As the world faces the COVID-19 global pandemic, the theme of ASCO 2020, Unite and Conquer, has never been more apt. Although the format of this year’s ASCO is not what we are used, ASCO organisers have done a tremendous job of bringing the oncology community together. While you might expect that with the tens of thousands ‘attendees’ viewing the live broadcasts there would be technical difficulties, so far I have not experienced any. The virtual experience has not diminished my feelings of inspiration and privilege that I am accustomed to experiencing when witnessing the first-hand sharing of data at ASCO. This blog will focus on LBA1, interim results of the Phase III JAVELIN Bladder 100 trial, evaluating the anti-PD-L1 immunotherapy avelumab (Merck KGaA / Pfizer’s Bavencio) as a first-line maintenance therapy for advanced urothelial carcinoma (UC), presented by Professor Thomas Powles, a lead for solid tumour research at Barts Cancer Centre. [1] The unmet need for more efficacious treatments in advanced UC is high, with the estimated 5-year survival rate for patients with distant metastases estimated to be less than 6%.[2] Following the approval of cisplatin in 1978 for advanced UC, the wait for a new drug approval in UC lasted 30 years, until the European approval of gemcitabine in 2008. A flurry of immune checkpoint inhibitors entered the advanced UC market from 2016, with the addition of two targeted treatments in the US in 2019. As data from these newly approved therapies mature, we hope to see more patients experiencing 5-year survival. Avelumab was granted accelerated approval by the FDA in 2017, for unresectable locally advanced or metastatic urothelial carcinoma, based on data from a Phase I, open-label, single-arm, multicentre study. JAVELIN Bladder 100 is the confirmatory study for the conversion to full approval. In JAVELIN Bladder 100, patients with unresectable locally advanced or metastatic UC in response (CR, PR or SD) with standard first-line platinum chemotherapy were randomised 1:1 to receive avelumab + BSC (n = 350) or BSC alone (n = 350) following a treatment-free interval of 4-10 weeks. Patients were stratified based on best response to first-line treatment (CR or PR vs SD), metastatic site, and PD-L1 status. PD-L1-positivity was assessed using the Ventana SP23 assay and defined as expression in ≥25% of tumour cells or ≥25% or 100% tumour-associated immune cells if the percentage of immune cells was >1% or ≤1%, respectively. Among patients evaluable for PD-L1 status, 58% of patients in the avelumab arm and 56% of patients in the control arm had a PD-L1+ tumour. The JAVELIN Bladder 100 trial met its primary endpoint of significantly improving OS. In the overall patient population, median OS in the avelumab arm was 21.4 months vs. 14.3 months in the control arm (HR 0.69; P<0.001). In the PD-L1+ patient population, median OS in the avelumab arm had not yet been reached vs. 17.1 months in the control arm (HR 0.56; P<0.001). Notably, patients in both arms of the trial had improved OS if they had PD-L1+ tumours, unusually indicating PD-L1-positivity as a positive prognostic indicator. The subgroup analysis of OS in the overall population broadly favoured avelumab across all groups, although most notably for patients with non-visceral metastasis (HR of 0.54) and for those with PD-L1+ tumours (HR of 0.56 for PD-L1-positive vs. 0.86 for PD-L1-negative tumours). The trial also met its secondary endpoint of PFS, with a PFS of 3.7 months in the avelumab arm vs. 2.0 months in the control arm, in the overall population (HR 0.62; P<0.001). In the PD-L1+ population, PFS was 5.7 months in the avelumab arm vs. 2.1 months in the control arm (HR 0.56; P<0.001). Objective response rate was also a secondary endpoint, however both the presenter and following discussant commented on the challenge of interpreting ORR given that most patients were already in response to first-line treatment. The discussant of the abstract, Dr Elizabeth Plimack, expressed that the data from JAVELIN Bladder 100, changes the treatment paradigm in advanced UC in two ways. The first is that the data provide a new framework for the consideration of a treatment break vs. maintenance therapy post-platinum. The data presented highlight the benefit of switching to a maintenance therapy with an immune checkpoint inhibitor as an alternative option to having a treatment break and initiating an immune checkpoint inhibitor as a second-line treatment, post-platinum progression. The second is that the data from JAVELIN Bladder 100 could mark a shift in first-line systemic therapy selection. Dr Plimack noted the significant overlap of patients who respond well to chemotherapy with patients who respond well to immune checkpoint inhibitors. This is supported by the finding that addition of atezolizumab (Roche’s PD-L1 inhibitor) to first-line platinum therapy for advanced UC did not significantly improve ORR over platinum therapy alone in the IMvigor130 trial. [3] Furthermore, while cross trial comparisons need to be made with caution, the median OS in IMvigor130, for patients treated with atezolizumab + platinum as a first-line treatment, was 16.0 months – lower than that achieved with avelumab maintenance in JAVELIN Bladder 100. Taking these findings together, do the data from JAVELIN Bladder 100 support the use of first-line platinum, without PD-1/L1 blockade, as a first-line induction therapy, allowing the opportunity to use avelumab maintenance for the ~85% of patient who are likely to achieve a CR, PR, or SD to platinum therapy, and reserving PD-1/L1 blockade as a second-line treatment for the ~15% of patients who experience disease progression on first-line platinum? JAVELIN Bladder 100 is the first trial in the first-line setting to show a significant survival advantage in advanced UC; the data are highly encouraging. With variation in clinical trial designs and patient recruitment across the multiple immune checkpoint inhibitors available in UC, cross trial comparisons are difficult. It is remarkable to think back to the 30-year drought of drug approvals in advanced UC as physicians now seek to work out the optimal way of using the new arsenal of drugs at their disposal… determining the optimal treatment approach in advanced UC, with the entrance of multiple therapies on the market, will be challenging but is by far a more preferable situation to be. Get in touch to find out more about HRW OR:BIT’s reflections on ASCO 2020. By Gemma McConnell, Research Director References 1. LBA1. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. 2. SEER 18, 2010 – 2016 http://seer.cancer/statfacts/html/urinb.html. Accessed 5/2020 3. Galsky MD, et al. Atezolizumab With or Without Chemotherapy in Metastatic Urothelial Cancer (IMvigor130): A Multicentre, Randomised, Placebo-Controlled Phase 3 Trial. 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