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P62: Regulatory Considerations for Drug Development in Metastatic Gastric Cancer

Poster Presenter

      Deanna Rubin

      • Manager, Global Regulatory Affairs
      • Glaxosmithkline
        United States


To provide an in-depth look at the dynamic regulatory landscape for metastatic gastric cancer (GC), including an evaluation of recent approvals and key trends from ongoing registrational trials to inform future drug development in this difficult-to-treat tumor type.


Regulatory precedent was assessed by searching FDA and EMA public databases from 2010-2021. Ongoing registrational trials in metastatic GC were then identified using predefined search criteria in TrialTrove and were analyzed for trends in design, endpoints, biomarkers, and standard of care (SOC).


Recent approvals in the US (n=9) and EU (n=5) were examined, including relevant tumor-agnostic indications (n=4 US; n=2 EU). Ongoing registration trials were analyzed by line of therapy (n=28). First-line SOC includes a fluoropyrimidine-platinum doublet, plus trastuzumab if HER2-positive. Trastuzumab approval was based on a randomized trial demonstrating an overall survival (OS) benefit. Ongoing trials (n=18) include agents targeting PD-1, CTLA-4, LAG-3, VEGFR, FGFR2b, and Claudin 18.2. Most agents are being combined with existing SOC (15/18) although some immunotherapy trials are testing chemotherapy-free regimens (3/18). OS remains the most common primary endpoint (15/18). Once patients progress to second-line, there is more variability in SOC. Recommended agents include ramucirumab, taxanes, and irinotecan. Tumor-agnostic indications can also be considered. The NTRK inhibitors have conditional approval in the US and EU based on single-arm studies with an overall response rate (ORR) endpoint. Further, pembrolizumab has US accelerated approval for MSI-H and TMB-H tumors based on ORR. Ongoing trials (n=5) target HER2, PD-1, and VEGFR. Most are pursuing a biomarker-driven, single-arm design using an ORR endpoint (3/5). Others are using a randomized design with an OS endpoint and a paclitaxel comparator (2/5). While SOC in third-line is limited, there have been advancements. Trifluridine/tipiracil was approved in the US and EU based on an OS benefit over best supportive care (BSC). Recently, trastuzumab deruxtecan gained US approval for HER2-positive GC based on an OS benefit over physician’s choice (paclitaxel/irinotecan). Of note, pembrolizumab received US accelerated approval based on a single-arm ORR-driven study; however, the confirmatory trial showed no OS benefit. Ongoing trials (n=5) include agents targeting PD-1 and VEGFR. These studies employ a randomized design with an OS endpoint, and use either BSC, physician’s choice, or placebo as a comparator.


Metastatic GC represents an area of high medical need. Major changes to the SOC are projected in the coming years, including a likely emergence of immunotherapy. Specifically, nivolumab has generated promising data in the first- and third-line settings. Additionally, based on the recent US approval of trastuzumab deruxtecan coupled with ongoing trials, management of HER2-positive GC is expected to further diverge beyond first-line treatment. Tumor-agnostic approaches and novel biomarker development are also expected to play a key role. Further, while placebo and BSC have previously been acceptable comparators in third-line trials, this is likely to fall out of favor ethically as more therapies become available. While randomized trials are the gold standard for obtaining traditional approval, single-arm studies in late-line, biomarker-driven populations have been accepted by FDA and EMA for conditional approval, as seen with the NTRK inhibitors. Notably, pembrolizumab received three relevant accelerated approvals in the US; however, these indications are not approved in the EU. When considering this approach, postmarketing requirements should be discussed early with regulatory agencies. In terms of endpoints, OS has historically been used to justify traditional approval. In second-line or later settings, regulators have granted conditional approval based on ORR. However, the lack of OS benefit observed in the confirmatory KEYNOTE-061 study for pembrolizumab illustrates the need to further validate whether ORR is a reliable surrogate endpoint in metastatic GC. Progression-free survival (PFS) is often included as a coprimary or secondary endpoint; however, there is no approval precedent based on PFS alone. Further, PFS is a suboptimal endpoint in late-line-settings because progression often occurs within the scan interval range. Thus, it is critical for sponsors to consider the changing treatment paradigm when designing future clinical trials in metastatic GC.