Avelumab initially received regulatory approval for patients with metastatic urothelial carcinoma in the post-platinum chemotherapy setting based on an objective response rate of 16.5%.1 In the post-platinum chemotherapy setting, both nivolumab and pembrolizumab also currently retain their regulatory approval status. However, the situation where avelumab has the strongest data is in the maintenance-switch setting. I initially discussed that topic in a Urotoday Clinical Trials Portal article almost 4 years ago.2 Of course, everything discussed in that article has been completed, and all highlighted trials were positive.
First, the Hoosier Cancer Research Network reported on GU14-182, a randomized phase 2 trial of switch maintenance with pembrolizumab vs. placebo for 200 patients who had received 8 or fewer cycles of platinum-based chemotherapy for metastatic urothelial carcinoma and who had stable disease or objective response.3 The experimental arm with pembrolizumab every 3 weeks up to 2 years offered a statistically significant improvement in progression-free survival with a median of 5.4 (95% CI 3.6-9.2) compared with 3.2 (95% CI 2.8-5.5) months (log rank p=0.038).
The concept was confirmed with the JAVELIN Bladder 100 randomized phase 3 trial. In this trial, 700 metastatic urothelial carcinoma patients with either stable disease or response to 4-6 cycles of first-line cisplatin/gemcitabine or carboplatin/gemcitabine chemotherapy were randomized 1:1 to either avelumab once every 2 weeks vs. best supportive care.4 The primary endpoint was overall survival and this was met with medians of 21.4 (95% CI 18.9-26.1) vs. 14.3 (12.9-17.9) months (HR 0.69; 95% CI 0.56-0.86; p=0.001). As a result, the United States Food and Drug Administration authorized full approval to avelumab for maintenance therapy on June 30, 2020.5
Although this is a win for our patients, we must recognize that not everyone is afforded the opportunity to potentially benefit from the utilization of avelumab. To be eligible for avelumab, one must have received previous platinum chemotherapy. It is well recognized that not all patients all eligible to receive cisplatin or even carboplatin due to comorbidities, performance status and/or other various reasons. Hence, there is an ongoing exploration with avelumab both in earlier disease states and also in combination with other agents.
One interesting trial is evaluating the current treatment paradigm of platinum chemotherapy followed by avelumab maintenance, but with the addition of trilaciclib, a CDK 4/6 inhibitor with the goal of achieving improved outcomes. This builds upon our most recent advances and wisely incorporates maintenance avelumab by introducing trilaciclib early with the initiation of platinum chemotherapy and continuing it throughout the course of immunotherapy maintenance. More trials of this sort should be performed in the future.
In conclusion, creating a new disease state of maintenance therapy for urothelial bladder cancer was logical to find a unique regulatory approval space. Yet, we should not be satisfied with this, as we need to find methods to reach all needy populations, not just unique niche populations. As a result, below I highlight ongoing clinical trials using avelumab for patients with urothelial carcinoma in various disease states and novel combinations.
Highlighted Trials utilizing Avelumab for Urothelial Carcinoma
- Avelumab with BCG for non-muscle invasive bladder cancer (NCT03892642)
- PREVERT - Bladder PREserVation by RadioTherapy and avelumab in BCG unresponsive non-muscle invasive bladder cancer (NCT03950362)
- Avelumab and radiation in muscle-invasive bladder cancer (NCT03747419)
- SWOG GAP Trial – Gemcitabine, carboplatin and avelumab neoadjuvant therapy for cisplatin-ineligible patients with muscle invasive urinary tract cancer (NCT04871529)
- AURA Trial - Avelumab neoadjuvant therapy for muscle invasive urothelial cancers (NCT03674424)
- GCISAVE - First-line gemcitabine/cisplatin +/- avelumab in locally advanced or metastatic bladder carcinoma (NCT03324282)
- Combination of Sacituzumab govitecan with cisplatin and avelumab in metastatic urothelial cancer (NCT03547973)
- Trilaciclib combination with chemotherapy then maintenance avelumab for metastatic urothelial carcinoma (NCT04887831)
- Pemetrexed and avelumab in MTAP-deficient metastatic urothelial cancer (NCT03744793)
- Combination of avelumab with Plinabulin and radiation after progression on PD-1 or PD-L1 antibody therapy (NCT04902040)
- Combination of AVB-S6-500 with avelumab (NCT04004442)
- Combination of FT516 with avelumab (NCT04551885)
- KHK2455 (IDO inhibitor) with avelumab (NCT03915405)
- AVETAX - Avelumab and taxane combination (NCT03575013)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington
- Apolo A, et al. Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. J Immunother Cancer 2020;8:e001246. doi:10.1136/jitc-2020-001246
- Yu EY. If Not 1st Line, How About Creating a 1.5 Line Therapy for Metastatic Urothelial Carcinoma? UroToday Clinical Trials Portal; January 1, 2018.
- Galsky MD, et al. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol 2020; 38:1797-1806.
- Powles T, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020; 383:1218-30.