Two potential new first-line standards of care in metastatic urothelial cancer

Results from two trials, the EV-302/KEYNOTE-A39 and CheckMate 901 trials, demonstrated significantly improved progression-free (PFS) and overall survival (OS) in participants with locally advanced or metastatic urothelial cancer.

For decades, platinum-based chemotherapy has been the first-line treatment for patients with locally advanced or metastatic urothelial cancer. Previous studies, evaluating chemotherapy concurrently with immunotherapy, have failed to demonstrate improved survival in these patients [1,2]. The current phase 3 EV-302/KEYNOTE-A39 (NCT04223856) explored the efficacy and safety of first-line enfortumab vedotin (EV) in combination with pembrolizumab compared with chemotherapy alone. The first results were presented by Prof. Thomas Powles (Queen Mary University of London, UK) [3].

A total of 886 participants with previously untreated locally advanced or metastatic urothelial cancer were randomised 1:1 to first-line EV/pembrolizumab until progression (max 35 cycles of pembrolizumab) or 6 cycles platinum-based chemotherapy (maintenance avelumab permitted). The primary endpoints were PFS and OS.

EV/pembrolizumab outperformed chemotherapy in both PFS and OS. Median PFS was 12.5 versus 6.3 months (HR 0.45; 95% CI 0.38–0.54; P<0.00001) and median OS was 31.5 versus 16.1 months (HR 0.47; 95% CI 0.38–0.58; P<0.00001) in the EV/pembrolizumab arm and chemotherapy arm, respectively (see Figure). The benefit of EV/pembrolizumab over chemotherapy was observed in all prespecified subgroups, including stratification by PD-L1 status and cisplatin eligibility. In addition, EV/pembrolizumab was superior to chemotherapy regarding objective response rate (ORR, 67.7% vs 44.4%). Moreover, the complete response rate more than doubled with EV/pembrolizumab (29.1% vs 12.5%). The rate of adverse events grade ≥3 was highest in the chemotherapy arm (70% vs 56% in the EV/pembrolizumab arm).

Figure: Overall survival was reduced by 53% in participants who received EV/pembrolizumab compared with chemotherapy alone, results from the EV-302/KEYNOTE-A39 showed [3]



CI, confidence interval; EV+P, enfortumab vedotin/pembrolizumab; HR, hazard ratio; NR, not reached; mOS, median overall survival.

Alternatively, the CheckMate 901 trial (NCT03036098), a randomised, phase 3 trial, combined chemotherapy (gemcitabine/cisplatin) with nivolumab. The trial enrolled 608 participants with previously untreated unresectable or metastatic urothelial cancer and randomised them 1:1 to gemcitabine/cisplatin for 6 cycles or nivolumab plus gemcitabine/cisplatin for 6 cycles followed by nivolumab until disease progression or a maximum of 1 year. The primary endpoints were PFS and OS. The results were presented by Dr Michiel van der Heijden (Netherlands Cancer Institute, the Netherlands) [5].

Nivolumab plus chemotherapy significantly outperformed chemotherapy alone both for PFS and OS. The median OS was 21.7 versus 18.9 months (HR 0.78; 95% CI 0.63–0.96; P=0.0171) and the median PFS was 7.9 versus 7.6 months (HR 0.72; 95% CI 0.59–0.88; P=0.0012) for nivolumab plus chemotherapy and chemotherapy alone, respectively. The benefit in the nivolumab arm was observed in all prespecified subgroups, including stratification by PD-L1 expression and liver metastasis.

The ORR was also improved in the nivolumab arm: 57.6% (21.7% complete responders) versus 43.1% (11.8% complete responders). Responses were rapidly achieved (median time-to-response 2 months in both arms) and the median duration of response was longer in the nivolumab arm (9.5 vs 7.3 months). The median duration of complete response was 37.1 versus 13.2 months, respectively. “Nivolumab plus gemcitabine/cisplatin is associated with rapid, deep, and durable responses,” said Dr Van der Heijden.

The rate of treatment-related adverse events was almost similar in both arms: 57% versus 48% (any grade) and 22% versus 18% (grade ≥3) for nivolumab plus chemotherapy versus chemotherapy alone, respectively. The most prominent adverse events were chemotherapy-related.

Based on these results, both Prof. Powles and Dr Van der Heijden concluded that, at last, the bar for OS in locally advanced or metastatic urothelial cancer has been raised. Both EV/pembrolizumab and chemotherapy/nivolumab could become a new first-line standard of care.

Discussant Dr Andrea Apolo (NCI Bethesda, MD, USA) fully agreed. “However, with new standards of care come new questions, such as ‘What will be the best second line?’ and ’What will be the role of checkpoint inhibition in later lines?’”

1. 
   
   1. Powles T, et al. Lancet Oncol. 2021;22(7):931–945.
   2. Galsky MD, et al. Lancet. 2020;395(10236):1547–1557.
   3. Powles TB, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Abstract LBA6, ESMO 2023, 20–24 October, Madrid, Spain.
   4. Van der Heijden MS, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial. Abstract LBA7, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December, 202315 February, 2024