Enfortumab Vedotin With Pembrolizumab Doubles Survival in Bladder Cancer

3D illustration of human bladder: © reineg - stock.adobe.com

Patients with untreated locally advanced or metastatic urothelial carcinoma treated with enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) had significantly improved outcomes, including strong overall survival (OS) and progression-free survival (PFS), compared with those treated with chemotherapy, according to findings from the phase 3 EV-302 clinical trial (NCT04223856).¹

High-level data from the phase 3 EV-302 trial were published in the New England Journal of Medicine and showed that the study met its dual primary end points of median OS and median PFS vs platinum-containing chemotherapy. In the combination arm, the median OS was 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy. The median PFS in each of these arms were 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), respectively.

In addition to the encouraging efficacy data, safety findings showed that grade 3 or higher treatment-related adverse events (TRAEs) were seen in 55.9% of the patients treated with enfortumab vedotin plus pembrolizumab compared with 69.5% of patients treated with chemotherapy. Any-grade TRAEs were observed in 97.0% of the enfortumab vedotin/pembrolizumab group vs 95.6% of patients in the chemotherapy group, and the most common TRAEs of any grade were peripheral sensory neuropathy (50.0%), pruritus (39.8%), and alopecia (33.2%) in the combination group and anemia (56.6%), neutropenia (41.6%), and nausea (38.8%) in the chemotherapy arm.

These findings represent the first time a treatment regimen in advanced urothelial cancer has demonstrated superiority to platinum chemotherapy, which for decades has been the gold standard of care for patients with previously untreated locally advanced or metastatic urothelial cancer.

“The EV-302 trial showed a significant and clinically meaningful benefit of enfortumab vedotin and pembrolizumab over chemotherapy with respect to progression-free survival and overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma,” wrote study authors.

“The EV-302 study is a randomized, phase 3 study which explores enfortumab vedotin in previously untreated metastatic urothelial cancer. It is a large, randomized, phase 3 study, but the important thing about it is we are not exploring monotherapy with enfortumab vedotin,” said Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology, Queen Mary University of London and director, Barts Cancer Center, in an interview with Targeted Oncology^TM.

Thomas Powles, MD, MBBS, MRCP

In the phase 3, global, open-label, randomized trial, 886 patients were enrolled and underwent randomization in a 1:1 fashion at 185 sites in 25 countries. A total of 442 were randomized to the enfortumab vedotin plus pembrolizumab group while 444 were randomized to the chemotherapy group. In the enfortumab vedotin plus pembrolizumab arm, patients received 3-week cycles of enfortumab vedotin at a dose of 1.25 mg/kg of body weight via intravenous (IV) infusion on days 1 and 8 along with pembrolizumab 200 mg, also via IV infusion, on day 1. Those in the chemotherapy arm were given gemcitabine and either cisplatin or carboplatin.

Adult patients were eligible for enrollment in the study if they had radiologically documented, histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. In addition to the dual primary end points of PFS and OS, secondary end points included overall response as assessed by blinded independent central review, the duration of response (DOR), the time to pain progression, and safety.

At baseline, each arm was generally balanced and were both representative of the overall patient population with advanced urothelial carcinoma. Across arms, the median age of patients was 69 years (range, 22-91), 76.7% of patients were men, 67.5% were White, and 21.6% were Asian. According to study investigators, Black patients were underrepresented in the trial population. Additionally, the upper tract was the primary site of origin of the disease, as seen in 27.0%.

At the time of the data cutoff of August 8, 2023, the median duration of treatment was 9.4 months (range, 0.3-31.9) in the enfortumab vedotin plus pembrolizumab arm, and patients received a median of 12 cycles (range, 1-46). Those given enfortumab vedotin received treatment for a median of treatment with 7.0 months (range, 0.3-31.9) over a median of 9 cycles (range, 1-46). The median duration of pembrolizumab treatment was 8.5 months (range, 0.3-28.5), over a median of 11 cycles (range, 1-35). In the chemotherapy group, patients received it for a median duration of 4.1 months (range, 0.0-7.7), over a median of 6 cycles (range, 1-6).

Nearly all patients (94.0%) eligible to receive cisplatin-based therapy received it in the first cycle, as per the protocol. Additionally, 97.6% of patients eligible for carboplatin-based therapy received it in the first cycle, according to the protocol.

The median duration of follow-up for survival as of August 8, 2023, was 17.2 months, and PFS was longer in the enfortumab vedotin and pembrolizumab group compared with the chemotherapy group (HR, 0.45; 95% CI, 0.38-0.54; P <.001). The same was true for OS (HR, 0.47; 95% CI, 0.38-0.58; P <.001).

Looking at overall response, rates were higher in the enfortumab vedotin plus pembrolizumab arm compared with those in the chemotherapy group at 67.7% (95% CI, 63.1%-72.1%) vs 44.4% (95% CI, 39.7%-49.2%; P <.001). In the enfortumab vedotin/pembrolizumab group, 29.1% of patients achieved a complete response vs 12.5% of those in the chemotherapy group. Additionally, the median DOR was not reached in the enfortumab vedotin/pembrolizumab group and was 7.0 months in the chemotherapy group.

In the enfortumab vedotin/pembrolizumab group, 67.3% and 59.6% of patients were still in remission at 12 months and 18 months, respectively, and 35.2% and 19.3% of patients were in remission in the chemotherapy group. For median time to pain progression, it was 14.2 months with enfortumab vedotin/pembrolizumab vs 10.0 months in the chemotherapy group.

“This trial showed a significant survival benefit of enfortumab vedotin and pembrolizumab as compared with chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma,” wrote the study authors.

“We need to think about when we stop the drug [and] how we reduce the dose, so there is education and training associated with that, but this is a new chapter for the treatment of metastatic urothelial cancer,” Powles told Targeted Oncology.

REFERENCE:

1. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390:875-88. doi: 10.1056/NEJMoa2312117