OS benefit with enfortumab vedotin plus pembrolizumab sustained across subgroups in urothelial carcinoma

Analyses from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) showed that the overall survival (OS) and other benefits reported with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in the overall study population of patients with previously untreated locally advanced or metastatic urothelial carcinoma were sustained across prespecified patient subgroups.¹

Michiel S. Van Der Heijden, MD, PhD

Primary results from the trial were first presented at the 2023 ESMO Congress. During the 2024 Genitourinary Cancers Symposium, lead study author Michiel S. Van Der Heijden, MD, PhD, reported new data illustrating the benefit of the combination in previously unpresented subgroups.

These results showed that the progression-free survival (PFS) benefit with the combination in patients with visceral metastases (HR, 0.45; 95% CI, 0.37-0.55) and those with lymph node–only disease (HR, 0.40; 95% CI, 0.26-0.62) was consistent with that of the overall population (HR, 0.45; 95% CI, 0.38-0.54; 2-sided P <.00001).^1,2 Moreover, the OS benefit was similar to that of the overall population (HR, 0.47; 95% CI, 0.38-0.58; 2-sided P <.00001), regardless of the presence (HR, 0.47; 95% CI, 0.37-0.60) or absence (HR, 0.46; 95% CI, 0.27-0.78) of visceral metastases. In the visceral metastases cohort, the median OS was 25.6 months with the combination vs 13.6 months with chemotherapy. In the lymph node–only cohort, the median OS was not reached with the combination vs 27.5 months with chemotherapy.

“The benefit of enfortumab vedotin plus pembrolizumab in all prespecified subgroups was consistent with the overall patient population. These results further support enfortumab vedotin plus pembrolizumab as a new standard of care in locally advanced or metastatic urothelial carcinoma,” Van Der Heijden, leader of the Michiel Van der Heijden Research Group at the Netherlands Cancer Institute, said in a presentation of the data. Notably, all hazard ratios in the subgroup analysis for PFS fell between 0.35 and 0.56, and all hazard ratios for OS fell between 0.36 and 0.71.

In December 2023, the FDA approved the combination for patients with locally advanced or metastatic urothelial cancer.³ The decision was based on primary results from the EV-302 trial, which enrolled patients with treatment-naive locally advanced or metastatic urothelial cancer with no contraindications to platinum, enfortumab vedotin, or pembrolizumab. Patients also had to have a glomerular filtration rate at or above 30 mL/min, an ECOG performance status of 0 to 2, and no prior exposure to a PD-(L)1 inhibitor.

Patients were randomly assigned 1:1 to the combination or up to 6 cycles of chemotherapy consisting of gemcitabine plus either cisplatin or carboplatin. Treatment in the investigational arm was continued until disease progression, clinical progression, unacceptable toxicity, or patients completed 35 cycles of pembrolizumab. Notably, maintenance therapy was allowed if deemed appropriate by the investigator following the completion and/or discontinuation of platinum-containing therapy.

PFS per blinded independent central review (BICR) and OS served as the coprimary end points of the trial. Select secondary end points included objective response rates (ORR) per RECIST v1.1 criteria by BICR and investigator assessment, as well as safety.

All patients were stratified by cisplatin eligibility (eligible vs ineligible), PD-L1 expression (low [combined positive score (CPS) <10] vs high [CPS ≥10]), liver metastases (present vs absent), age (<65 vs ≥65 years), region (North America vs Europe vs rest of world), sex (female vs male), race (White vs other), ECOG performance status at baseline (0 vs 1 to 2), metastases (visceral vs lymph node only), primary disease site of origin (upper tract vs lower tract), and renal function (normal vs mild vs moderate vs severe).

Previous findings from the primary analysis showed a PFS advantage with the combination in cisplatin-eligible (HR, 0.48; 95% CI, 0.38-0.62) and ineligible (HR, 0.43; 95% CI, 0.33-0.55), as well as PD-L1–high (HR, 0.42; 95% CI, 0.33-0.53) and PD-L1–low (HR, 0.50; 95% CI, 0.38-0.65) subgroups. Similar results were seen in patients with (HR, 0.53; 95% CI, 0.38-0.76) and without (HR, 0.43; 95% CI, 0.35-0.52) liver metastases.

