The standing ovation for Keytruda and Padcev in metastatic bladder cancer at the 2023 European Society for Medical Oncology (ESMO) Congress still echoes, and, now, the pair from Merck & Co., Pfizer and Astellas has pulled off similarly showstopping results in certain patients with muscle-invasive bladder cancer (MIBC).
The combination of Merck’s Keytruda and Pfizer and Astellas’ Padcev reduced patients' risk of death by a whopping 50% when used before and after bladder removal surgery in those with MIBC who are not eligible for or declined cisplatin-based chemotherapy compared with surgery alone, according to results to be presented at the 2025 ESMO Congress.
The PD-1/antibody-drug conjugate combo also significantly improved event-free survival (EFS) by 60% versus surgery alone. A negative event includes progression of disease that precludes surgery or failure to undergo surgery, gross residual disease left behind during surgery, cancer recurrence or death.
The results, from the phase 3 Keynote-905 or EV-303 study, are “transformational,” Marjorie Green, M.D., Merck’s head of oncology global clinical development, said in an interview with Fierce Pharma.
There have been no treatment advances in more than 25 years for MIBC patients who can’t take cisplatin, Green noted.
Patients who underwent surgery alone went a median 15.7 months without experiencing a negative event and lived a median 41.7 months. The median for both EFS and overall survival were not reached for the Keytruda-Padcev arm, meaning more than half of patients were alive without a negative event at the time of the analysis.
The trial included two different patient populations: patients who are actually cisplatin-ineligible and those who declined cisplatin. As evidenced by Roche’s recent failed bid for Columvi in diffuse large B-cell lymphoma, the FDA’s oncology department has historically raised uncertainty about results from patients who declined a standard treatment, especially if they appear to be driving positive results, because it can be challenging to characterize those patients.
In Keynote-905/EV-303, 83.5% of patients are actually cisplatin-ineligible, according to Merck. The magnitude of Keytruda and Padcev’s EFS benefit was actually larger in those patients, at 63%, versus 42% in patients who declined chemotherapy.
The other question facing the regimen is whether the FDA will take issue with the perioperative trial design. As highlighted by an advisory committee meeting last year on perioperative lung cancer treatment, the agency and doctors want trial designs and data that tease out the contributions of treatments between the presurgical and postsurgical settings.
The companies are preparing to discuss that topic with the FDA and believe that existing data suggest both the neoadjuvant and the adjuvant components are necessary, Johanna Bendell, M.D., Pfizer’s oncology chief development officer, said in a separate interview with Fierce.
“With data strong like this, it makes it much easier to have those discussions,” Bendell said.
The Keynote-905 trial appears to show a utility for neoadjuvant use of Keytruda and Padcev. At the time of surgery, 57.1% patients who got the combo—versus 8.6% in the control arm—achieved pathological complete response (pCR), meaning no signs of cancer were detected in resected tissue samples.
But questions remain as to whether patients who have achieved a pCR still need to get adjuvant Keytruda and Padcev after surgery. Green noted that there are less data to support the surrogacy and outcomes of pCR in bladder cancer compared with some other tumor types such as breast and lung cancers.
PD-1/L1 inhibitors have historically shown some good results in the adjuvant setting of bladder cancer, including the phase 3 Keynote-123 trial, also dubbed Ambassador, which showed a disease-free survival benefit for Keytruda in localized MIBC and locally advanced bladder cancer. When that result was announced two years ago, the trial remained ongoing to evaluate its other dual primary endpoint of overall survival, and Merck has not laid out a regulatory plan based on the study.
More recently, Roche and its diagnostic partner Natera announced a positive readout for the Swiss pharma’s Tecentriq for adjuvant treatment of MIBC but in a select group of patients who tested positive for molecular residual disease after surgery for up to 12 months. The results from the study, coded IMvigor011, will also be presented at ESMO 2025. That study’s baseline patient population is different, Green noted, as it allowed patients who had or hadn’t received neoadjuvant chemo.
Green argued that the tendency within the medical community is to offer a perioperative treatment in bladder cancer, where the biggest value for patients lies.
While Keytruda-Padcev is the first PD-1/L1 regimen to claim a perioperative win in cisplatin-ineligible MIBC, AstraZeneca has projected a readout this year for its Volga trial, which adds Imfinzi on top of Padcev with or without the British pharma’s CTLA-4 inhibitor Imjudo.
For patients who are eligible for cisplatin, which is a larger MIBC population, the Keynote-B15/EV-304 trial is testing the Keytruda-Padcev regimen. The efficacy bar for that study will be higher compared with the current Keynote-905/EV-303 trial because, rather than surgery alone, patients are also receiving neoadjuvant chemotherapy. Besides, AZ’s Imfinzi, used on top of neoadjuvant cisplatin-based chemo, already won an FDA approval in MIBC. Merck has a matching study for Keytruda-chemo, coded Keynote-866, which is expected to read out soon.