Keytruda falls short on OS endpoint in bladder cancer study
26 Jan 2024
Clinical ResultPhase 3ASCODrug ApprovalImmunotherapy
Merck & Co.'s Keytruda (pembrolizumab) closed out on a high note towards the end of last year, with two positive readouts in bladder cancer and the FDA signing off on full approval for a combination with Padcev (enfortumab vedotin-ejfv). However, efforts to expand Keytruda's position in this treatment space could face some challenges, according to new Phase III results unveiled Friday at the American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium.
While Merck confirmed that its PD-1 inhibitor improved disease-free survival (DFS) by a significant 31% when used as adjuvant therapy, it fell short on the trial's other co-primary endpoint of overall survival (OS). Marjorie Green, head of oncology, global clinical development, at Merck Research Laboratories, was nevertheless pleased with the pivotal KEYNOTE-123 results, saying they "demonstrate the expanding role of Keytruda into earlier stages of resectable muscle-invasive bladder cancer (MIUC)."
KEYNOTE-123 trial, also known as AMBASSADOR, enrolled 702 patients with localised MIUC and locally advanced urothelial carcinoma who were randomised to receive Keytruda or undergo observation. Merck in October reported that the trial had achieved the dual primary endpoint of DFS.
Observation cohort edge in survival
Median DFS was 29 months with Keytruda, or 15 months longer than what was reported in the observation arm, according to Friday's late-breaking presentation at ASCO GU. This first interim analysis of the study also showed that the DFS results were consistent regardless of a patient's PD-L1 expression status.
However, the other survival endpoint did not achieve statistical significance, with the analysis suggesting OS favoured the observation arm. Specifically, after a median follow up of roughly 3 years, median OS with Keytruda was 50.9 months, compared to 55.8 months for the comparator group. Merck said the OS endpoint would continue to be monitored as the data mature.
The noted that 17.4% of patients receiving Keytruda withdrew from the trial without experiencing a DFS event, while the rate was 27.2% in the observation arm. It said that 22% of those in the observation group received an immune checkpoint inhibitorimmune checkpoint inhibitor following a DFS event. Bristol Myers Squibb rival immunotherapy Opdivo (nivolumab) in 2021 became the first adjuvant treatment to be approved in the US for high-risk bladder cancer patients.
The KEYNOTE-123 results amount to a partial victory for Keytruda, particularly in light of results Merck reported last year at the European Society of Medical Oncology (ESMO) congress. When paired with Astellas and Pfizer's antibody-drug conjugate Padcev, Keytruda reduced the risk of death by 53% versus chemotherapy in the Phase III KEYNOTE-A39 trial of patients with previously untreated locally advanced or metastatic urothelial carcinoma. The results led to the FDA in December converting an earlier accelerated approval of the combo to a full approval.
Aside from the Padcev combination, Keytruda's current label also includes use as monotherapy for previouslybtreated patients with locally advanced or metastatic urothelial carcinoma, and certain patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ, with or without papillary tumours.
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