Results from the Phase 3 EV-302/KEYNOTE-A39 clinical trial for enfortumab vedotin (Padcev®; Astellas/Seagen) in combination with pembrolizumab (Keytruda®; Merck & Co/MSD) versus chemotherapy, presented at the European Society for Medical Oncology (ESMO) Congress 2023 as part of the Presidential Session (Abstract #LBA6), shows that the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.
Bladder cancer is the sixth most common cancer in the United States after lung cancer, prostate cancer, breast cancer, colon cancer, and melanoma. It is the fourth most common cancer in men and the eleventh most common cancer in women. Of the roughly 82,000 new cases annually diagnosed in the United States*, about 62,000 are in men and about 20,000 are in women. Of the roughly 17,000 annual deaths, more than 12,000 are in men and fewer than 5,000 are in women. The reasons for this disparity between the sexes are not well understood.
Urothelial carcinoma. which is also called transitional cell carcinoma, is cancer that begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs. Almost all bladder cancers are urothelial carcinomas. 
- If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease.
- Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.
- Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.
Enfortumab vedotin is a first-in-class antibody-drug conjugate or ADC directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.  Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).
The EV-302/KEYNOTE-A39 study met its dual primary endpoints of OS and PFS, compared to platinum and gemcitabine chemotherapy. Patients treated with enfortumab vedotin and pembrolizumab experienced:
- Median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) in the chemotherapy arm.
- Significantly prolonged OS, reducing the risk of death by 53% compared to treatment with chemotherapy (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001).
- An Independent Data Monitoring Committee determined that OS crossed the pre-specified efficacy boundary at interim analysis.
- Median PFS of 12.5 months (95% CI: 10.4-16.6) compared to 6.3 months (95% CI: 6.2-6.5) in the chemotherapy arm.
- 55% reduction in the risk of cancer progression or death compared to treatment with chemotherapy (HR=0.45; 95% CI: (0.38-0.54); P<0.00001).
- Consistent OS results across all pre-defined subgroups, including cisplatin eligibility and PD-L1 expression level.
The most common (≥3%) Grade 3 or higher adverse events (AEs) related to treatment with enfortumab vedotin and pembrolizumab were rash maculo-papular, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia.
The safety results in EV-302/KEYNOTE-A39 are consistent with those previously reported with this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.
“The remarkable findings presented today demonstrate that the combination of enfortumab vedotin and pembrolizumab could offer longer survival and more time without disease progression for patients with advanced urothelial cancer,” noted Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas.
“The presentation of this data is an important milestone for this patient population, and we look forward to continued discussions with regulatory authorities as we work to expedite bringing this therapy to those who need it most,” Arozullah added.
“The combination of enfortumab vedotin and pembrolizumab, if approved, represents a potential paradigm shift in the treatment of metastatic urothelial cancer. The results of this historic trial presented today show improvements in overall survival and progression free survival not previously achieved in a broad population of patients,” explained Roger Dansey, M.D., President, Research and Development, Seagen.
Difficult to treat
“An advanced urothelial cancer diagnosis is difficult for patients and their families, and physicians have limited treatment options for these patients,” said Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302/KEYNOTE-A39 Primary Investigator.
“The results of this Phase 3 trial are unlike any we have seen so far and open a new chapter in advanced urothelial cancer treatment. This presents a great opportunity for this medicine to make a meaningful impact on advanced urothelial cancer patients, who face an urgent need for new therapies,” Powles added.
Among secondary endpoints, results demonstrated a 68% confirmed objective response rate (ORR) (95% CI: 63.1-72.1, P<0.00001) in patients treated with enfortumab vedotin plus pembrolizumab, versus an ORR of 44% (95% CI: 39.7-49.2) in patients treated with chemotherapy. In the enfortumab vedotin plus pembrolizumab arm, 29.1% of patients experienced a complete response, and 38.7% of patients experienced a partial response, compared with 12.5% and 32.0% in the chemotherapy arm, respectively. The median duration of response (DOR) was not reached in the enfortumab vedotin plus pembrolizumab arm, versus 7 months (95% CI: 6.2-10.2, P<0.00001) in the chemotherapy arm.
The EV-302/KEYNOTE-A39 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.
Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.
The EV-302/KEYNOTE-A39 trial is intended to serve as the basis for global submissions and as the confirmatory trial for the U.S. accelerated approval of this combination. In April 2023, the U.S. Food and Drug Administration (FDA) granted an accelerated approval to enfortumab vedotin in combination with pembrolizumab for the treatment of adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy based on tumor response rate and durability of response from the EV-103 trial. The EV-302 trial is part of an extensive program evaluating this combination in multiple stages of urothelial cancer and other solid tumors.
Ongoing Investigational Trials
- The EV-302/KEYNOTE-A39 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating the impact of treatment with enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.
- The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).
- Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and in MIBC has not been proven safe or effective.
- The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma.
Note: *Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually. Furthermore, approximately 200,000 people in Europe and 24,000 people in Japan are diagnosed with bladder cancer annually.
Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302) – NCT04223856
Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/ KEYNOTE-B15 / EV-304) (KEYNOTE-B15) – NCT04700124
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303) – NCT03924895
A Study to Evaluate Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) – NCT04225117
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Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.