EV-302/Keynote-A39: A “Landmark Achievement”

According to the latest estimates, more than 80,000 new cases of bladder cancer are diagnosed annually, and there are nearly 17,000 bladder cancer-associated deaths.¹ The 5-year overall survival (OS) of patients diagnosed with bladder cancer is nearly 80%, but that number drops dramatically (to just 5%) when considering those with metastatic disease.² For decades, since the introduction of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) by Sternberg et al,³ platinum-based chemotherapy has been the mainstay treatment in this patient population. In a trial comparing commonly used gemcitabine and cisplatin with MVAC, the authors noted a 13.8-month and 14.8-month improvement in OS, respectively. The latest datasets have suggested a slightly longer median OS of 15 months.

In recent years, many new immunotherapeutic agents have been released and utilized for the treatment of metastatic urothelial carcinoma (mUC), including atezolizumab and pembrolizumab for patients who are ineligible for platinum chemotherapy.⁴ The clinical trials that have supported these developments have altered the landscape for second-line therapy in mUC. In the first-line setting, chemotherapy has remained the mainstay; however, landmark findings presented during the 2023 European Society for Medical Oncology Congress may change that. Dr. Thomas Powles shared the results of EV-302 (NCT04223856⁵), a phase 3 clinical trial comparing the use of enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) with chemotherapy (gemcitabine plus cisplatin or carboplatin) at the meeting.⁶

Pembrolizumab is a well-known immunotherapeutic agent that targets PD-1 by inhibiting its interaction with PD-L1 ligands on tumor cells, thereby allowing T cells to effectively target cancer cells.⁷ Enfortumab vedotin is a combination antibody-drug conjugate designed to directly deliver monomethyl auristatin E, a microtubule-disrupting agent, against cells that harbor the nectin-4 receptor.⁸ One main benefit of enfortumab vedotin is that it can be used in patients with pre-existing chronic kidney disease, which is a common concern for clinicians treating patients with mUC.

The EV-302 trial (also referred to as Keynote-A39) sought to analyze the use of enfortumab vedotin plus pembrolizumab in patients with untreated locally advanced/mUC. The trial’s primary end points were OS and progression-free survival (PFS) as compared with traditional first-line chemotherapy.

Dr. Powles began his presentation by emphasizing the importance of this trial, noting that mUC results in over 20,000 deaths annually. He reviewed the downsides of chemotherapeutic agents, which are often limited in use in pre-existing renal dysfunction. Furthermore, he remarked that prior immunotherapy trials failed to show OS benefits that would supplant the use of chemotherapy in the first-line setting. Rather, agents such as avelumab have been used to prolong OS in patients after chemotherapy.⁹

In prior trials, enfortumab vedotin plus pembrolizumab has shown benefit in patients with prior chemotherapy exposure, resulting in US Food and Drug Administration approval for its use in patients who are ineligible for platinum-based chemotherapy, Dr. Powles noted. Patients enrolled in the trial were previously untreated and eligible for chemotherapy (enfortumab vedotin plus pembrolizumab) and had no prior exposure to PD-L1 inhibitors. All patients had a glomerular filtration rate above 30 and an Eastern Cooperative Oncology Group (ECOG) performance status less than two.

Dr. Powles explained that patients were randomized in a 1:1 ratio to either enfortumab vedotin plus pembrolizumab or chemotherapy. In the immunotherapy arm, a maximum cycle count of 35 was set for pembrolizumab, but no limit was set for enfortumab vedotin. The goal was to continue treatment until disease progression or intolerable toxicity was noted. Patients in the trial were further substratified to groups of cisplatin eligibility, PD-L1 expression, and presence of liver metastasis.

The 2 cohorts were evenly balanced between enfortumab vedotin plus pembrolizumab and chemotherapy. The median patient age was 69 years in each arm. Patients were of similar racial backgrounds and from similar geographical locations. The majority had good ECOG performance status (0-1). More than half were cisplatin eligible, and nearly 72% had visceral metastatic disease.

Before presenting the primary outcome results, Dr. Powles spoke about the current status of patients in the trial. Notably, he mentioned that since the immunotherapy arm (enfortumab vedotin particularly) has no end point in stopping drug administration, it has a higher adverse event percentage compared with chemotherapy (21.9% vs 14.0%) due to the continued administration of immunotherapy compared with a fixed number of cycles for chemotherapy.

Comparing the 2 cohorts, Dr. Powles noted there was a 55% reduction in progression of disease in patients who received the enfortumab vedotin plus pembrolizumab combination (hazard ratio [HR], 0.45; P<.00001). Furthermore, the enfortumab vedotin plus pembrolizumab arm had nearly double the PFS (12.5 months vs 6.3 months) compared with chemotherapy. Remarking on the various subgroup analyses completed, such as cisplatin eligibility, he noted all groups favored the immunotherapy combination.

Dr. Powles received a standing ovation when he presented the OS data. The median OS in the enfortumab vedotin plus pembrolizumab arm was 31.5 months, nearly double the OS of the chemotherapy arm at 16.1 months (HR, 0.47; P<.0001).⁶ Subgroup analysis demonstrated that, regardless of cisplatin eligibility, patients showed statistically significant benefit from enfortumab vedotin plus pembrolizumab compared with chemotherapy (eligible HR, 0.53; ineligible HR, 0.43). Similar findings of enfortumab vedotin plus pembrolizumab benefit were seen for PD-L1 status.

Finally, Dr. Powles showed data regarding response rates, where enfortumab vedotin plus pembrolizumab had a 29.1% complete response rate compared with 12.5% for chemotherapy. The rate of toxicity (grade 3+) was higher in the chemotherapy arm (69.5% vs 55.9%) compared with the immunotherapy arm.

The EV-302 trial results demonstrate that the combination of enfortumab vedotin plus pembrolizumab is a promising therapeutic option for new onset mUC. Dr. Powles said this is the first trial that has shown an OS benefit improvement compared with chemotherapy in the first-line mUC setting, a landmark achievement. The patients who participated in the trial, and all prior negative trials, were thanked.

Akhil Abraham Saji, MD, Fellow at the University of Southern California, is a urologist specializing in minimally invasive surgery and urologic oncology with an interest in technology-driven innovation within health care.

References

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3. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133(3):403-407. doi:10.1016/S0022-5347(17)48996-8
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6. KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) reduced risk of death by more than half versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer. Merck. Accessed October 26, 2023. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-reduced-risk-of-death-by-more-than-half-versus-chemotherapy-in-patients-with-previously-untreated-locally-advanced-or-metasta/
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9. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. New Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788