Pembrolizumab Yields Meaningful DFS in Muscle-Invasive Urothelial Carcinoma

The FDA granted accelerated approval to pembrolizumab plus enfortumab vedotin-ejfv for patients with locally advanced or metastatic urothelial carcinoma who are not candidates to receive cisplatin-based chemotherapy in April 2023.

Adjuvant treatment with pembrolizumab (Keytruda) produced a statistically significant and clinically meaningful improvement in disease-free survival (DFS) compared with observation among patients with localized muscle-invasive urothelial carcinoma and locally advanced urothelial carcinoma following surgery, according to findings from a prespecified interim analysis of the phase 3 AMBASSADOR trial (NCT03244384).¹

Based on a review from the independent data monitoring committee, investigators reported that the DFS benefit achieved with pembrolizumab met one of the trial’s dual primary end points. The trial will continue with an assessment of overall survival (OS), the other dual primary end point. Additionally, treatment with pembrolizumab raised no new safety signals.

Investigators will present results from the AMBASSADOR trial at a future medical meeting and discuss their findings with regulatory health authorities.

“Up to half of patients with bladder cancer who undergo surgery will experience recurrence within a year, underscoring the need for new treatment options in the adjuvant setting,” Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development at Merck Research Laboratories, said in the press release.¹ “These positive results highlight the potential of [pembrolizumab] to prevent recurrence after surgery for patients with localized muscle-invasive or locally advanced urothelial carcinoma.”

Investigators of the open-label, randomized phase 3 AMBASSADOR/A031501/KEYNOTE-123 trial are assessing pembrolizumab compared with observation as an adjuvant treatment for patients with localized muscle-invasive urothelial carcinoma and locally advanced urothelial carcinoma. Overall, 702 patients were randomly assigned to undergo a CT scan, CT urography, and/or MRI throughout the trial with or without intravenous pembrolizumab administered over 30 minutes every 3 weeks for up to 18 cycles or until disease progression or unacceptable toxicity.

The trial’s secondary end points include OS and DFS in patients with PD-L1–positive and PD-L1–negative disease for up to 5 years.

Patients 18 years and older with histologically confirmed muscle-invasive carcinoma of the bladder, urethra, upper tract, or lymph node–positive disease and available paraffin tissue samples were able to enroll on the trial. Additional eligibility criteria included having an ECOG performance status of 0 or 1; adequate absolute neutrophil counts, leukocytes, platelet counts, and hemoglobin levels; and available central PD-L1 testing results.

Those who received a live vaccine within 30 days of beginning study treatment or prior postoperative/adjuvant systemic therapy were not able to enroll on the trial. Patients were also unable to enroll if they had received prior anti–PD-1 or anti–PD-L1 treatment; any other investigational agent, major surgery, radiotherapy, or neoadjuvant chemotherapy within 4 weeks prior to registration; or had gross cancer at the surgical margins.

The FDA granted accelerated approval to pembrolizumab plus enfortumab vedotin-ejfv (Padcev) for patients with locally advanced or metastatic urothelial carcinoma who are not candidates to receive cisplatin-based chemotherapy in April 2023.² Supporting data for the approval came from the phase 1b/2 EV-103 or KEYNOTE-869 trial (NCT03288545). It was reported that patients receiving the regimen experienced an objective response rate of 68% (95% CI, 59%-76%), which included a complete response rate of 12%.

References

1. Merck’s KEYTRUDA® (pembrolizumab) met primary endpoint of disease-free survival (DFS) in certain patients with muscle-invasive urothelial carcinoma (MIUC) after surgery. News release. October 5, 2023. Accessed October 5, 2023. https://bit.ly/3PLPtau
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. News release. FDA. April 3, 2023. Accessed October 5, 2023. http://bit.ly/3nGtsjh