Eli Lilly’s Cyramza™ (ramucirumab)—approved in April for advanced stomach cancer—suffered its second Phase III failure in less than a year, as the pharma giant said today that the compound failed to meet its primary endpoint of statistically significant overall survival (OS) in a pivotal study assessing its effectiveness on liver cancer.

Cyramza was assessed for hepatocellular carcinoma in the REACH trial, a global, randomized, double-blind study that enrolled 565 patients in 27 countries since its launch in 2010. REACH compared Cyramza plus best supportive care to placebo and 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. 

REACH’s secondary endpoints included progression-free survival, overall response rate, time to progression, and safety. According to Lilly, top-line safety data were consistent with that seen in previous single-agent Cyramza studies. Hypertension and asthenia (fatigue) were the most common adverse events occurring at a higher rate on the Cyramza treatment arm compared to the control arm.

Lilly cited what it called “encouraging” activity associated with Cyramza as a single agent—namely “meaningful improvements in key secondary endpoints of progression-free survival, overall response rate and time to progression.” Lilly did not quantify those improvements, saying it planned to present data from the REACH trial later this year at an unspecified scientific meeting.

“Although the REACH study did not achieve statistical significance for survival, we are encouraged by the efficacy seen overall, especially in specific subpopulations. We plan to discuss these results with regulatory authorities,” Richard Gaynor, M.D., svp, product development and medical affairs for Lilly Oncology, said in a statement.

In announcing REACH results, Lilly added: “Liver cancer is a very difficult-to-treat tumor type and no Phase III study has been able to demonstrate improved survival in the second-line setting.  This is an area of very high unmet need for which there are no approved therapies.

Cyramza is a vascular endothelial growth factor receptor-2 (VEGFR-2) antagonist designed to work by binding and blocking activation of VEGF Receptor 2, and by binding VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. Cyramza has received orphan drug designations by the FDA and the European Commission for treatment of hepatocellular carcinoma in the U.S. and EU, respectively. Lilly took over development of Cyramza in 2008 when it acquired ImClone Systems.

On April 21, the FDA approved Cyramza for advanced or metastatic gastric or gastroesophageal junction adenocarcinoma—a form of cancer located in the region where the esophagus joins the stomach—with disease progression on or after prior chemotherapy containing fluoropyrimidine or platinum.

FDA reviewed Cyramza under its priority review program, which provides faster reviews for drugs deemed to have the potential, at the time the application was submitted, to show “significant” improvement in safety or effectiveness in the treatment of a serious condition.

But in September, Lilly disclosed that the drug failed a Phase III trial in a breast cancer indication by not meeting the primary endpoint of progression-free survival in the Phase III ROSE (TRIO-012) trial, conducted with the global cancer research group TRIO (Translational Research in Oncology).

ROSE compared Cyramza and docetaxel to placebo and docetaxel as a first-line treatment in patients with unresectable, locally recurrent or metastatic HER2-negative breast cancer. ROSE’s primary endpoint favored Cyramza but was not statistically significant, while an interim analysis for OS showed no benefit for the drug.

Lilly has sought to develop Cyramza for numerous cancer indications, including non-small cell lung cancer (NSCLC), and colorectal cancers. Last week at the American Society of Clinical Oncology (ASCO) Annual Meeting, Lilly trumpeted positive data from the Phase III REVEL trial in the trial’s primary endpoint of OS from the combination of Cyramza with chemotherapy in patients with second-line NSCLC.

The 628 patients in the Cyramza-plus-docetaxel treatment arm achieved a median OS of 10.5 months compared to 9.1 months for the 625 patients on the placebo-plus-docetaxel arm. The OS hazard ratio was 0.86, which corresponded to a 14% reduction in risk of death.

Lilly expects later this year to have top-line results for RAISE, a Phase III trial of Cyramza for metastatic colorectal cancer.

[This story was corrected from an earlier edition to note that Lilly has sought to develop Cyramza for numerous cancer indications but has not sought formal approval for them, and to clarify the REACH trial arms.] 

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