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Merck’s struggles in gastric adenocarcinoma continue

The influence of Merck & Co’s Keytruda in gastric adenocarcinoma – a setting that paints an increasingly confusing picture for doctors prescribing PD-(L)1 drugs – has waned some more. Today the drug failed in the perioperative setting in Keynote-585, falling behind Bristol Myers Squibb’s rival Opdivo, which carries an adjuvant US label based on Checkmate-577. Keynote-585 might separately also have confirmed a third- line accelerated label for Keytruda, but that indication has already been pulled. More concerning is Keynote-811, a study backing accelerated approval of a first-line Keytruda/Herceptin/chemo combo in Her2-positive patients, which on Friday yielded a PFS benefit only in PD-L1 expressers; accordingly Merck is moving to restrict that US label. Interestingly, Opdivo has full US approval for a first-line chemo combo in all comers, even though its Checkmate-649 trial only tested Her2-negatives, though inthe EU the label is much narrower, stating that patients have to be Her2-negative and PD-L1 ≥5% expressing. Keytruda’s next US battleground is a first-line chemo combo, which has a 16 December Pdufa date; the corresponding Keynote-859 trial concerned Her2-negatives only, and showed no effect in PD-L1 non-expressers, so the FDA’s verdict will be interesting.

 

Table 1. Keytruda's struggles in gastric/gastroesophageal junction adenocarcinoma

DateSetting/eventRelevant trial
Sep 20173rd-line PD-L1 +ve (≥1%), accelerated US approvalKeynote-059
Dec 20172nd-line PD-L1 +ve (≥1%), failed for OSKeynote-061
Apr 20191st-line PD-L1 +ve, inconclusiveKeynote-062
May 20211st-line Her2 +ve, accelerated US approval for Herceptin comboKeynote-811
Jul 20213rd-line accelerated US approval withdrawnKeynote-061 & 062
Jun 20231st-line Her2 +ve, US label for Herceptin combo being narrowed to PD-L1 +ve (≥1%)Keynote-811
Jun 2023Neoadj (chemo combo)/adjuvant, failed for EFSKeynote-585
Dec 20231st-line (Her2 -ve? PD-L1 +ve?), Pdufa date for chemo comboKeynote-859

Source: company statements.

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Molecular Drug Targets