When Avastin® (bevacizumab, Genentech/Roche) burst onto the oncology scene in the mid-2000s, the potential of VEGF inhibition became one of the hottest trends in cancer therapy. The ensuing race to find additional methods of disrupting VEGF signaling led Eli Lilly to throw their hat into the ring with ramucirumab, a fully human, immunoglobulin G1 (IgG1) monoclonal antibody that binds to the extracellular domain of VEGFR Receptor-2 (VEGFR-2). This mechanism of action is unique when compared with Avastin and Zaltrap® (ziv-aflibercept, Regeneron/Sanofi), which inhibit the VEGF ligands. Lilly advanced the development of ramucirumab quickly and aggressively, focusing the Phase III trials in indications where other anti-angiogenic agents are either already approved or in late-stage development: breast, colorectal, gastric, hepatocellular and non-small cell lung cancers. In gastric cancer, the company took ramucirumab directly from Phase I into Phase III, despite limited data suggesting substantial efficacy. Later, the failure of Avastin plus first-line chemotherapy in the AVAGAST study cast a large shadow over the hopes for VEGF inhibitors in gastric cancer.
In October 2012, however, Lilly announced that ramucirumab met its primary endpoint of improving overall survival in the Phase III REGARD study (NCT00917384), which compared best supportive care (BSC) with or without ramucirumab in patients with previously treated gastric or gastroesophageal junction cancer. On Thursday at the 2013 ASCO Gastrointestinal Cancers Symposium, full results from the REGARD study were presented as a late-breaking poster abstract (Fuchs, Abstract LBA5). The poster generated a large amount of attention at the conference, but ultimately the results seemed underwhelming. The study showed that adding ramucirumab to BSC improved progression-free survival by 0.8 months (2.1 months versus 1.3 months; HR = 0.483, p<0.0001) and overall survival by 1.4 months (5.2 months versus 3.8 months; HR = 0.776, p=0.0473), just meeting statistical significance.
With an interesting juxtaposition (as these posters were adjacent to each other), physicians at the conference could easily contrast the REGARD results with those of the Phase III COUGAR-02 study, which evaluated docetaxel plus active symptom control (ASC; essentially this was BSC) in relapsed esophago-gastric cancer (Ford, Abstract LBA4; this abstract was also presented in an oral session). The efficacy results in this study were strikingly similar to those of ramucirumab. The COUGAR-02 study showed that adding docetaxel to ASC provided an overall survival benefit of 1.6 months (5.2 months versus 3.6 months with ASC alone; HR = 0.67, p=0.01).
It looks as though docetaxel and ramucirumab provide similar levels of efficacy benefit in relapsed patients, and the choice of second-line agent may come down to how comfortable physicians feel with treating the myelosuppression of docetaxel or the hypertension and bleeding associated with ramucirumab. Rates of hypertension and bleeding in the REGARD study were unremarkable, 7.6% and 3.4%, respectively, very similar to what was observed with Avastin in the AVAGAST study. This hypothetical choice presupposes that Lilly will file for regulatory approval based upon the REGARD results, but this course of action may not be on the agenda.
After the initiation of the REGARD trial, Lilly seems to have become aware of the potential difficulties in gaining an approval with a placebo-controlled trial in second-line gastric cancer. The results of the COUGAR-02 study highlight the benefit that patients get from an active second-line therapy, and in reality most fit patients are being actively treated in clinical practice today with either a fluoropyrimidine- or a taxane-based regimen (Kantar Health, CancerMPact, Treatment Architecture). Recognizing this weakness, one year after the initiation of the REGARD study, Lilly initiated the Phase III RAINBOW study (NCT01170663) to compare paclitaxel with or without ramucirumab in patients with previously treated gastric cancer. In the eyes of the oncology community, this is the make-or-break study for ramucirumab in gastric cancer. Will ramucirumab be able to show an additive benefit when combined with an active agent in a tumor type where Avastin failed to do so? This is a huge unanswered question for ramucirumab: is the mechanism of action different enough to surpass the activity of Avastin? Perhaps so, since the fact that ramucirumab demonstrates single-agent activity is something Avastin and Zaltrap have never demonstrated in a gastrointestinal tumor. If RAINBOW is positive, approval will be a foregone conclusion, and given the fact that it was initiated only one year after REGARD, it seems likely that top-line results should come later this year. Lilly may be waiting for these results to strengthen their case for approval, but one thing is for sure: in 2013, we will learn whether ramucirumab has what it takes to succeed where prior VEGF inhibitors have failed.
By Neesha Suvarna, PhD, Consultant, Kantar Health and Josh Garcia, Associate Consultant, Kantar Health
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