First IO+ADC Combination Achieves Dual Primary Endpoints in Phase 3 Trial for Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma

Keytruda+Padcev (Nectin-4 ADC) versus ChemotherapyNewly diagnosed but locally invasive or advanced urothelialCancerThe Phase III clinical trial KEYNOTE-A39 met the dual primary endpoints of PFS and OS, with the key secondary endpoint being the overall response rate (ORR). K drug + Padcev also showed significant superiority over the control group.

First Phase 3 results for the KEYTRUDA® (pembrolizumab) and Padcev® (enfortumab vedotin-ejfv) combination showed a statistically significant and clinically meaningful improvement in OS, PFS and key secondary endpoint of overall response rate versus chemotherapy in these patients, who may or may not be eligible for cisplatin-based chemotherapy

RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced positive topline results from the Phase 3 KEYNOTE-A39 trial (also known as EV-302), which was conducted in collaboration with Seagen and Astellas, evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with Padcev (enfortumab vedotin-ejfv) versus chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). The trial enrolled patients who may or may not be eligible for treatment with cisplatin-based chemotherapy, regardless of PD-L1 status.

In the trial, KEYTRUDA in combination with enfortumab vedotin met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS), demonstrating a statistically significant and clinically meaningful improvement versus chemotherapy in patients with previously untreated la/mUC. The combination also showed a statistically significant improvement in overall response rate (ORR), a key secondary endpoint, versus chemotherapy. The safety profile of KEYTRUDA and enfortumab vedotin in this study was consistent with previously reported studies of this combination.

“The results of this pivotal Phase 3 study are highly encouraging and showed a statistically significant survival benefit for the combination of KEYTRUDA with the antibody-drug conjugate enfortumab vedotin in cisplatin-eligible or cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “This is an important milestone, as many patients with advanced urothelial carcinoma still experience disease progression following chemotherapy. We look forward to sharing these data with the medical community and regulatory authorities.”

The Phase 3 KEYNOTE-A39 trial is intended to serve as the confirmatory trial for the current U.S. accelerated approval of KEYTRUDA in combination with enfortumab vedotin as first-line treatment for patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy based on data from the KEYNOTE-869 trial (also known as EV-103) dose escalation cohort, Cohort A and Cohort K.

Merck, in collaboration with Seagen and Astellas, are evaluating this combination as part of an extensive clinical development program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in muscle-invasive bladder cancer in KEYNOTE-B15 (NCT04700124, also known as EV-304) and KEYNOTE-905 (NCT03924895, also known as EV-303).

About the KEYNOTE-A39 (EV-302) trial

The KEYNOTE-A39 trial (ClinicalTrials.gov, NCT04223856) is an open-label, randomized, controlled Phase 3 trial evaluating KEYTRUDA in combination with enfortumab vedotin compared with chemotherapy (gemcitabine plus cisplatin or carboplatin) for the treatment of patients with previously untreated la/mUC who may or may not be able to receive treatment with cisplatin-based chemotherapy. The dual primary endpoints are PFS as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and OS. Key secondary endpoints include ORR per RECIST v1.1 by BICR, time to pain progression and duration of response per RECIST v1.1 by BICR. The study enrolled 886 patients who were randomized to receive either:

• KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first) plus enfortumab vedotin (125 mg/m2 by IV on Days 1 and 8 of each three-week cycle for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs); or

• Gemcitabine (administered as IV infusion on Days 1 and 8 of each three-week cycle) plus platinum-containing chemotherapy (either carboplatin [administered by IV on Day 1 of each three-week cycle] or cisplatin [administered by IV on Day 1 of each three-week cycle]) for a maximum of six cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.