At the end of May, thousands of oncology professionals usually gather in Chicago for the annual American Society of Clinical Oncology (ASCO) meeting to learn about the latest developments in cancer research and multidisciplinary patient care. However, this year, with the COVID-19 pandemic precluding an in-person meeting, ASCO adopted a virtual platform to disseminate the latest advances in cancer science, with 250 oral and 2,500 poster presentations. Among the five late breaking abstracts (LBA) presented during the virtual plenary session, Thomas Powles, MD, PhD, FCRP (Barts Cancer Institute, London, United Kingdom) presented results from the randomized, global phase III JAVELIN Bladder 100 trial (LBA1) that evaluated maintenance therapy with the anti-PD-L1 antibody avelumab in patients with advanced urothelial cancer (UC) who had not progressed after first-line platinum-based chemotherapy. 

In general, advanced UC is an incurable disease. Systemic platinum-based chemotherapy is the standard first-line treatment approach. While initial responses to chemotherapy are high, the duration of response is relatively short, and most patients progress after developing resistance to therapy. Less than half of these patients receive second-line treatment, which includes PD-1 or PD-L1 inhibitors; however, only a minority of patients obtain a durable clinical benefit. Immunotherapy, as monotherapy and in combinations, is being investigated in the first-line setting. A combination of atezolizumab and platinum-based chemotherapy improved PFS, but did not significantly prolong survival (IMvigor130). Switch maintenance immune checkpoint inhibition after first-line induction therapy is an attractive treatment approach that may prolong disease control after initial chemotherapy and result in more patients receiving treatment. In the JAVELIN Bladder 100 trial, patients with previously untreated, unresectable locally advanced or metastatic UC (n = 700) whose disease had not progressed after 4 – 6 cycles of platinum-based therapy (gemcitabine with either cisplatin or carboplatin), were randomized to receive avelumab maintenance (10 mg/kg intravenous every 2 weeks) plus BSC or BSC alone. Patients were stratified according to best response to first-line chemotherapy (complete or partial response versus stable disease), and by visceral versus non-visceral disease at the beginning of chemotherapy. Crossover was not allowed. The primary endpoint was OS in all randomized patients (intention-to-treat population) and in patients with confirmed PD-L1 positive tumors (Ventana SP263 assay). After a median follow-up of approximately 19 months, 24% of patients continued receiving avelumab treatment in the overall population and 7% continued with BSC alone. Disease progression was the most common cause for treatment discontinuation. The study met its primary endpoint and demonstrated impressive prolongation of OS with avelumab maintenance. The median OS was 21.4 months in the avelumab plus BSC arm versus 14.3 months in the BSC alone arm (hazard ratio [HR] 0.69, P < 0.001). In patients with PD-L1 positive tumors, median OS was not reached in the avelumab arm versus 17.1 months with BSC (HR 0.56, P < 0.001). The OS benefit of maintenance avelumab was consistent across all prespecified patient subgroups. In addition, progression free survival (PFS) by independent radiology review was also significantly prolonged with avelumab maintenance in the overall population and in the PD-L1 positive population, and about one third of patients were progression free at 12-months. The toxicity profile of avelumab was manageable and consistent with previous monotherapy studies, with 12% of discontinuations due to treatment-related adverse events (TRAEs) and 2 treatment-related deaths. However, there were no grade 4/5 immune-related AEs. Hypothyroidism was the most common immune-related AEs.

This is the first front-line trial that has demonstrated a survival benefit in advanced UC and Dr Powles concluded that ‘’avelumab first-line maintenance in patients whose disease has not progressed with platinum-based induction chemotherapy represents a new first-line standard of care for advanced urothelial cancer’’. Discussant of this abstract, Elizabeth R. Plimack MD, MS (Fox Chase Cancer Center, Temple Health, Philadelphia, United States) highlighted, “This is notably the longest OS ever documented in a phase III metastatic UC trial, in any line of therapy” and added that switch maintenance is now the preferred option for most patients after platinum-based induction therapy.

Reference

Powles T, et al. J Clin Oncol.2020;38 (suppl; abstract LBA1)