow tumor growth.
The committee based its decision on the results of the positive Phase III RELAY study (NCT02411448).
“Given the unmet need that remains in treating metastatic epidermal growth factor receptor (EGFR-) mutated non-small cell lung cancer, we are encouraged that the majority of these experts agree ramucirumab plus erlotinib has a favorable benefit/risk profile for the first-line treatment of these patients,” said Maura Dickler, M.D., vice president of late-phase development, Lilly Oncology.
“We believe in the clinical meaningfulness of the data from the RELAY trial, which targeted the VEGFR and EGFR pathways together,” Dickler added.
“We look forward to continuing to work with the FDA on this application to offer a new front-line treatment option for people with metastatic EGFR-mutated non-small cell lung cancer,” she concluded.
Safety and efficacy
The ODAC considered the safety and efficacy data from the Phase III RELAY trial, which is the basis for the ramucirumab supplemental Biologics License Application (sBLA) currently under review by the FDA.
In the RELAY study, ramucirumab, in combination with erlotinib, a globally approved EGFR-targeting tyrosine kinase inhibitor (TKI), demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to erlotinib alone.
The median PFS for patients on the ramucirumab + erlotinib arm was 19.4 months compared to 12.4 months on the placebo-plus-erlotinib arm, an improvement of seven months (HR 0.59; 95% CI, 0.46-0.79; P<0.0001).
This safety profile, observed in the RELAY study, was consistent with what has been previously observed for ramucirumab in Phase III clinical trials and the established safety profile of erlotinib. The most common (>5% incidence) Grade ≥3 adverse events occurring at a higher rate (≥5% difference) on the ramucirumab-plus-erlotinib arm compared to the placebo-plus-erlotinib arm were hypertension, dermatitis acneiform (an acne-like rash), and diarrhea.
Globally, lung cancer is the leading cause of cancer death, killing nearly 1.8 million people worldwide each year. In the U.S., lung cancer is the second most common cancer and the leading cause of cancer death, responsible for approximately 22% of all cancer deaths, more than those from colorectal, breast and prostate cancers combined.
It is estimated that there will be 228,820 new cases of lung cancer and 135,720 deaths from lung cancer in the U.S. in 2020.
Non-small cell lung cancer (NSCLC) is much more common than other types of lung cancer and accounts for about 80% to 85% of all lung cancer cases.
Stage IV NSCLC is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.  Fifty percent of NSCLC patients present with advanced or metastatic disease at diagnosis. The five-year survival rate for metastatic NSCLC is six percent. 
EGFR is a protein that helps cells grow and divide. When the EGFR gene is mutated it can cause the protein to be overactive, resulting in the formation of cancer cells. EGFR mutations may occur in 10% to 35% of NSCLC tumors globally. In the U.S., it is estimated that approximately 15% of people diagnosed with NSCLC have an EGFR mutation.
Activating EGFR mutations are found in about 10% to 20% of Caucasian patients with lung adenocarcinomas and in up to 40% to 60% of Asian patients. 
Regardless of ethnicity, these mutations are commonly found in females, non-smokers and those with adenocarcinoma histology.
The most common activating mutations in EGFR are deletions within exon 19 and a substitution in exon 21 (L858R), which are present in over 90% of EGFR-mutated tumors. The presence of these activating EGFR mutations in advanced NSCLC is associated with sensitivity to small-molecule EGFR TKIs. 
There is no cure for people with metastatic EGFR-mutated lung cancer and disease progression following acquired resistance remains a challenge. Most patients receive several lines of treatment and the therapeutic regimen prescribed for first-line treatment can impact a person’s options for later lines of therapy.
Tyrosine kinase inhibitors (TKIs), including erlotinib which was used in the trial, are the current standard treatment option for EGFR-mutated NSCLC. There remains an ongoing need for additional first-line therapeutic options that provide clinically meaningful benefits, including delaying disease progression and the use of chemotherapy as long as possible. Moreover, new treatment options could allow oncologists greater choice on how to use the available agents, in shared decision-making with their patients.
