(UPDATE) Enfortumab Vedotin-ejfv

Commentary by Bladder Cancer Site Editor for JNCCN 360

Thomas Flaig, MD,

Professor, Medicine-Medical Oncology and Vice Chancellor for Research, Anschutz Medical Campus, Aurora, Colorado

Enfortumab vedotin-ejfv is approved for use as subsequent-line therapy in locally advanced or metastatic bladder cancer and considered a preferred regimen after receiving both a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy. The combination of enfortumab vedotin and pembrolizumab has shown a response rate of approximately 70% in small studies of untreated patients with metastatic urothelial carcinoma. Ongoing, randomized studies are assessing this combination in the metastatic and perioperative settings, which will provide a clear assessment of the combination’s efficacy across these disease states. 

DISCLOSURES

Dr. Flaig has received clinical research support/data safety monitoring board from Agensys, Astellas Pharma US, AstraZeneca, Bristol Myers Squibb, Genentech, Janssen Pharmaceutica Products, Merck & Co, sanofi-aventis U.S., and Seattle Genetics; has served on a scientific advisory board or as a consultant or expert witness for Aurora Oncology (founder), Janssen Pharmaceutica Products, and Seattle Genetics; and was issued patent for work done at the University of Colorado and now Aurora Oncology.

In December 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the Nectin-4–directed antibody-drug conjugate enfortumab vedotin-ejfv for adults with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy, based on the results from cohort 1 of the pivotal phase II EV-201 trial.^1,2 Since the Spotlight was posted in February 2021, the FDA granted regular approval to enfortumab vedotin in this clinical context in the summer of 2021.³ It was also approved for cisplatin-ineligible patients who received at least one prior line of therapy.

Data Supporting Regular Approval of Enfortumab Vedotin

Based on the primary findings from cohort 2 of the multicenter EV-201 trial, in patients with platinum-naive, cisplatin-ineligible, locally advanced or metastatic urothelial cancer who experienced disease progression during or after PD-1/PD-L1 inhibition, the confirmed objective response rate was 52%.⁴ The median durations of response, progression-free survival, and overall survival were 10.9, 5.8, and 14.7 months, respectively. The safety profile appeared to be consistent with previous reports.

The confirmatory phase III EV-301 trial demonstrated improved overall (12.9 vs. 9.0 months) and progression-free (5.6 vs. 3.7 months) survival outcomes with enfortumab vedotin versus the investigator’s choice of chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who received a prior platinum-containing chemotherapy regimen and experienced disease progression during or after PD-1/PD-L1 inhibition.⁵ The objective response and disease control rates were 40.6% and 71.9% with enfortumab vedotin and 17.9% and 53.4% with chemotherapy, respectively. These efficacy data, along with a tolerable safety profile, support enfortumab vedotin as a new standard of care and preferred regimen in this clinical setting.⁶

Additional Clinical Trial Updates

In the EV-301 trial, after 23.8 months of follow-up, patients continued to experience prolonged median durations of overall (12.9 vs. 8.9 months) and progression-free (5.6 vs. 3.7 months) survival with enfortumab vedotin versus chemotherapy.⁷ The rates of treatment-related adverse events (93.9% vs. 91.8%), including serious treatment-related adverse events (22.6% vs. 23.4%), were found to be comparable between the arms. No new safety signals were observed.

The ongoing, multicohort phase Ib/II EV-103 trial is being conducted to investigate the safety and efficacy of first- and second-line enfortumab vedotin alone and in combination with other therapies for urothelial cancer. Since the enfortumab vedotin Spotlight was initially posted on JNCCN 360, the investigators have reported updated dose-escalation and -expansion results from cohort A. These treatment-naive, cisplatin-ineligible patients with locally advanced or metastatic disease demonstrated a confirmed objective response rate of 73.3% with enfortumab vedotin plus pembrolizumab.^8,9 The median durations of response and overall survival were 25.6 months and 26.1 months, respectively. According to the investigators, enfortumab vedotin plus pembrolizumab had a manageable safety profile; the most frequently reported treatment-related adverse events were peripheral sensory neuropathy, fatigue, and alopecia.

Cohort K of the EV-103 trial was included to further evaluate the combination of these agents in a treatment-naive, cisplatin-ineligible population. The confirmed objective response rates with and without pembrolizumab were 64.5% and 45.2%, respectively.¹⁰ Compared with enfortumab vedotin monotherapy, the median duration of response was prolonged with pembrolizumab (not reached vs. 13.2 months). The safety profiles in both arms appeared to be consistent with previous reports.

Based on preliminary data from cohort H of the EV-103 trial, neoadjuvant monotherapy with enfortumab vedotin demonstrated a pathologic complete response rate of 36.4% and a pathologic downstaging rate of 50.0% in patients with muscle-invasive bladder cancer who were ineligible for cisplatin-based chemotherapy but were eligible for surgical treatment.¹¹ The safety data were consistent with the known safety profile of this agent.

Next Steps

Given the potential clinical benefits of enfortumab vedotin plus pembrolizumab, this combination has become the focus of many actively enrolling trials. The phase III EV-302 trial (ClinicalTrials.gov identifier NCT04223856) is being conducted to evaluate enfortumab vedotin plus pembrolizumab versus standard-of-care gemcitabine plus either cisplatin or carboplatin in patients with previously untreated locally advanced or metastatic urothelial cancer.

Additionally, this combination is currently under investigation in two phase III studies in muscle-invasive bladder cancer. In the EV-303 trial (NCT03924895), patients who are cisplatin-ineligible or decline cisplatin will be randomly assigned to undergo radical cystectomy and pelvic lymph node dissection alone or in combination with perioperative pembrolizumab therapy plus or minus enfortumab vedotin. The EV-304 (NCT04700124) trial, which is assessing perioperative enfortumab vedotin plus pembrolizumab versus neoadjuvant gemcitabine plus cisplatin in cisplatin-eligible patients, should also shed light on the safety and efficacy of the combination in this setting of muscle-invasive disease.

References

1. S. Department of Health and Human Services. U.S. Food and Drug Administration. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-metastatic-urothelial-cancer. Accessed February 1, 2023.
2. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37:2592–2600.
3. S. Department of Health and Human Services. U.S. Food and Drug Administration. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer. Accessed February 1, 2023.
4. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol 2021;39(suppl):Abstract 394.
5. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: a phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol 2021;39(suppl):Abstract 393.
6. Flaig TW, Spiess PE, Abern M, et al. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 1.2023. Accessed March 1, 2023. To view the most recent version, visit nccn.org.
7. Rosenberg JE, Powles T, Sonpavde G, et al. Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. J Clin Oncol 2022;40(suppl):Abstract 4516.
8. Friedlander TW, Milowsky MI, Bilen MA, et al. Study EV-103: update on durability results and long term outcome of enfortumab vedotin + pembrolizumab in first line locally advanced or metastatic urothelial carcinoma. J Clin Oncol 2021;39(suppl):Abstract 4528.
9. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol 2023;41:22–31.
10. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 cohort K: antitumor activity of enfortumab vedotin monotherapy or in combination with pembrolizumab in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. Ann Oncol 2022;33(suppl):Abstract LBA73.
11. Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 cohort H: antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle invasive bladder cancer who are cisplatin-ineligible. J Clin Oncol 2022;40(suppl):Abstract 435.