The first-line combination of enfortumab vedotin-ejfv (EV; Padcev) and pembrolizumab (Keytruda) elicited a response in nearly two-thirds of patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-based therapy, according to findings from cohort K of the phase 1b/2 EV-103 trial published in the Journal of Clinical Oncology (JCO).1
Cohort K of the trial randomized patients to the combination of EV and pembrolizumab (n = 76) or EV alone (n = 73). While positive clinical activity was observed in both treatment arms, the confirmed objective response rate (ORR) was stronger with the combination at 64.5%, compared with 45.2% with EV monotherapy. The median duration of response was not yet reached with EV/pembrolizumab vs 13.2 months with EV alone. Among responders, 65.4% vs 56.3% of the 2-arms, respectively, remained in response at 12 months.
The study investigators reported that toxicity was manageable with the combination, with no new safety signals compared with previously reported research. Grade ≥3 treatment-related adverse events TRAEs occurring most frequently with EV plus pembrolizumab were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). Additionally, the investigators noted that EV-related TRAEs of special interest across all grades that occurred in the combination group were skin reactions (67.1%) and peripheral neuropathy (60.5%).
“This report provides a strong foundation for the ongoing phase 3 studies of the EV and pembrolizumab combination in muscle invasive bladder cancer. Toxicities although manageable are increased over EV alone and maturation of the survival data may also shed light on addressing toxicity, both clinical and financial, concerns as well as sequencing approaches,” JCO associate editor Michael A. Carducci, MD, who was not an author on the study, wrote in an accompanying commentary.
FDA approval of EV/pembrolizumab in this setting
The FDA granted an accelerated approval to EV plus pembrolizumab in April 2023 for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.2
The approval was supported by results from a combined population of 121 patients treated with the combination in either the dose escalation cohort, cohort A, or cohort K from the EV-103 trial. The ORR in this combined population was 68%. Of the responders, 12% had a complete response, and 55% of patients had a partial response.
Regarding safety, adverse events occurring in at least 20% of patients included, glucose increased (74%), aspartate aminotransferase increased (73%), rash (71%), hemoglobin decreased (69%), creatinine increased (69%), peripheral neuropathy (65%), lymphocytes decreased (64%), fatigue (60%), alanine aminotransferase increased (60%), sodium decreased (60%), lipase increased (59%), albumin decreased (59%), alopecia (52%), phosphate decreased (51%), decreased weight (48%), diarrhea (45%), pruritus (40%), decreased appetite (38%), nausea (36%), dysgeusia (35%), potassium decreased (35%), neutrophils decreased (32%), urinary tract infection (30%), constipation (27%), potassium increased (27%), calcium increased (27%), peripheral edema (26%), dry eye (25%), dizziness (23%), arthralgia (23%), and dry skin (21%).
Since combination received an accelerated it approval from the FDA, it means that continued approval of the combination is eventually contingent on a confirmatory trial validating the regimen’s efficacy.
1. O'Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer [published online ahead of print June 27, 2023]. J Clin Oncol. doi: 10.1200/JCO.22.02887
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. Published online and accessed April 3, 2023. https://bit.ly/3MdWuAJ