Pembrolizumab/enfortumab vedotin linked to improvements in patient-reported outcomes

The combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) is associated with a preservation or improvement in quality-of-life (QOL), functioning, and symptoms among patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy, according to an analysis of cohort K from the EV-103 trial (NCT03288545) published in the Journal of Clinical Oncology.¹

The randomized phase 3 EV-302 trial remains ongoing to assess the efficacy, safety, and patient-reported outcomes of the combination therapy.

Among patients who received the combination therapy, QOL was maintained through week 24 based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core Questionnaire (EORTC QLQ-C30). Clinically meaningful improvements were also observed in emotional functioning (10.20 [2.43]), pain (–14.99 [3.56]), and insomnia (–15.22 [3.92]) from baseline to week 24.

A worsening of fatigue, appetite loss, and dyspnea were observed at week 3, as well as a clinically meaningful worsening of diarrhea (12.57 [2.73]). Levels returned to baseline following week 3.

A clinically meaningful improvement was seen in worst pain, as measured by the Brief Pain Inventory Short Form (BPI-SF), from baseline to week 24 (–2.07 [0.37]). Consistent improvements were also noted in average pain (–0.66 [0.30] to –1.38 [0.31]), pain interference (–0.52 [0.32] to –1.32 [0.33]) and pain severity (–0.62 [0.29] to –1.16 [0.30]) from baseline vs weeks 8 to 24.

In the enfortumab vedotin monotherapy arm, QOL was maintained through week 24. A mild to moderate improvement in emotional functioning was observed at weeks 8 (6.88 [2.43]) and 24 (5.49 [2.89]). Clinically meaningful improvements were observed in EORTC QLQ-C30 pain (–12.55 [4.27]), insomnia (–14.46 [4.69]), and constipation (–10.09 [4.35]) at week 24.

Mild to moderate transient worsening of QOL, role, and physical and social functioning at week 3 (≤–7.61) was observed, but all improved over time. The investigators also noted a worsening of fatigue, appetite loss, dyspnea, nauseas, and vomiting as well as a clinically meaningful worsening in diarrhea at week 3. Levels returned to baseline following week 3.

Small to moderate improvements were observed in BPI-SF worst pain, average pain, pain interference, and pain severity from baseline to weeks 8, 12, and 24.

In total, the EV-103 cohort K analysis included 65 patients who received enfortumab vedotin plus pembrolizumab and 63 who received enfortumab vedotin alone.

Patient-reported outcomes were assessed at baseline, once per week for cycles 1-3, and in every cycle through the end of treatment using EORTC QLQ-C30 and BPI-SF.

The authors concluded, “These [patient-reported outcome] data are supportive of the use of [enfortumab vedotin plus pembrolizumab] as a 1L therapy option for patients who are cisplatin-ineligible.”

They also note that the randomized phase 3 EV-302 trial remains ongoing to assess the efficacy, safety, and patient-reported outcomes of the combination therapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (NCT04223856).

Additional data on enfortumab vedotin plus pembrolizumab

The FDA granted accelerated approval to the combination of enfortumab vedotin and pembrolizumab for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy in April 2023.²

The approval was supported by results from combined dose escalation/cohort A and cohort K of the phase 1b /2 EV-103 trial, which showed an objective response rate of 68% (95% CI, 58.7-76.0) in the efficacy population. Of the responders, 12% had a complete response and 55% of patients had a partial response.

In the dose escalation cohort and cohort A, the median duration of response was 22.1 months (range, 1.0+ to 46.3+). In cohort K, the median duration of response had not been reached (range, 1.2 to 24.1+).

In December 2023, the FDA converted the accelerated approval of the combination into a full approval based on data from the confirmatory phase 3 EV-302 trial.³ The full approval for pembrolizumab plus enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer includes the cisplatin-ineligible population from the accelerated approval and expands the indication to also include patients who are eligible to receive cisplatin chemotherapy.

References

1. Milowsky MI, O’Donnell PH, Hoimes CJ, et al. Patient-reported outcomes in patients with advanced urothelial cancer who are ineligible for cisplatin and treated with first-line enfortumab vedotin alone or with pembrolizumab. J Clin Oncol. 2024;JCO2301547. doi:10.1200/JCO.23.01547

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 January 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic

3. PADCEV (enfortumab vedotin-ejfv) with KEYTRUDA (pembrolizumab) approved by FDA as the first and only ADC plus PD-1 to treat advanced bladder cancer. News release. Astellas. Published online and accessed December 15, 2023. https://newsroom.astellas.us/2023-12-15-PADCEV-R-enfortumab-vedotin-ejfv-with-KEYTRUDA-R-pembrolizumab-Approved-by-FDA-as-the-First-and-Only-ADC-Plus-PD-1-to-Treat-Advanced-Bladder-Cancer