When it comes to the use of PD-1 inhibitors in stomach cancer, the FDA has put its money where its mouth is.
After questioning the benefits of checkpoint inhibitors in stomach cancer cases without PD-L1 expression, the FDA has moved to restrict the use of Merck & Co.’s and Bristol Myers Squibb’s immunotherapies in those patients.
BMS’ Opdivo, used in combination with chemotherapy, is now allowed in advanced or metastatic gastric, gastroesophageal junction (GEJ) and esophageal cancers only among patients whose tumors express PD-L1. Simultaneously, the approval for a combination of Opdivo and BMS’ Yervoy in first-line esophageal squamous cell carcinoma has also been limited to PD-L1-positive disease.
Similarly, the label for Merck’s Keytruda in gastric, GEJ and esophageal cancers has been narrowed to PD-L1-positive tumors as well. The amendment to Keytruda’s gastric or GEJ adenocarcinoma uses only touches HER2-negative disease in this situation because the drug’s HER2-positive approvals in those settings had already been narrowed to PD-L1-positive cases in March.
The revised indications reflect the patient populations for whom the drugs have favorable risk-benefit assessments, the FDA said in two separate letters (PDFs) sent to the drugmakers late May.
In the phase 3 Keynote-859 trial, Keytruda and chemo showed a statistically significant improvement in overall survival versus chemo alone in a broad population of patients with HER2-negative gastric or GEJ adenocarcinoma. However, an exploratory analysis of the PD-L1-negative subgroup showed a mere 8% death-risk reduction, indicating that the improvement in the overall population was primarily attributed to the results observed in PD-L1-positive patients, according to Keytruda’s updated label.
The FDA's move was expected after the regulator last year raised concerns over the use of PD-1 inhibitors in PD-L1-negative cancers affecting the upper gastrointestinal tract. Before that, the agency had signed off on broad approvals for the therapies without any PD-L1 biomarker restrictions.
After combing through PD-L1 subgroup data from separate phase 3 trials of three PD-1 inhibitors, the FDA found that the drugs’ risk-benefit profiles appeared unfavorable in PD-L1-negative patients.
An external advisory committee in September voted overwhelmingly in support of the FDA’s updated view.
Following that meeting, BeOne (formerly BeiGene) was the first to receive a verdict—given it had an open FDA application at the time. In December, the company’s Tevimbra, used in combination with chemotherapy, was approved in first-line, PD-L1-positive HER2-negative gastric or GEJ cancers.
Then Merck and BMS, despite having argued for continued broad labels at the advisory committee meeting, filed revisions to their existing indications late February, according to the FDA letters.
This isn’t the first time that the FDA has pared back existing approvals for PD-1/L1 inhibitors. Back in 2018, after noticing a potential detriment to patient survival, the FDA restricted the use of Keytruda and Roche’s Tecentriq as single agents in certain bladder cancer patients who are not eligible for cisplatin-containing chemotherapy.
In an updated formal clearance granted in 2021, Keytruda monotherapy’s use in newly diagnosed bladder cancer only covers patients who are ineligible for any platinum-based chemo.