RAINFALLs On Lilly's Cyramza Stomach Cancer Parade
Executive Summary
A lack of overall survival benefit in first-line stomach cancer in a Phase III trial has scuppered Eli Lilly's hopes of expanding Cyramza's use into a new and relatively empty market.
Eli Lilly & Co.'s VEGF inhibitor Cyramza (ramucirumab) has failed to improve overall survival when used first line in stomach cancer, top-line data from the RAINFALL study show. The company has dropped plans to file for a supplemental approval in what could have been a lucrative expanded indication where there is limited competition.
Lilly said that while the 645-patient study met its primary endpoint of progression-free survival, it did not provide a benefit on overall survival, a secondary endpoint, when Cyramza was used in combination with cisplatin and capecitabine or 5-FU (5-fluorouracil) in the first-line treatment of patients with HER2-negative metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
"While we hoped that the positive PFS outcome would have translated into an OS benefit, these RAINFALL results highlight the challenges associated with improving outcomes for people with advanced gastric cancer," said Dr Levi Garraway, senior vice president, global development and medical affairs at Lilly Oncology, in a statement. Safety was consistent with previous studies and the full results will be presented in due course, the company said.
Cyramza became the first FDA-approved drug to treat advanced gastric cancer after prior chemotherapy in 2014 based on two pivotal Phase III studies, and it is now a standard of care in this setting. But the company had hoped to move the product forward in the treatment arc, as a bulwark against advancing competition in the later-line setting from the PD-1/L1 inhibitors, particularly Merck & Co. Inc.'s Keytruda (pembrolizumab).
Keytruda gained an accelerated approval from the FDA in September for third-line advanced gastric cancer supported by response rate data in a single arm Phase II study. (Also see "FDA Approval Round Up: Keytruda, Opdivo Add Claims" - Pink Sheet, 24 Sep, 2017.)
But there was some respite for Cyramza with the recent failure of Merck KGAA/Pfizer Inc.'s PD-L1 inhibitor Bavencio (avelumab) in the Phase III JAVELIN Gastric 300 trial, which tested the drug as a single agent against chemotherapy (paclitaxel or irinotecan) in all comers, regardless of PD-L1 expression, in third-line treatment of unresectable, recurrent or metastatic gastric or GEJ adenocarcinoma. (Also see "Pfizer/Merck KGAA's Bavencio Gastric Cancer Failure Not As Bad As It Seems" - Scrip, 28 Nov, 2017.)
Other IO products in late-stage development in gastric cancer include Bristol-Myers Squibb Co.'s Opdivo (nivolumab) with Yervoy (ipilumumab).
By contrast, the first-line HER2-negative gastric cancer setting has seen no major advances over standard chemotherapy in the last decade. Roche's Herceptin (trastuzumab) is the only other targeted therapy currently available for first-line advanced or metastatic gastric cancer. This drug is only approved for first-line patients who are human epidermal growth factor receptor-2-positive, which is overexpressed in approximately 6–23% of patients, representing a significant minority of patients for whom first-line treatment with the drug is appropriate.
"Despite the trial meeting its primary endpoint of PFS, it’s rather disappointing that Cyramza will not gain first-line regulatory approval considering the lack of effective treatment options in gastric cancer," Datamonitor Healthcare analyst Dustin Phan told Scrip. Success in the first-line setting would have positioned Cyramza as the only targeted therapy available for the majority of gastric cancer patients, boosting Cyramza's commercial potential and enabling it to establish a dominant position in the gastric cancer market. Before the failure, Datamonitor Healthcare was estimating that approval in the first-line setting could have generated approximately $200-300m in annual sales for Cyramza.
Phan noted that the gastric cancer market in the West is quite small in comparison with Asia. Over 60% of patients are in Japan, where gastric cancer is one of the leading causes of cancer death. In comparison, gastric cancer is relatively rare in the Western countries: gastric cancer is the 15th most common cancer in the US and UK.
Nonetheless, the drug continues to gain uptake as the second-line standard of care, and could find a role in the treatment of gastric cancer patients who fail to respond to immunotherapies, Phan said. It also appears that Cyramza is under investigation for potential use in combination with Keytruda in a number of solid tumor indications that include gastric cancer (ClinicalTrials.gov identifier: NCT02443324). "This provides an opportunity for the drug to remain relevant as immunotherapies play an increasingly important role in gastric cancer."
Phase III trials of Cyramza are ongoing in advanced urothelial carcinoma (PFS endpoint met, OS data expected in mid-2018), and in hepatocellular carcinoma and EGFR-positive non-small cell lung cancer, with expected data readouts in 2018.
Cyramza is also approved in combination with docetaxel as a treatment for metastatic non-small cell lung cancer that has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
Lilly reported third quarter sales for Cyramza of $196m, up by 23%.