Enfortumab Vedotin Plus Pembrolizumab Approved in Canada for Advanced Bladder Cancer

Health Canada has approved the combination of enfortumab vedotin (Padcev) and pembrolizumab (Keytruda) for use in adult patients with unresectable locally advanced or metastatic urothelial cancer who had not previously received systemic treatment for metastatic disease.¹

The decision is supported by data from the phase 3 EV-302/KEYNOTE-A39 study (NCT04223856), which had been shared at the 2023 ESMO Congress.² Treatment with the doublet (n = 442) led to a median progression-free survival (PFS) of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (n = 444), translating to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .00001). The 12-month PFS rate with enfortumab vedotin plus pembrolizumab was 50.7% vs 21.6% with chemotherapy; at 18 months, these respective rates were 43.9% and 11.7%.

Additionally, the median overall survival (OS) with the doublet was 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy, translating to a 53% reduction in the risk of death (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). In the doublet arm, the 12- and 18-month OS rates were 78.2% and 69.5%, respectively; in the chemotherapy arm, these respective rates were 61.4% and 44.7%.

“Metastatic urothelial cancer is an aggressive disease with limited treatment options and a poor prognosis,” Srikala Sridhar, MD, head of the Genitourinary Medical Oncologists of Canada, professor and medical oncologist at the Princess Margaret Cancer Centre, in Toronto, stated in a news release.¹ “This approval represents an important step forward in the treatment of advanced bladder cancer. This combination of an antibody-drug conjugate and immunotherapy in the first-line setting offers new hope for our patients and their families.”

EV-302 included patients with treatment-naive locally advanced or metastatic urothelial cancer who had a glomerular filtration rate of at least 30 mL/min and an ECOG performance status ranging from 0 to 2.² Patients must have been eligible to receive platinum, enfortumab vedotin, and pembrolizumab, and they must have not had prior exposure to a PD-1 or PD-L1 inhibitor.

Participants (n = 886) were randomized 1:1 to receive the doublet or chemotherapy in the form of cisplatin or carboplatin paired with gemcitabine. There were no maximum treatment cycles for enfortumab vedotin, a maximum of 35 cycles of pembrolizumab, and a maximum of 6 cycles for chemotherapy.

Treatment continued until progressive disease by blinded independent central review (BICR), clinical progression, intolerable toxicity, or maximum cycles were completed. Patients were stratified by cisplatin eligibility (yes vs no), PD-L1 expression (high vs low), and liver metastases (present vs absent).

The dual primary end points of the trial were PFS by BICR and OS, and important secondary end points included objective response rate (ORR) by BICR and per RECIST 1.1 criteria as well as investigator assessment. Safety was also evaluated.

Demographic and baseline disease characteristics were well balanced between the treatment arms and representative of the first-line locally advanced or metastatic bladder cancer population, according to study authors. In the doublet arm, 54.3% of patients were cisplatin eligible vs 54.5% of those in the chemotherapy arm. Liver metastases were present in 22.6% and 22.3% of patients, respectively. Regarding PD-L1 expression, 58.0% of those in the doublet arm had high expression, defined as a combined positive score (CPS) of at least 10, and 42.0% had low expression, defined as a CPS below 10; these respective rates in the chemotherapy arm were 57.9% and 42.1%.

Additional efficacy data indicated that the ORR achieved with enfortumab vedotin plus pembrolizumab was higher than that achieved with chemotherapy, at 67.7% (95% CI, 63.1%-72.1%) vs 44.4% (95% CI, 39.7%-49.2%; P < .00001). Of those who responded to the doublet, 29.1% achieved a complete response (CR) and 38.7% experienced a partial response (PR). Of those who responded to chemotherapy, 12.5% achieved a CR and 32.0% experienced a PR. The median duration of response in the doublet and chemotherapy arms was not reached (NR; 95% CI, 20.2-NR) and 7.0 months (95% CI, 6.2-10.2), respectively.

Regarding safety, 97.0% of those in the doublet arm (n = 440) experienced grade 1 or 2 treatment-related adverse effects (TRAEs) vs 95.6% of those in the chemotherapy arm (n = 443); these effects were grade 3 or higher for 55.9% and 69.5% of patients, respectively. Serious TRAEs occurred in 27.7% of those who received enfortumab vedotin plus pembrolizumab and 19.6% of those given chemotherapy.

The most common TRAEs reported in the doublet arm included peripheral sensory neuropathy (grade 1/2, 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%; 0.5%).

The treatment-emergent adverse effects of special interest experienced in the doublet arm included severe skin reactions (any grade, 17.0%; grade ≥3, 11.8%), hypothyroidism (10.7%; 0.5%), pneumonitis (9.5%; 3.6%), hyperthyroidism (4.5%; 0.2%), hepatitis (3.2%; 1.8%), colitis (2.7%; 1.6%), gastritis (2.0%; 0%), adrenal insufficiency (1.6%; 0.5%), infusion reactions (1.4%; 0%), and pancreatitis (1.1%; 0.9%).

Four patients each in the doublet and chemotherapy arms experienced TRAEs that proved fatal.

“We are thrilled that Health Canada has approved a new treatment option for advanced bladder cancer, and we are excited about the hope it will provide to members of the bladder cancer patient community,” Michelle Colero, executive director of Bladder Cancer Canada, added in the news release.¹ “Despite recent advances in the treatment of advanced bladder cancer, there remains an important need for new therapies for patients.”

References

1. Padcev (enfortumab vedotin) in combination with pembrolizumab approved by Health Canada to treat advanced bladder cancer. News release. Pfizer Canada. August 22, 2024. Accessed August 22, 2024. https://www.newswire.ca/news-releases/padcev-r-enfortumab-vedotin-in-combination-with-pembrolizumab-approved-by-health-canada-to-treat-advanced-bladder-cancer-862646661.html
2. Powles TB, Valderrama BP, Gupta S, et al. LBA6 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