FDA checks checkpoint inhibitors

It’s been brewing for a while, and the FDA has finally restricted checkpoint inhibitors to PD-L1 expressers in stomach cancers. Letters posted by the agency in May, but first reported by Fierce Pharma this week, show that Merck & Co’s Keytruda and Bristol Myers Squibb’s Opdivo will now only be indicated for first-line oesophageal and gastric cancer patients with PD-L1 expression of 1% or higher. This has looked likely since an FDA adcom last year raised questions about the benefit of checkpoint inhibitors in patients with PD-L1 levels below 1%. Merck and Opdivo chemo combos (and a Yervoy combo of the latter) were previously approved in all comers, except in HER2-positive gastric cancer, where Keytruda had already been restricted to ≥1% expressers, based on the Keynote-811 trial. The FDA set the tone with BeOne’s Tevimbra, which wasn’t approved at the time of the adcom, but later got the go ahead in PD-L1 ≥1% expressers only. The latest decision could cut the addressable populations by 10-20%, the agency previously said. It also brings US indications largely into line with those in the EU – although there are some instances where the European regulator has imposed even stricter cutoffs.  Anti-PD-(L)1 drugs in stomach cancersTrialRegimenPrecise 1st-line settingUS statusEU statusCheckmate-648Opdivo + YervoyOesophageal squamous cell carcinomaApproval restricted to PD-L1 ≥1% May 2025*Approved in PD-L1 ≥1% Apr 2022Opdivo + chemoOesophageal squamous cell carcinomaApproval restricted to PD-L1 ≥1% May 2025*Approved in PD-L1 ≥1% Apr 2022Checkmate-649Opdivo + chemoGastric/GEJ/oesophageal adenocarcinomaApproval restricted to PD-L1 ≥1% May 2025*Approved in PD-L1 ≥5% Oct 2021Keynote-590Keytruda + chemoOesophageal/GEJ carcinomaApproval restricted to PD-L1 ≥1% May 2025*Approved in PD-L1 ≥10% Jun 2021Keynote-811Keytruda + Herceptin + chemoHER2+ve gastric/GEJ adenocarcinomaFull approval in PD-L1 ≥1% Mar 2025**Approved in PD-L1 ≥1% Sep 2023Keynote-859Keytruda + chemoHER2-ve gastric/GEJ adenocarcinomaApproval restricted to PD-L1 ≥1% May 2025*Approved in PD-L1 ≥1% Dec 2023Rationale-305Tevimbra + chemoHER2-ve gastric/GEJ adenocarcinomaApproved in PD-L1 ≥1% Dec 2024Approved in PD-L1 ≥5% Nov 2024Rationale-306Tevimbra + chemoOesophageal squamous cell carcinomaApproved in PD-L1 ≥1% Mar 2025Approved in PD-L1 ≥5% Nov 2024Notes: *previously carried all comer labels; **followed AA in all comers May 2021, restricted to PD-L1 ≥1% in Nov 2023. Source: OncologyPipeline.