Lilly Phase 3 REACH-2 Trial Data Published in The Lancet Oncology Shows Improvement in Overall Survival with CYRAMZA® (ramucirumab) in Second-Line AFP-High Hepatocellular Carcinoma Patients
INDIANAPOLIS, Jan. 18, 2019 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) announced that results from the global Phase 3 REACH-2 study of CYRAMZA® (ramucirumab) as a single agent in the second-line treatment of people with AFP-High (alpha-fetoprotein ≥400 ng/mL) hepatocellular carcinoma (HCC) were published online today in The Lancet Oncology. Data from REACH-2 are also being presented today at the 2019 Gastrointestinal Cancers Symposium in San Francisco. HCC is also known as liver cancer, which is a leading cause of cancer-related death worldwide.1 In the U.S., liver cancer is one of the few major cancers with incidence rates that continue to rise every year2 and is the fastest rising cause of cancer death.3
REACH-2 showed a statistically significant improvement in the primary endpoint of overall survival (OS) as well as in the secondary endpoint of progression-free survival (PFS). The safety profile observed in the REACH-2 study was consistent with what has been previously observed for single-agent CYRAMZA in patients with HCC. Additionally, in a pooled analysis comprised of all AFP-High HCC patients across both the REACH-2 and REACH studies, CYRAMZA treatment also resulted in an improvement in median OS.
"AFP has been used as a prognostic factor for hepatocellular carcinoma for decades. Some studies have suggested that AFP-producing tumors have an aggressive phenotype and increased angiogenesis," said Andrew X. Zhu, M.D., Director of Liver Cancer Research at Massachusetts General Hospital Cancer Center, Professor of Medicine at Harvard Medical School, and principal investigator of the REACH-2 and REACH trials. "These results not only further add to the body of evidence that poor prognosis tumors with elevated AFP may have a distinct biology, but also show a tailored treatment approach is feasible."
REACH-2, the first positive Phase 3 HCC trial in a biomarker-selected patient population, evaluated the benefit of CYRAMZA treatment in AFP-High HCC patients who were intolerant to, or had disease progression while on or following treatment with, sorafenib. Approximately half of all advanced HCC patients are AFP-High, and these patients are among those with the poorest prognosis relative to the general HCC patient population.
On the primary endpoint of OS, treatment with CYRAMZA significantly improved the OS of patients compared to placebo (HR 0.71; 95% CI, 0.53-0.95; P=0.02). The median OS was 8.5 months with CYRAMZA (95% CI, 7.0-10.6), compared to 7.3 months with placebo (95% CI, 5.4-9.1). On the secondary endpoint of PFS, median PFS was significantly improved with CYRAMZA (2.8 months [95% CI, 2.8-4.1] vs. 1.6 months for placebo [95% CI, 1.5-2.7]) (HR 0.45; 95% CI, 0.34-0.60; P<0.0001). Objective response rate (ORR) was numerically higher with CYRAMZA compared to placebo (4.6% vs. 1.1%; P=0.1697). Disease control rate (ORR + stable disease) was higher with CYRAMZA than with placebo (59.9% vs. 38.9%).
In a pooled analysis of AFP-High patients (n=542) from REACH-2 and REACH, which provided a larger data set to assess outcomes in this particular patient population, CYRAMZA improved OS compared to placebo (HR 0.69; 95% CI, 0.57-0.84; P=0.0002), and an improvement of 3.1 months in median OS was observed (8.1 and 5.0 months with CYRAMZA and placebo, respectively). The HR for OS across all pre-specified pooled subgroup analyses favored the CYRAMZA treatment arm. PFS, ORR and disease control rate were consistent with those in REACH and REACH-2, and supported the pooled OS result.
"Demonstrating a significant improvement in survival for this group of patients with advanced liver cancer and elevated AFP is particularly exciting as these patients have the poorest prognosis – with an expected survival of only a few months following first-line treatment if they don't go onto a second-line therapy. Treatment options are still limited in second-line liver cancer, and CYRAMZA is the first treatment specifically evaluated in this biomarker-selected population of liver cancer patients," said Maura Dickler, M.D., vice president, late phase development, Lilly Oncology. "The published results of REACH-2 demonstrate the potential for CYRAMZA to make an impact on the treatment of people with this aggressive cancer, which is encouraging for healthcare providers and the patient community."
The safety profile observed in the REACH-2 study was consistent with what has been previously observed for single-agent CYRAMZA in patients with HCC. The Grade ≥3 adverse events occurring at a rate of five percent or greater in the CYRAMZA arm were hypertension and hyponatremia (low sodium).
