Enfortumab vedotin plus pembrolizumab to be reviewed for urothelial carcinoma approval in EU, Japan

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The applications in the EU and Japan are both based on findings from the phase 3 EV-302 trial.

Regulatory developments in the European Union (EU) and Japan may lead to the first-line combination of enfortumab vedotin (Padcev) and pembrolizumab (Keytruda) being available in these areas for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC).

At a median follow-up of 17.2 months, treatment with enfortumab vedotin plus pembrolizumab reduced the risk of death by 53% versus chemotherapy in patients with locally advanced or mUC.

At a median follow-up of 17.2 months, treatment with enfortumab vedotin plus pembrolizumab reduced the risk of death by 53% versus chemotherapy in patients with locally advanced or mUC.

In the EU, the European Medicines Agency (EMA) has initiated its centralized review process of an application for the treatment combination for use in frontline locally advanced or mUC.1 This start of the EMA’s review process of the application is officially called, “validation of a type II variation application.”

In Japan, Astellas Pharma reported that it had submitted a supplemental New Drug Application to Japan's Ministry of Health, Labour and Welfare for the use offirst-line enfortumab vedotin plus pembrolizumab in the same patient population as the potential EU indication.2

The applications in the EU and Japan are both based on findings from the phase 3 EV-302 trial (NCT04223856), which showed that the frontline combination extended overall survival (OS) compared with chemotherapy in patients with locally advanced or mUC.3

At a median follow-up of 17.2 months, treatment with enfortumab vedotin plus pembrolizumab (EVP) reduced the risk of death by 53% versus chemotherapy. The median OS was 31.5 months (95% CI, 25.4-NR) in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin, and was not impacted by PD-L1 status or existence of visceral metastases.

Treatment with the combination also led to a significant improved in progression-free survival (PFS) versus chemotherapy. The median PFS was 12.5 months (95% CI, 10.4-16.6) with EVP compared with 6.3 months (95% CI, 6.2-6.5) with chemotherapy, translating to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95%, 0.38-0.54; P < .00001). The PFS benefit was sustained across all pre-specified subgroups, such as those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.

Overall, the open-label EV-302 trial included 886 patients with previously untreated locally advanced or mUC with an ECOG performance status of ≤2 who were eligible for cisplatin- or carboplatin-containing chemotherapy. The median age in both arms was 69 years and about three-fourths of patients were male. The majority of patients in the trial were White, making up 69.7% and 65.3% of the EVP and control arms, respectively. About 97% of patients in both arms had an ECOG performance status of 0 or 1.3

In the EVP arm, the primary tumor location was upper tract for 30.5% of patients and lower tract for 69.0%. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and 72% had visceral metastases. Regarding PD-L1 status, 58% of in each arm had high expression (combined positive score [CPS] ≥10), with the remaining 42% having low expression (CPS <10).

Patients were randomized to standard of care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (n = 444) or enfortumab vedotin (1.25 mg/kg IV) on days 1 and 8 and pembrolizumab (200 mg IV) on day 1 of 3-week cycles (n = 442). The maximum number of pembrolizumab cycles allowed was 35 and there was no maximum number of cycles for enfortumab vedotin. The co-primary end points were OS and PFS (per blinded independent central review).

The confirmed objective response rate (ORR) was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP group consisted of a complete response (CR) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%.

The median number of cycles received was 12 (range, 1-46) for EVP and 6 (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Adverse event (AE)-related discontinuations occurred in 21.9% and 14.0% of the 2 arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/L1 inhibitor and 30% of patients received maintenance avelumab.

Safety data showed that 56% of patients receiving EVP and 70% of patients in the chemotherapy arm experienced grade ≥3 treatment-related AEs (TRAEs). Serious TRAEs occurred in 27.7% vs 19.6% of the 2 arms, respectively.

Commenting on the EU development, Ahsan Arozullah, MD, MPH, senior vice president, head of Oncology Development, Astellas, stated in a news release, “Patients in Europe need better treatment options for advanced stage urothelial cancer, and we look forward to working with the EMA on their review of the combination of enfortumab vedotin and pembrolizumab. If approved, the combination would be the first alternative to a chemotherapy-based treatment for this patient population. This milestone is another opportunity to affirm our commitment to helping patients with advanced urothelial cancer live longer.”1

On the Japanese filing, Arozullah stated, "The initiation of MHLW's review of our application for enfortumab vedotin and pembrolizumab is encouraging, as we are working to improve upon current treatment options for patients in Japan with advanced stage urothelial cancer, who face poor outcomes at the advanced stage. This submission brings us one step closer to the possibility of offering these patients a treatment that demonstrated improved survival and slowed disease progression compared to platinum-containing chemotherapy."2

References

1. European Medicines Agency Validates Type II Variation Application for PADCEVTM (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) for First-Line Treatment of Advanced Bladder Cancer. Published onlineJanuary 26, 2024. https://www.astellas.com/en/news/28801

2. Astellas Submits Supplemental New Drug Application in Japan for PADCEV™ (enfortumab vedotin (genetical recombination)) with KEYTRUDA® (pembrolizumab (genetical recombination)) for First-Line Treatment of Advanced Bladder Cancer. Published onlineJanuary 30, 2024. https://www.prnewswire.com/news-releases/astellas-submits-supplemental-new-drug-application-in-japan-for-padcev-enfortumab-vedotin-genetical-recombination-with-keytruda-pembrolizumab-genetical-recombination-for-first-line-treatment-of-advanced-bladder-cancer-302048608.html

3. 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). Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA6.

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