The Relay study, which started in 2015, randomized 449 patients across North America, Europe and Asia. The primary endpoint of the RELAY trial is progression-free survival; key secondary endpoints include safety, response rate, overall survival (OS), and patient-reported outcomes.
On the primary endpoint of investigator-assessed PFS, ramucirumab + erlotinib (N=224) demonstrated statistically significant and clinically meaningful improvement in median PFS – the time patients live without their cancer growing or spreading after starting treatment – by seven months compared to placebo plus erlotinib (N=225) [19.4 months with the ramucirumab-containing arm compared to 12.4 months with the placebo-containing arm (HR 0.59; 95% CI, 0.46-0.79; P<0.0001)].
Improvements with ramucirumab + erlotinib were also consistently observed across secondary and exploratory endpoints including duration of response, progression after the next line of therapy (PFS2) and time on targeted therapy. Improvements were also consistently seen across all specified subgroups, including patients with tumors that had exon 19 and 21 mutations. OS was immature at the time of analysis. The trial will continue until it reaches its final number of OS events.
The most common mechanism of acquired resistance to first-line treatment with first-and second-generation EGFR-TKI is the T790M mutation, with approximately 30 to 60% of patients whose disease progresses acquiring the mutation. In the study, the rate of T790M mutations following disease progression was similar between treatment groups.
The most common Grade ≥3 adverse events occurring at a rate of five percent or greater in the ramucirumab-containing arm were hypertension (N=52 [24%, Grade 3 only]), dermatitis acneiform (an acne-like rash) (N=33 [15%, Grade 3 only)], and diarrhea (N=16 [7%, Grade 3 only]).
Lilly has also made regulatory submissions outside the U.S. based on the RELAY data. In January 2020, the European Commission granted European Union approval for ramucirumab in combination with erlotinib for the first-line treatment of adult patients with metastatic NSCLC with activating EGFR mutations. Lilly has submitted in Japan and expects regulatory action in the second half of 2020.
A Study of Ramucirumab (LY3009806) in Combination With Erlotinib in Previously Untreated Participants With EGFR Mutation-Positive Metastatic NSCLC (RELAY) – NCT02411448
 International Agency for Research on Cancer. 2018 Lung Cancer Fact Sheet. Online. Last accessed on February 24, 2020.
 American Cancer Society. Cancer Facts and Figures 2020. Online. Last accessed on February 24, 2020.
 American Cancer Society. Key Statistics for Lung Cancer. Online. Accessed February 24, 2020.
 American Cancer Society. What is non-small cell lung cancer? Online. . Accessed February 24, 2020.
 American Cancer Society. Non-Small Cell Lung Cancer Survival Rates, by Stage. Online. Last accessed on February 24, 2020.
 Riess, J. Shifting Paradigms in Non-Small Cell Lung Cancer: An Evolving Therapeutic Landscape Supplement. Am J Manag Care. 2013;19:S390-S397.
 Cancer.Net. Lung Cancer – Non-Small Cell: Statistics. Online. Last accessed on February 24, 2020.
 Dong L, Lei D, Zhang H. Clinical strategies for acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small-cell lung cancer patients. Oncotarget. 2017 Sep 8; 8(38): 64600–64606.
 Li Y, Appius A, Pattipaka T, Feyereislova A, Cassidy A, Ganti AK. Real-world management of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in the USA [published correction appears in PLoS One. 2019 Feb 20;14(2):e0212831]. PLoS One. 2019;14(1):e0209709. Published 2019 Jan 4. doi:10.1371/journal.pone.0209709.
 Girard N. Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when? Future Oncol. 2018 May;14(11):1117-1132. doi: 10.2217/fon-2017-0636.
 Hirsh V. Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors. Ther Adv Med Oncol. 2018 Jan 22;10:1758834017753338. doi: 10.1177/1758834017753338.
 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology 2019: Non-Small Cell Lung Cancer (Version 3). Online. Last accessed on February 24, 2020.
 Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015 Aug 15;5(9):2892-911.
 Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol. 2008 May;21 Suppl 2:S16-22. doi: 10.1038/modpathol.3801018.