These data were first presented at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) and 2018 World Congress on Gastrointestinal Cancer.
Lilly has made regulatory submissions in the U.S., European Union and Japan based on the REACH-2 results. CYRAMZA is not yet approved for the HCC indication.
Notes to Editors
REACH-2 is a global, randomized, double-blind, placebo-controlled Phase 3 study of CYRAMZA and best supportive care (BSC) compared to placebo and BSC in hepatocellular carcinoma (HCC) patients who were intolerant to, or who had disease progression while on or following treatment with, sorafenib and had a high alpha-fetoprotein (AFP-High), defined as an AFP of ≥400 ng/mL.
Initiated in 2015, the study has enrolled 292 patients across 20 countries in North America, Asia, Europe and Latin America. Patients were assigned to 8 mg/kg of intravenous CYRAMZA (n=197) or placebo (n=95) at every two weeks until disease progression, unacceptable toxicity, or withdrawal of consent, with all patients receiving BSC. The primary endpoint of the REACH-2 trial is overall survival (OS) and key secondary endpoints include progression-free survival, objective response rate, quality of life and safety.
The design of the REACH-2 trial was based on the findings of the Phase 3 REACH study,4 which also evaluated single-agent CYRAMZA in the second-line treatment of HCC following first-line treatment with sorafenib. The REACH trial's primary endpoint of OS favored the CYRAMZA arm but was not statistically significant. However, in the prespecified subgroup of patients with baseline AFP-High treatment with CYRAMZA led to an improvement in OS (7.8 months versus 4.2 months in placebo; HR=0.674 (95% CI: 0.508, 0.895)). No OS benefit was observed in patients with baseline AFP <400 ng/mL (OS HR=1.093; 95% CI: 0.836, 1.428). The OS result in the subgroup with AFP-High was supported by improvements in key secondary endpoints and a safety profile consistent with what has been previously observed for single-agent CYRAMZA.
REACH is a global, randomized, double-blind Phase 3 study of CYRAMZA plus best supportive care compared to placebo plus best supportive care as a second-line treatment in patients with hepatocellular carcinoma who have been previously treated with sorafenib in the first-line setting. Initiated in 2010, the study enrolled 565 patients across 27 countries; as defined in the trial protocol, the primary analyses are focused on patients with a Child-Pugh score of <7 (Child-Pugh Class A only). The primary endpoint of the REACH trial was overall survival and key secondary endpoints include: progression-free survival; objective response rate; time to progression; and safety.
Alpha-fetoprotein (AFP) is a glycoprotein that is produced in early fetal life by the liver and by a variety of tumors including HCC, hepatoblastoma, and nonseminomatous germ cell tumors of the ovary and testis. A person's AFP, measured in nanograms per milliliter (ng/mL), is assessed through a blood test. An AFP level of less than 10 ng/mL is generally considered normal for adults.5,6 It is estimated that approximately half of all people with advanced HCC are AFP-High (≥400 ng/mL) and these patients are known to have a poorer prognosis relative to the general HCC patient population.4
About Liver Cancer
Liver cancer is the sixth most common cancer worldwide and the fourth-leading cause of cancer-related death. Each year an estimated 841,080 new cases of liver cancer are diagnosed worldwide, and an estimated 781,631 will die due to the disease. According to the World Health Organization, approximately 38,000 people are diagnosed with liver cancer, and 30,000 will die from the disease each year in the United States.1 Liver cancer is one of the only major cancers with incidence rates that continue to rise every year in the United States2 and is the fastest rising cause of cancer death.3 In Europe and Japan, an estimated 82,000 and 36,000 people are diagnosed with liver cancer, and 77,000 and 29,000 will die, respectively.1
The prognosis for advanced HCC patients is typically very poor. Surgery is not an option for the majority of advanced HCC patients, as the tumor has often grown or metastasized to the extent that resection is not feasible. Advanced HCC is a disease with few approved systemic treatments, and most patients have significant liver damage which can further limit therapy options. Once patients who are AFP-High enter the second-line treatment setting, the expected survival is three to five months if untreated.4
Despite recent advances in the treatment of chronic liver disease, the incidence of HCC is still expected to rise in the coming decades due to several factors: under-diagnosis of chronic liver disease; increasing prevalence of diabetes, obesity and fatty liver disease; and, lack of access to viral hepatitis disease therapy and the persistent risk of cancer even after viral hepatitis cure.7
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 linking to the 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.
About CYRAMZA® (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
CYRAMZA is being investigated in a broad global development program that has enrolled more than 14,000 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 specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. CYRAMZA inhibited angiogenesis in an in vivo animal model.
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.
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.