Merck’s Keytruda is riding a winning streak in bladder cancer.
Following FDA approvals in the metastatic and non-muscle invasive settings, the anti-PD-1 therapy has delivered a positive readout in localized muscle-invasive and locally advanced urothelial carcinoma.
Compared with simple observation, Keytruda lowered the risk of disease recurrence or death when used after surgery in a phase 3 trial, Merck said Thursday.
The Ambassador trial hit its primary endpoint of disease-free survival at an interim analysis, and the study remains ongoing to evaluate whether Keytruda can prolong patients’ lives, the other dual primary endpoint. The study will also analyze results in PD-L1 expression subgroups.
With the dual primary endpoint design, the National Cancer Institute-sponsored trial can be called successful by hitting just one goal. Merck said it will discuss the results with regulators.
Keytruda’s success as an adjuvant therapy in the muscle-invasive trial was expected. Since 2021, Bristol Myers Squibb’s rival PD-1 inhibitor Opdivo has boasted FDA approval for this use.
Compared with placebo, adjuvant Opdivo more than doubled the average time patients with resected, high-risk bladder cancer lived without disease recurrence to 22 months from 10.9 months, according to a longer-term follow-up of the CheckMate-274 trial.
Up to half of patients with bladder cancer experience recurrence within one year after surgery, Marjorie Green, M.D., head of late-stage oncology clinical development at Merck Research Laboratories, said in a statement Thursday.
Keytruda first entered the bladder cancer arena in 2017 with an accelerated approval to treat patients with newly diagnosed, advanced disease who are ineligible for cisplatin-based chemo, plus a regular approval for chemo-experienced patients.
But after a phase 3 flop, the FDA in 2021 restricted Keytruda monotherapy’s first-line use, allowing it to be only used in patients who can’t take any form of platinum chemo.
Then this April, Keytruda returned to its original position in the first-line cisplatin-ineligible setting as part of a combination with Seagen and Astellas’ antibody-drug conjugate Padcev.
The PD-1/ADC combo also made a splash two weeks ago with a positive readout from the closely watched EV-302 trial, which tested the medicines in first-line patients regardless of platinum chemo eligibility.
Before the success of the Padcev combo, Merck and its partner Eisai tried to improve Keytruda’s prospects by joining it with the tyrosine kinase inhibitor Lenvima. But the negative outcome from the phase 3 LEAP-011 trial proved Lenvima worthless in certain front-line patients who don’t qualify for platinum chemo.
Alongside the roller coaster ride in the first-line metastatic setting, Keytruda monotherapy in early 2020 won an FDA nod to treat high-risk non-muscle invasive bladder cancer that’s unresponsive to standard BCG treatment.
Merck and Seagen/Astellas also hope to expand the Keytruda-Padcev pairing for additional bladder cancer areas. The phase 3 EV-303 trial is testing Keytruda with or without Padcev for use both before and after surgery in muscle-invasive bladder cancer patients who are cisplatin-ineligible or decline cisplatin treatment.
Meanwhile, the phase 3 EV-304 trial is pitting the Keytruda-Padcev combo—used in both pre- and post-surgical muscle-invasive settings—against neoadjuvant cisplatin-based chemo. In that same cisplatin-eligible population, Merck by itself is running Keynote-866 for Keytruda and chemo around surgery.