CYRAMZA in combination with erlotinib recommended for approval in the EU for the first-line treatment of adult patients with metastatic non-small cell lung cancer with activating EGFR mutations
Positive opinion based on Phase 3 RELAY study, which showed significant improvement in progression-free survival
INDIANAPOLIS, IN, USA I December 13, 2019 I Eli Lilly and Company (NYSE: LLY) announced today that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending a new indication and associated label update for CYRAMZA® (ramucirumab). The Committee agreed that the label should include an indication for CYRAMZA in combination with erlotinib for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. The CHMP positive opinion is now referred for final action to the European Commission, which grants approval in the European Union.
The CHMP opinion is based on the efficacy and safety demonstrated in the Phase 3 RELAY trial – a global randomized, double-blind, placebo-controlled trial evaluating CYRAMZA in combination with erlotinib, compared to placebo in combination with erlotinib, as a first-line treatment in patients with metastatic NSCLC whose tumors have activating EGFR mutations. CYRAMZA, in combination with erlotinib, significantly improved progression-free survival, or the time patients lived without their disease getting worse, in previously untreated NSCLC with activating EGFR mutations. RELAY is the second positive Phase 3 trial of CYRAMZA in NSCLC. The first was REVEL, which supported the approval of CYRAMZA plus docetaxel as a treatment for people with metastatic NSCLC whose cancer has progressed after prior platinum-based chemotherapy.
“There is no cure for people with metastatic EGFR-mutated lung cancer and, despite recent advancements, there remains an unmet need for additional first-line therapeutic options and new treatment strategies,” said Anne White, president of Lilly Oncology. “We are pleased with this opinion that recognizes the relevance of the RELAY data, which demonstrate the benefit of combining inhibition of the EGFR and VEGFR2 pathways to treat this type of cancer. Today marks an important step toward making this treatment regimen available for metastatic non-small cell lung cancer patients with an EGFR mutation, and further demonstrates Lilly’s commitment to people living with lung cancer.”
In addition to the EU, Lilly has made submissions based on the RELAY data in the U.S. and Japan, with regulatory action expected in the first half and second half of 2020, respectively.
The safety profile observed in the RELAY study was consistent with what has been previously observed for CYRAMZA in Phase 3 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 CYRAMZA-plus-erlotinib arm compared to the placebo-plus-erlotinib arm were hypertension, dermatitis acneiform (an acne-like rash), and diarrhea.
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 treatment. EGFR-targeting tyrosine kinase inhibitors (TKIs) are the current standard treatment options for EGFR-mutated NSCLC. Erlotinib, the TKI included in the RELAY trial regimen, is a globally approved treatment option for this type of lung cancer.
Information on previously approved EU CYRAMZA indications can be found here.
About the RELAY Trial
RELAY is a global randomized, double-blind, placebo-controlled Phase 3 study of CYRAMZA in combination with erlotinib, compared to placebo in combination with erlotinib, as a first-line treatment in previously untreated patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR (epidermal growth factor receptor) exon 19 deletions or exon 21 (L858R) substitution mutations. Initiated in 2015, the study randomized 449 patients across North America, Europe and Asia. The primary endpoint of the RELAY trial is progression-free survival (PFS); key secondary endpoints include safety, response rate, overall survival (OS), and patient-reported outcomes.
On the primary endpoint of investigator-assessed PFS, CYRAMZA plus erlotinib (N=224) demonstrated statistically significant and clinically meaningful improvement in median PFS – the time patients lived without their cancer growing or spreading after starting treatment – by seven months compared to placebo plus erlotinib (N=225) [19.4 months with the CYRAMZA-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 CYRAMZA plus erlotinib were also consistently observed across secondary and exploratory endpoints including duration of response, 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. Historically, patients receiving single-agent EGFR-TKIs with exon 21 (L858R) point mutations typically have had lower PFS benefit than those with exon 19 mutations. OS was immature at the time of analysis. No detriment to OS was observed at this interim assessment, and the trial will continue until it reaches its final number of OS.
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 percent of patients whose disease progresses acquiring the mutation. In RELAY, the rate of T790 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 CYRAMZA-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]).
Detailed RELAY efficacy and safety results were recently published in The Lancet Oncology.
About Lung Cancer and EGFR Mutations
Globally, lung cancer is the leading cause of cancer death, killing nearly 1.8 million people worldwide each year. Europe accounts for 22 percent of both the world’s new cases of and deaths from lung cancer, with an estimated 470,039 people diagnosed and 387,913 people dying from the disease annually.1 In the U.S., lung cancer is responsible for approximately 25 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.2 Non-small cell lung cancer (NSCLC) is much more common than other types of lung cancer and accounts for about 80 to 85 percent of all lung cancer cases.3 Stage IV NSCLC is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.4
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 percent of NSCLC tumors globally.5 Activating EGFR mutations are found in about 10 to 20 percent of Caucasian patients with lung adenocarcinomas and in up to 40 to 60 percent of Asian patients.6,7,8 Regardless of ethnicity, these mutations are commonly found in females, non-smokers and those with adenocarcinoma histology.9,10 The most common EGFR mutations are activating exon 19 deletion and exon 21 (L858R) substitution mutations, which are present in over 90 percent of EGFR-mutated tumors.7,8
About CYRAMZA® (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) has five FDA approvals to treat four different types of cancers. CYRAMZA is being investigated in a broad global development program that has enrolled more than 15,000 patients across more than 100 trials worldwide. These include several studies investigating CYRAMZA in combination with other anti-cancer therapies for the treatment of multiple tumor types.
CYRAMZA is an antiangiogenic therapy. It 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. CYRAMZA inhibited angiogenesis in an in vivo animal model.
About Angiogenesis and VEGF Protein
Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.
Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from binding to the receptors located on the surface of blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.
U.S. INDICATIONS FOR CYRAMZA
Gastric Cancer
CYRAMZA, as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.
Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
Hepatocellular Carcinoma
CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha-fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.
About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.
About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and http://newsroom.lilly.com/social-channels. P-LLY
© Lilly USA, LLC 2019. ALL RIGHTS RESERVED.
CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.
1 International Agency for Research on Cancer. 2018 Lung Cancer Fact Sheet. Available at: http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed December 11, 2019.
2 American Cancer Society. Cancer Facts and Figures 2019. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed December 11, 2019.
3 American Cancer Society. What is non-small cell lung cancer? Available at: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed December 11, 2019.
4 American Cancer Society. Non-Small Cell Lung Cancer Survival Rates, by Stage. Available at: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Accessed December 11, 2019.
5 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.
6 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.
7 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.
8 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology 2019: Non-Small Cell Lung Cancer (Version 3). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed December 11, 2019.
9 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.
10 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.
SOURCE: Eli Lilly
