The era of antibody–drug conjugates (ADCs) has yielded advances in outcomes in advanced urothelial carcinoma (aUC) and led to the US FDA approval of enfortumab vedotin (EV) and sacituzumab govitecan. EV extended overall survival (OS) versus taxane or vinflunine chemotherapy following platinum and PF1/L1 inhibitor therapy and also yielded a robust objective response rate (ORR) in the second-line setting of cisplatin-ineligible disease following PD-1/PD-L1 inhibitors.1,2 The combination of EV and PD-1/PD-L1 inhibition was a rational next step. Indeed, promising data were presented to support the activity of first-line EV plus pembrolizumab from two cohorts of patients with cisplatin-ineligible aUC from the EV-103 trial. In cohort A of the Phase Ib/II, multi-center EV-103 trial evaluating combination EV (1.25 mg/kg, Days 1 and 8) and pembrolizumab (200 mg, Day 1) intravenously in 3-week cycles as first-line therapy in 45 cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC), the confirmed objective response rate (ORR) was 73.3%, the complete response (CR) rate was 15.6%, the median duration of response (DOR) was 25.6 months, and the median OS was 26.1 months.3 This activity was observed independent of PD-L1 expression level, site of primary (upper or lower tract) and liver metastases. The toxicities were consistent with expected toxicities from EV and pembrolizumab, and one death (2.2%) occurred owing to treatment-related adverse events (multiple organ dysfunction). More recently, these data were corroborated by the EV-103 cohort K, a randomized phase II cohort investigating EV alone (n = 73) or in combination with pembrolizumab (n = 76) as first-line treatment in patients with cisplatin-ineligible mUC; the data were presented at the ESMO Congress on September 12, 2022.4 In this study, EV plus pembrolizumab showed a confirmed ORR (64.5% vs 45.2%), median DOR (not reached vs 13.2 months), and a promising 12-month progression-free survival (55.1% vs 35.8%) compared with EV alone. The safety profile was consistent with the known profile for EV and pembrolizumab (neuropathy, rash, hyperglycemia, ocular, immune events). The randomized phase III EV-302 study enrolled an unselected first-line mUC population and compared EV plus pembrolizumab versus cisplatin or carboplatin plus gemcitabine. Additionally, EV plus pembrolizumab is undergoing investigation in two randomized phase III studies in muscle-invasive bladder cancer (MIBC) accruing cisplatin-ineligible and cisplatin-eligible patents, respectively (EV-303 and EV-304). Despite the caveats that both cohorts A and K of EV-103 are phase II cohorts, these outcomes are unprecedented and highly promising for an unselected first-line cisplatin-ineligible population. It is possible that EV–pembrolizumab will become available in the clinic for cisplatin-ineligible patients based on these data (pending regulatory reviews), while we await data from the definitive phase III EV-302 trial.
An important conundrum is the optimal first-line treatment strategy in cisplatin-ineligible patients if EV–pembrolizumab becomes available for this population following review by regulatory agencies. The JAVELIN Bladder 100 paradigm of carboplatin plus gemcitabine followed by maintenance avelumab has been validated by a phase III trial and long-term follow-up.5,6 Maintenance avelumab significantly prolonged OS compared with best supportive care (median OS, 21.4 months vs 14.3 months; HR for death, 0.69; P = .001) regardless of PD-L1 status in patients with mUC who had not progressed after four to six cycles of first-line platinum-based chemotherapy. However, the JAVELIN Bladder-100 paradigm of maintenance avelumab is applicable only to those who attain stable or responding disease with platinum-based chemotherapy. Hence, the JAVELIN Bladder-100 paradigm will continue to play a major role, especially in those cisplatin-ineligible patients with poorer performance status, frailty, and contraindications for EV (eg, hyperglycemia, neuropathy ≥ grade 2).
For cisplatin-eligible patients, the conventional therapy remains four to six cycles of cisplatin-based combination therapy followed by maintenance avelumab in those with stable/responding disease. However, given the high ORR (and low rate of progressive disease as the best response), EV–pembrolizumab competes with the JAVELIN Bladder-100 paradigm for cisplatin-ineligible mUC to control this generally aggressive symptomatic disease. Real-world data have repeatedly demonstrated the significant attrition of patients receiving second-line therapy, suggesting that the most effective regimen should be prioritized for first-line administration. Nevertheless, the administration of EV–pembrolizumab in platinum-ineligible patients (as opposed to cisplatin-ineligible), frail patients, and those with both poor performance status ≥2 and renal dysfunction should be probably avoided as such patients were rarely or not included in EV-103. Informed decision-making is necessary following a discussion of all of these data with patients. The high ORR has provided the impetus for a phase II trial (NCT05239624) evaluating EV–pembrolizumab with neoadjuvant intent for node-positive MIBC to render such patients eligible for radical cystectomy and to assess pathologic complete remission. First-line PD-1/PD-L1 inhibitors are approved by the FDA and are reasonable for selected patients: pembrolizumab for platinum-ineligible and atezolizumab for platinum-ineligible or cisplatin-ineligible patients with PD-L1 high-expressing tumors. The paradigm of first-line PD-1/PD-L1 inhibitor monotherapy in these selected patients is reasonable and is likely driven by patient decision, but it needs to be considered carefully given the absence of phase III data to support it. Finally, optimal biomarkers of drug sensitivity need to be discovered to enable precision medicine. In addition to markers of benefit, markers of severe toxicities will allow an improved therapeutic index and rational informed decisions.