In a first, Merck's Keytruda snags FDA nod for esophageal cancer as stomach cancer label hangs in the balance

PD-1/L1 inhibitors have had a relatively low success rate against cancers that affect the digestive system. But Merck & Co. can now tout a first-in-class approval for one disease type—though its archrival Bristol Myers Squibb isn’t so far behind.

Merck’s Keytruda, used in tandem with platinum- and fluoropyrimidine-based chemotherapy, is now cleared in the U.S. for newly diagnosed esophageal or gastroesophageal junction carcinoma, the company said Tuesday.

The go-ahead covers tumors regardless of PD-L1 expression, but it’s limited to those that aren’t amenable to surgical removal or definitive chemoradiation.

It marks the first time a PD-1/L1 agent is allowed for the first-line treatment of this type of gastrointestinal cancer. “There have been few advances in improving survival outcomes in the first-line treatment setting for esophageal cancer over the last three decades,” Roy Baynes, Merck SVP and head of global clinical development, noted in a statement.

Regulators based the green light on data showing the Keytruda-chemo combo could top a chemo pairing of cisplatin and fluorouracil at extending patients' lives in the phase 3 Keynote-590 trial. In that study, the Merck regimen cut the risk of death by 27% over chemotherapy, as patients on Keytruda lived a median 12.4 months versus 9.8 months for chemo.

RELATED: ESMO: Merck's Keytruda pushes for 2nd esophageal cancer nod with first-line survival win

Before the first-line nod, Keytruda, as a single agent, already had an FDA green light for previously treated esophageal or gastroesophageal junction cancer. But that label is being confined to the squamous cell subtype with tumors that express PD-L1 at a high level, with a combined score of at least 10%; the drug failed to beat chemo in all randomized patients in the Keynote-181 trial, which also enrolled patients with lower PD-L1 levels. In the U.S., about one-third of newly diagnosed esophageal cancer cases are squamous cell carcinoma, and the rest are adenocarcinoma, according to Merck.

In the second-line setting, Bristol Myers Squibb’s PD-1 rival Opdivo also boasts a label in esophageal squamous cell carcinoma after prior chemotherapy treatment, but the FDA nod doled out last June covers tumors regardless of PD-L1 expression level.

RELATED: ESMO: Bristol Myers' Opdivo racks up GI cancer data for 2 potentially practice-changing FDA nods

Bristol’s also chasing Merck in front-line esophageal cancer. Adding Opdivo to chemo reduced the risk of death by 20% in all trial participants regardless of PD-L1 expression, and the risk reduction amounted to 29% in patients with PD-L1 levels of at least 5%, according to data unveiled from the CheckMate-649 trial at last year’s European Society of Medical Oncology virtual annual meeting. The study is also testing Bristol’s dual immunotherapy regimen that combines Opdivo with CTLA4 inhibitor Yervoy, but data aren't yet mature.

One key difference between Keynote-590 and CheckMate-649 is that the Bristol study also includes patients with gastric cancer, another hard-to-treat disease type.  

Keytruda has had a mixed showing in stomach cancer. In 2017, the blockbuster secured an accelerated FDA approval for the third-line treatment of PD-L1-positive gastric or gastroesophageal junction adenocarcinoma. But that conditional nod was recently put under question amid an industrywide FDA review.

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That’s because the drug failed in the second-line Keynote-061 trial. And in previously untreated stomach cancer, the Keynote-062 trial found a combination of Keytruda and chemo failed to outdo solo chemo at extending patients’ lives, and solo Keytruda matched chemo in terms of overall survival. Both trials were meant to confirm the original third-line nod.

The Keytruda third-line gastric cancer indication is now scheduled to be discussed at an upcoming FDA advisory committee meeting in April.