Earlier findings also showed an OS advantage with the combination in cisplatin-eligible (HR, 0.53; 95% CI, 0.39-0.72) and ineligible (HR, 0.43; 95% CI, 0.31-0.59), as well as PD-L1–high (HR, 0.49; 95% CI, 0.37-0.66) and PD-L1–low (HR, 0.44; 95% CI, 0.31-0.61) subgroups. Additionally, the presence of liver metastases did not seem to affect the magnitude of OS benefit seen with the combination (with: HR, 0.47; 95% CI, 0.32-0.71; without: HR, 0.47; 95% CI, 0.36-0.61).

Additional findings from the current analysis showed that consistent with the primary analysis, which showed an ORR of 67.7% with the combination vs 44.4% with chemotherapy, patients in all prespecified subgroups experienced superior response rates with the combination, surpassing at least 60% in all cases.

In cisplatin-eligible patients, the ORR was 70.8% with the combination vs 53.0% with chemotherapy (absolute difference, 17.8%; 95% CI, 9.1%-26.2%). In cisplatin-ineligible patients, the ORRs were 63.9% vs 34.9% (absolute difference, 29.0%; 95% CI, 19.4%-38.0%). In the PD-L1–low subgroup, the ORRs were 63.3% vs 41.0% (absolute difference, 22.3%; 95% CI, 12.1%-32.1%). In the PD-L1–high subgroup, the ORRs were 71.1% vs 46.6% (absolute difference, 24.5%; 95% CI, 16.0%-32.6%). Patients with liver metastases experienced ORRs of 60.0% vs 41.4% (absolute difference, 18.6%; 95% CI, 4.7%-31.8%). Patients without liver metastases had ORRs of 70.0% vs 45.3% (absolute difference, 24.7%; 95% CI, 17.4%-31.8%). Regarding metastatic disease site, patients with visceral metastases experienced ORRs of 64.1% vs 39.6% (absolute difference, 24.5%; 95% CI, 16.8%-31.9%). Patients with lymph node–only disease had ORRs of 77.5% vs 53.4% (absolute difference, 24.1%; 95% CI, 11.1%-36.3%).

The toxicity profile of the doublet was found to be generally manageable. No new safety signals were observed. Grade 3 or greater events were reported in 56% of patients who received enfortumab vedotin plus pembrolizumab vs 70% of those given chemotherapy.

The most common treatment-related adverse effects (TRAEs) reported in the enfortumab vedotin/pembrolizumab arm (n = 440) included peripheral sensory neuropathy (any grade, 50.0%; grade ≥3, 3.6%), pruritus (39.8%; 1.1%), alopecia (33.2%; 0.5%), maculopapular rash (32.7%; 7.7%), fatigue (29.3%; 3.0%), diarrhea (27.5%; 3.6%), decreased appetite (26.8%; 1.1%), nausea (20.2%; 1.1%), anemia (13.9%; 3.4%), neutropenia (9.1%; 4.8%), and thrombocytopenia (3.4%; 5.0%).

In the enfortumab vedotin/pembrolizumab arm, 4 TRAEs led to death: asthenia, diarrhea, immune-mediated lung disease, and multiple organ dysfunction syndrome. In the chemotherapy arm, 4 TRAEs resulted in death: febrile neutropenia, myocardial infarction, neutropenic sepsis, and sepsis.

Editor’s Note: Dr Van Der Heijden disclosed stock ownership in Gilead Sciences; having a consulting or advisory role for Astellas Pharma (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Janssen (Inst), MSD Oncology (Inst), Pfizer (Inst), Roche/Genentech (Inst), and Seagen (Inst); receiving research funding from 4SC (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), and Seagen (Inst); and having travel expenses covered by Astellas Pharma, MSD Oncology, Novartis, and Roche.

References

1. Van Der Heijden M, Powles T, Gupta S, et al. Enfortumab vedotin (EV) in combination with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC): subgroup analyses results from EV-302, a phase 3 global study. J Clin Oncol. 2024;42(suppl 4):LBA530. doi:10.1200/JCO.2024.42.4_suppl.LBA530

2. Powles TB, Perez Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106

3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed January 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer