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An FDA advisory committee will consider whether PD-L1 expression cutoffs should guide use of checkpoint inhibitors to treat advanced gastroesophageal cancers.

Current approved indications for three different PD-1/PD-L1 inhibitors allow use of the drugs in advanced gastroesophageal cancers irrespective of PD-L1 expression levels. FDA staff reports suggest the agency might want to rethink those approvals in light of new evidence the drugs' efficacy is limited to certain subgroups that can be defined by PD-L1 expression.

The (ODAC) will convene in separate sessions on Thursday to consider the evidence and recommend maintaining the status quo or setting PD-L1 expression levels for the indications. In the morning, ODAC panelists will hear from FDA staff and representatives of three drug companies about use of PD-1/PD-L1 inhibitors to treat metastatic/unresectable HER2-negative gastric adenocarcinoma. The afternoon session will cover immune checkpoint inhibitors (ICIs) for metastatic/unresectable esophageal squamous cell carcinoma.

Since the FDA granted PD-L1 expression-agnostic approvals for first-line treatment of gastric/gastroesophageal junction (GEJ) adenocarcinoma, consistent evidence from a patient-level pooled population and a meta-analysis has emerged for a predictive role for PD-L1 expression. As such, approval of PD-1/PD-L1 inhibitors "for all randomized patients may not be in the best interest of patients with tumors with low PD-L1 expression," FDA staff stated in the report.

"Addition of ICIs to standard-of-care [SOC] chemotherapy for the treatment of patients with PD-L1 <1 does not appear to result in benefit," the report continued. "Benefit for patients with PD-L1 >10 have the greatest magnitude of benefit. Benefit is unclear in patients with PD-L1 levels less than 10 across the [drug] class."

"If patients with low or no PD-L1 expression are not expected to benefit based on the available data, then administering anti-PD-1 therapy has the potential for harm, including serious immune-related adverse events on top of a malignancy that can markedly affect a patient's quality of life."

The drug companies have submitted reports outlining evidence that supported the PD-L1 expression-agnostic approvals. Merck points out that the KEYNOTE-811 and KEYNOTE-859 randomized trials showed that "the addition of pembrolizumab [Keytruda] to SOC treatment resulted in statistically significant and clinically meaningful improvements in OS [overall survival], PFS [progression-free survival], and [objective response rate] in all patients enrolled in these studies." Company officials also note that the trials followed an "FDA-agreed protocol and protocol-specified analysis plans."

The Bristol Myers Squibb report notes that the CheckMate-649 trial with nivolumab (Opdivo) showed "clinically meaningful improvements" in PFS and OS among patients with a PD-L1 cumulative positive score (CPS) >5, OS in patients with PD-L1 CPS >1 and all randomized patients, and PFS in patients with PD-L1 CPS ≥1 and all randomized patients.

BeiGene officials reviewed results of the RATIONALE-305 study with tislelizumab (Tevimbra). The trial showed clinically meaningful improvement in OS among patients with PD-L1 ≥5% and a trend toward improved survival in PD-L1 subgroups (≥5%, ≥5% to <10%, and ≥10%). Efficacy in the intention-to-treat population and additional PD-L1 expression levels "are comparable with the results seen in other agents in this class."

The panel will vote on the question of whether first-line PD-1/PD-L1 inhibition for HER2-negative, microsatellite stable gastric/GEJ adenocarcinoma has a favorable risk/benefit profile for patients with PD-L1 expression <1.

During the afternoon session, ODAC will hear similar presentations related to evidence for PD-L1 expression-agnostic approval of PD-1/PD-L1 inhibitors for esophageal squamous cell carcinoma. The FDA staff report states that efficacy data submitted by the sponsors to FDA "suggest that PD-L1 expression is a predictive biomarker in identifying patients most likely to benefit from the use of ICIs. In these three studies, the OS benefit observed in the [intention-to-treat] population appears to be predominantly attributable to subgroups of patients with higher PD-L1 expression, with limited efficacy in terms of OS benefit observed in patients with low or no PD-L1 expression."

For their part, the company representatives will review evidence from the KEYNOTE-590 trial with pembrolizumab, the CheckMate-648 trial with nivolumab and ipilimumab (Yervoy), and the trial with tislelizumab.

The question to the panel is identical to the one from the morning session, except pertaining to unresectable/metastatic esophageal squamous cell carcinoma.

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