Pembrolizumab Combo Improves PFS/OS Vs Chemo in Urothelial Carcinoma

The FDA previously granted accelerated approval to pembrolizumab plus enfortumab vedotin for patients with locally advanced or metastatic urothelial carcinoma who were unable to receive cisplatin-based chemotherapy in April 2023.

Pembrolizumab (Keytruda) plus enfortumab vedotin-ejfv (Padcev) produced statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) compared with chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma, according to a press release on topline results from the phase 3 KEYNOTE-A39 trial (NCT04223856).¹

Investigators also reported a statistically significant improvement with respect to overall response rate (ORR) among patients receiving pembrolizumab in combination with enfortumab vedotin. Additionally, the safety profile of pembrolizumab plus enfortumab vedotin was comparable with previous reports of the combination.

The FDA previously granted accelerated approval to pembrolizumab plus enfortumab vedotin for patients with locally advanced or metastatic urothelial carcinoma who were unable to receive cisplatin-based chemotherapy in April 2023.² Supporting data for the accelerated approval came from the phase 1b/2 EV-103 or KEYNOTE-869 trial (NCT03288545), in which investigators reported an ORR of 68.0% (95% CI, 59%-76%) among patients receiving the combination, which included a complete response rate of 12.0%.

Developers intend to confirm the accelerated approval of pembrolizumab and enfortumab in the previously described population with data from the phase 3 KEYNOTE-A39 trial.

“The results of this pivotal phase 3 study are highly encouraging and showed a statistically significant survival benefit for the combination of [pembrolizumab] with the antibody-drug conjugate enfortumab vedotin in cisplatin-eligible or cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma,” Eliav Barr, MD, senior vice president and head of global clinical development and chief medical officer at Merck Research Laboratories, said in the press release.¹ “We look forward to sharing these data with the medical community and regulatory authorities.”

In the phase 3 KEYNOTE-A39 or EV-302 trial, investigators assessed 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma regardless of their eligibility to receive cisplatin-based chemotherapy. In the experimental arm, patients received 200 mg of pembrolizumab intravenously every 3 weeks plus 125 mg/m² of enfortumab vedotin intravenously on days 1 and 8 of each 3-week cycle. In the comparator arm, patients received intravenous gemcitabine on day 1 and 8 of each 3-week cycle plus carboplatin or cisplatin intravenously every 3 weeks.

The trial’s primary end points were PFS based on RECIST v1.1 criteria and OS. Secondary end points included ORR as assessed by blinded independent central review per RECIST v1.1 criteria, time to pain progression, duration of response, disease control rate, and adverse effects.

Patients 18 years and older with histologically documented unresectable locally advanced or metastatic urothelial carcinoma and measurable disease per RECIST v1.1 criteria were able to enroll on the study. Additional eligibility criteria included having archival tumor tissue for PD-L1 testing, an ECOG performance status of 0 to 2, and adequate hematologic and organ function.

Those who received previous treatment with enfortumab vedotin or a PD-L1 inhibitor for any malignancy were unable to enroll on the trial. Patients were also unable to enroll if they had uncontrolled diabetes, a life expectancy of lower than 12 weeks, and active central nervous system metastases.

References

1. Merck announces phase 3 KEYNOTE-A39/EV-302 trial met dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in certain patients with previously untreated locally advanced or metastatic urothelial cancer. News release. Merck. September 22, 2023. Accessed September 25, 2023. https://shorturl.at/izHLS
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 September 25, 2023. http://bit.ly/3nGtsjh