Immune checkpoint inhibitors haven’t had tons of success in stomach cancer. Now, Merck has added one failure to the mix.
Merck’s Keytruda didn’t move the needle in terms of preventing tumors from returning when used around surgery for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma, the New Jersey pharma said Tuesday.
The phase 3 KEYNOTE-585 trial therefore failed on event-free survival (EFS), one of its two primary endpoints. The trial tested Keytruda alongside chemotherapy before surgery in the neoadjuvant setting, followed by a short period of the Keytruda-chemo combo in the adjuvant setting and then Keytruda monotherapy for up to 11 cycles. The control group didn’t receive Keytruda.
Keytruda was recently successful in prolonging EFS in a similar perioperative regimen in early-stage non-small cell lung cancer. Adding Keytruda in both the neoadjuvant and adjuvant settings cut the risk of disease recurrence, progression or death by 42% in resectable stage 2 to 3b NSCLC in the KEYNOTE-671 trial. That regimen doesn’t include any chemo in the adjuvant phase.
Perioperative Keytruda showed some improvements in EFS in the current stomach cancer trial, but the magnitude didn’t reach statistical significance, Merck said.
The PD-1 inhibitor did help more patients achieve no sign of cancer in resected tissue, thereby meeting the trial’s other primary endpoint on pathologic complete response. But pCR is an earlier measurement of efficacy. Regulators likely won’t consider a pCR win with a failure in the more mature EFS marker for a potential approval.
Before the early stomach cancer flop, Keytruda's chemo combo significantly pared down the risk of death by 22% over chemo alone in patients with newly diagnosed advanced HER2-negative gastric or GEJ cancers.
In addition, Keytruda, used alongside Herceptin and chemo, carries an FDA accelerated approval in first-line HER2-positive gastric or GEJ adenocarcinoma. But Merck is seeking to limit that indication after updated tumor progression data found Keytruda only conferred a benefit in a subgroup of patients with PD-L1-positive tumors.
As for Keytruda’s competitors, Bristol Myers Squibb’s Opdivo in 2021 won an FDA approval as an adjuvant therapy for completely resected esophageal or GEJ cancers following neoadjuvant chemoradiotherapy.
As the metastatic cancer market becomes saturated, companies have been testing their PD-1/L1 inhibitors in earlier stages of cancer. Merck currently counts about 20 ongoing Keytruda registrational studies across multiple types of early-stage cancers. These include the Keynote-975 trial, which is evaluating adding Keytruda to chemoradiotherapy in esophageal cancer to prevent recurrence.