Dr. Siefker-Radtke notes that we now have level 1 evidence with overall survival benefit for enfortumab vedotin in the 3rd line for metastatic urothelial carcinoma. EV-301 (NCT03474107) is a global, open-label phase III study of enfortumab vedotin versus chemotherapy conducted in patients with locally advanced or metastatic urothelial carcinoma who had received prior platinum-containing chemotherapy and had disease progression during or after PD-1/L1 inhibitor treatment. Patients were randomized 1:1 to receive enfortumab vedotin (1.25 mg/kg) on Days 1, 8, and 15 of each 28-day cycle or investigator choice of standard docetaxel, paclitaxel, or vinflunine chemotherapy. After an 11.1 month follow-up, median overall survival was significantly prolonged by 3.9 months with enfortumab vedotin compared with chemotherapy (median overall survival: 12.9 vs 9.0 months, respectively; HR 0.70, 95% CI 0.56-0.89, 1-sided p = 0.00142):
Additionally, progression-free survival was also improved with enfortumab vedotin (5.6 months) versus chemotherapy (3.7 months) (HR 0.62, 95% CI 0.51-0.75; 1-sided p<0.00001), as was objective response rate (40.6% versus 17.9%, 1-sided p<0.001) and disease control rate (71.9% versus 53.4%, 1-sided p<0.001). Although these benefits come at risk of toxicity, compared to historical regimens in this disease space, enfortumab vedotin does appear quite tolerable.
Dr. Siefker-Radtke then discussed EV-201, an open-label, multicenter, multinational study in which patients received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. Confirmed objective response per blinded independent central review was 52% (95% CI 40.8–62.4), including a 20% complete response rate among treated patients. The median duration of response was 10.9 months (95% CI 5.8–NR). Over a median follow-up of 13.4 months, the median progression free survival was 5.8 months (95% CI 5.0-8.3) and median overall survival was 14.7 months (95% CI 10.5-18.2):
Dr. Siefker-Radtke notes that there were several grade 5 adverse events in EV-201, including patients ≥75 years of age with multiple comorbidities: 3 events were ≤30 days of first enfortumab vedotin dose in patients with BMI ≥30 (acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndromes) and 1 event > 30 days after the last dose (pneumonitis). Additionally, the most common all-grade treatment-related adverse events were alopecia (51%), peripheral sensory neuropathy (47%), and fatigue (34%). Treatment-related adverse events of interest included rash (61% all grade, 17% ≥ grade 3), peripheral neuropathy (54% all grade, 8% ≥ grade 3), and hyperglycemia (10% all grade, 6% ≥ grade 3). She notes that these adverse events appear to be higher than those reported in EV-301.
Looking at the metabolism of enfortumab vedotin, there may be insights into why there were more adverse events in EV-201. The metabolite for enfortumab vedotin (MMAE), which is recovered in the feces (17%) and urine (6%) over a 1 week period. In a trial with the majority of patients having a renal impairment (EV-201 cohort 2, cisplatin-ineligible) it would seem intuitive that this may explain some of the adverse events, however, the FDA label for enfortumab vedotin states that there was no difference in AUC for mild/moderate/severe renal impairment and thus no dose reductions were recommended. When looking at the metabolism of MMAE in the liver, mild hepatic impairment was associated with a 48% AUC increase in MMAE. Furthermore, the trial does report grade >=3 adverse events in patients with moderate or severe hepatic impairment and thus should be avoided in these patients. Thus, Dr. Siefker-Radtke notes that the findings of grade 3-4 hyperglycemia increasing in patients with a greater BMI may be explained by a hepatic dysfunction perhaps secondary to a fatty liver. Summarizing which patients she would hold enfortumab vedotin treatment, Dr. Siefker-Radtke highlights that this would include patients with: (i) glucose >250 mg/dL as this could be a sign of liver toxicity, (ii) peeling skin or bullous skin lesions, as they may have worsening of skin lesions with subsequent treatment, and (iii) patients with grade 3 diarrhea.
Dr. Siefker-Radtke concluded her discussion of these two enfortumab vedotin trials with the following conclusions:
- There is level 1 evidence for 3rd line enfortumab vedotin based on an improvement in overall survival and progression-free survival, a safe and manageable safety profile, and activity in visceral and liver metastases
- There is early evidence in post-immunotherapy cisplatin-ineligible patients, which is currently an unmet need
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021