Checkpoint Inhibitors in Advanced Upper GI Cancers After 2024 FDA Shift

Ronan J. Kelly, MD, MBA, director of Oncology at Baylor Scott & White Charles A. Sammons Cancer Center and director of Scientific Discovery and Precision Medicine at Baylor University Medical Center, reviews the evolving frontline treatment paradigm for advanced gastric and gastroesophageal (GE) junction cancers, emphasizing the integration of immune checkpoint inhibition into routine practice.

Historically, outcomes in metastatic upper gastrointestinal cancers were poor. According to Kelly, the phase 3 CheckMate 649 trial (NCT02872116) marked a turning point, demonstrating a statistically and clinically meaningful overall survival benefit with the addition of nivolumab (Opdivo) to chemotherapy in the first-line setting. These data established chemoimmunotherapy as a standard of care for appropriately selected patients.

A key clinical consideration highlighted by Kelly is the role of PD-L1 expression, measured by combined positive score (CPS), in guiding treatment selection. While initial regulatory approvals, including the nivolumab approval, permitted use irrespective of PD-L1 status, subsequent review by the FDA Oncologic Drug Advisory Committee (ODAC) in 2024 led to refinement of the indication. Current approvals restrict use of checkpoint inhibitors in this setting to tumors with CPS ≥1, reflecting data showing that therapeutic benefit is largely confined to this biomarker-defined population.

From a practical standpoint, this decision underscores the necessity of PD-L1 testing at diagnosis of advanced disease. The majority of patients demonstrate CPS ≥1 and are therefore candidates for nivolumab-based regimens. In contrast, patients with CPS <1 derive minimal benefit, and treatment strategies in this subgroup remain an area of active investigation.

Kelly notes the expanding therapeutic landscape, including established targets such as HER2 and emerging biomarkers like Claudin 18.2. Ongoing trials are focused on optimizing treatment sequencing and developing effective approaches for immunologically “cold” tumors.

TRANSCRIPTION:

0:06 | This is a difficult group of tumors to treat historically… The advent of the immune checkpoint inhibitors, though, have really started moving things in the right direction. Because before that, we weren't really able to break through median overall survival barrier of 1 year in that advanced metastatic gastric or GE junction space. But thankfully, as a result of the immune checkpoint inhibitors, we have broken through there, and we're also seeing newer targets emerging—including HER2, which we've known about, and Claudin 18.2 has been the newer one—but the immune checkpoint inhibitors, really, in the last number of years, since 2020, 2021 have emerged as really significant contributors to improving patient outcomes.

So we saw the first study, CheckMate 649, [which] was published in The Lancet in 2021, and this study was the first study that showed the efficacy improvement with immune checkpoint inhibitors plus chemotherapy. Now, subsequently, as a result of an FDA ODAC meeting, there were some changes in the regulatory approval around the use of PD-L1 CPS scoring. When those initial studies came out, the approval was for allcomers, regardless of PD-L1 score. But as a result of that FDA ruling, the change has occurred that only patients [whose tumors] have CPS ≥1 would continue to have the FDA approval. So really, PD-L1 CPS is a really important biomarker... And what we've seen is most of the benefits—in fact, all the benefits are occurring in those tumors that are immunologically “hot,” so CPS ≥1.

The FDA ruling [was] that [for] those tumors that are “cold,” CPS 0 or <1, the approval to give immune checkpoint inhibitors there would be taken away. And that was actually the ruling for all 3 drug companies that had immune checkpoint inhibitors approved in that space. Nivolumab was the first, but then came pembrolizumab [Keytruda], and then tislelizumab [Tevimbra]. So all 3, that change occurred that only patients that have CPS ≥1 would be allowed have those medications. So, the good news is for about 70% to 80% of all patients with gastric cancer, their tumors will be CPS ≥1. So you know, what to do for those that are cold? That's the source of many clinical studies at the minute in tumors that are immunologically cold.