By Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Before Cyramza® (ramucirumab, Eli Lilly and Co) was approved by the U.S. Food and Drug Administration (FDA) in 2014, no targeted therapy regimens were approved for use in relapsed/refractory gastric cancer. Cyramza’s approval as a monotherapy or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing systemic therapy was based on the positive results of two Phase III studies in relapsed gastric patients: the REGARD trial, which showed a significant overall survival (OS) benefit of 5.2 months for Cyramza versus 3.8 months for placebo,1 and the RAINBOW trial, which compared Cyramza plus paclitaxel versus paclitaxel alone, demonstrating a significant progression free survival (PFS) and OS benefit for the Cyramza combination (OS: 9.63 months in Cyramza plus paclitaxel arm versus 7.36 months in paclitaxel alone arm).2 Cyramza had a significant first-to-market advantage in this indication and is currently highly utilized in this space (30.4% as monotherapy or with paclitaxel in second-line in the U.S.).3 However, given the limited number of treatment options, new agents still have a lot of potential, including immunotherapies, which have already made a splash in other solid tumor types.
While gastric cancer is a relatively rare tumor type in the United States (ranks 16th in terms of incidence), it is the most commonly diagnosed tumor type in Japan.3 In part due to this, Ono Pharmaceuticals took the lead in evaluating immunotherapy in gastric cancer in Asia Pacific. In 2014, Ono Pharmaceuticals (which is co-developing Opdivo along with Bristol-Myers Squibb) initiated a randomized (2:1), double-blind, Phase III trial of Opdivo® (nivolumab) in gastric and gastroesophageal junction (GEJ) cancer patients in Japan, Korea and Taiwan (ONO-4538-12; NCT02267343). In this trial, Opdivo (3 mg/kg q2w) was compared against placebo in patients refractory or intolerant to standard therapies. The primary endpoint was OS. In yesterday’s oral abstract session at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, positive data from this trial were presented.4 The trial enrolled 493 patients with unresectable advanced or recurrent gastric/GEJ cancer who had failed two or more previous chemotherapy regimens, including Cyramza. As of the data cut-off on August 13, 2016, 5.6 months after the last patient was randomized, median OS was 5.32 months with Opdivo versus 4.14 months with placebo (hazard ratio, 0.63; 95% confidence interval (CI), 0.50-0.78; p<0.0001), and OS rates at six and 12 months were 46.4% versus 34.7% and 26.6% versus 10.9%, respectively. The overall response rate was 11.2% with Opdivo versus 0% with placebo (p<0.0001). Median PFS was 1.61 months with Opdivo versus 1.45 months with placebo (HR, 0.60; 95% CI, 0.49-0.75; p<0.0001). Grade ≥ 3 drug-related adverse events (AEs) occurred in 11.5% of Opdivo-treated patients and in 5.5% of placebo-treated patients; 2.7% and 2.5% of patients, in the respective arms, discontinued study treatment due to drug-related AEs (any grade). The most common AEs were pruritus, diarrhea, rash, fatigue, and decreased appetite. These data were well received by the conference audience. Of particular excitement was the characteristic OS plateau or “tail” in the Kaplan-Meier curve that we have come to expect from the checkpoint inhibitor class of immunotherapy agents; while the OS difference at the median was modest (1.18 months), a strong separation between the two curves that appears to be maintained long-term. Biomarker analysis was not reported, but is ongoing.
Not surprisingly, Ono has already filed for approval of Opdivo in gastric cancer in Japan with this data. Despite the Japanese filing, BMS has not stated that it has plans to file in the U.S. based on this data, perhaps given the enrollment was limited to Asian populations. Indeed during the discussion, Dr. Lenz of USC Norris Comprehensive Cancer Center took care to point out the molecular differences in gastric cancer between Asian and non-Asian populations citing reported differences in immune signatures.5 Furthermore, subgroup analysis in this trial showed a stronger magnitude of benefit (HR 0.59) in patients with intestinal histologic type (a better prognostic subset that is more common in Asian gastric cancer patients) compared with patients with diffuse histology type (HR 0.82; a worse prognostic subset that is more common in Caucasian gastric cancer patients). Together, this information raise doubts about the translatability of these data in Asian patients to a broader U.S. population. During the question-and-answer portion, however, the issue of U.S. filing based on these Asian data was raised, and some felt that, rather than wait for a new Phase III trial readout, a confirmatory Phase II trial in a U.S. population could warrant filing. Although not raised in yesterday’s session, an alternative scenario could be the National Comprehensive Cancer Network (NCCN) recommending Opdivo for use in relapsed/refractory gastric/GEJ. Such action (NCCN guideline recommendation for U.S. patients based strictly on Asian data) has not previously occurred but might not be entirely outside the realm of possibility given the unmet needs in gastric cancer and the well-established safety profile for Opdivo in other indications, even if balanced against the histologic subgroup data from the Japanese trial. In the absence of accelerated filing or NCCN recommendation, filing with the FDA may need to await the results of the ongoing global Phase III CheckMate 649 trial (NCT02872116) that is being conducted in the first-line setting and is investigating the combination of Opdivo plus Yervoy® (ipilimumab, BMS/Ono), data from which is not expected for several years.
Opdivo is not the only immunotherapy under late-stage development in gastric cancer. Keytruda® (pembrolizumab, MSD) has multiple Phase III trials underway in first-line and relapsed/refractory disease and may be the first immunotherapy agent to enter the gastric cancer market in the United States. Pfizer and Merck KGaA are also developing their PD-L1 inhibitor avelumab in relapsed/refractory gastric cancer. And of course non-immunotherapy approaches are also under late-stage development, including napabucasin (BBI608, Boston Biomedical/Sumitomo Dainippon) in second-line (NCT02178956), Lonsurf® (trifluorothymidine/tipiracil hydrochloride, Taiho) in third-line, GS-5745 (Gilead) in first-line, and Cyramza in first-line. Although the results of this Asian Phase III trial may not have an immediate impact in the U.S. gastric cancer market, these remain highly impactful results globally. Opdivo could gain approval in this indication in Japan as early as late 2017, putting it well-ahead of other competitors in this setting and bringing a new option to this population of high unmet need.