Aly-Khan A. Lalani, MD, FRCPC
Toni K. Choueiri, MD
AS REVIEWED in this issue of The ASCO Post, Patel and colleagues have presented data from the phase I JAVELIN study evaluating avelumab (Bavencio) in platinum-refractory patients with advanced urothelial carcinoma.1 The drug is active with durable responses when compared with historical single-agent salvage chemotherapy. The primary endpoint, an independent-review confirmed objective response rate of 17%, is interpreted in the context of a similar range of objective response rates seen with other programmed cell death protein 1/programmed cell death ligand 1 (PD-1/ PD-L1) agents.2-5
“Given the limitations of cross-trial comparisons, the treatment choice may well hinge on the frequency of delivery, the physician’s familiarity with the agent, and the level of evidence for the agent.”— Aly-Khan A. Lalani, MD, FRCPC, and Toni K. Choueiri, MD
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In this trial, the objective response rate is reported with an arbitrary follow-up of at least 6 months, which may introduce a selection bias. Given the median time to response with this class of agents is typically 8 weeks, studies should aim to report objective response rates in the entire cohort, particularly when considering the generalizability of results to the unselected setting. This caveat may explain the relatively short median overall survival seen in this study (6.5 months), and the interpretability of survival will also be enhanced by a longer follow-up. Although avelumab is reported to be equipped with antibody-dependent cellular cytotoxicity, which may confer direct antitumor activity independent of T-cell activity, the results of this trial do not suggest markedly improved activity compared with other approved PD-1/PD-L1 inhibitors.6
Plethora of Options
A PLETHORA of options are now available for patients and physicians to choose from in metastatic urothelial carcinoma. Recent U.S. Food and Drug Administration approval has led to five PD-1/PD-L1 inhibitors in the platinum-refractory setting, and pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are also approved in the United States as first-line therapy for cisplatin-ineligible patients.
Ongoing phase III trials of adjuvant therapy, as well as combinations with chemotherapy or other checkpoint inhibitors in the front-line space, may establish these agents for a broader group of patients in earlier disease settings. We note that administration of a different PD-1/PD-L1 inhibitor after previously receiving one is not proven, at this time, to provide clinical benefit.7
Moreover, the combination of ramucirumab (Cyramza) with docetaxel following platinum-based chemotherapy (with a small minority who had received PD-1/PD-L1 inhibitors) yielded a modest extension of progression-free survival in the RANGE phase III trial, although the clinical utility of these results awaits overall survival data.8 With randomized trials comparing various checkpoint inhibitors unlikely to materialize, and given the limitations of cross-trial comparisons, the treatment choice may well hinge on the frequency of delivery, the physician’s familiarity with the agent, and the level of evidence for the agent.9 In this context, pembrolizumab remains the only agent demonstrated to extend overall survival, in the phase III KEYNOTE-045 trial, with the failure of the IMvigor211 trial to demonstrate a survival benefit for atezolizumab.4,10 It is important to note that although immune-related adverse events experienced with avelumab are comparable to those of similar agents, the 29% rate of infusion reactions (albeit of low grade) appears higher and requires premedication.
“The therapeutic role for avelumab monotherapy over others in metastatic urothelial carcinoma remains unclear.”— Aly-Kahn A. Lalani, MD, FRCPC, and Toni K. Choueiri, MD
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Predictive Biomarkers Needed
AS IS THE case for immune checkpoint inhibitors in a variety of settings, identifying predictive biomarkers for prolonged clinical benefits or refractory disease remains an unmet need. Patel et al appropriately noted the challenges of evaluating PD-L1 tumor expression and the limited power in their study to assess tumor mutational burden. Along with gene-expression subtypes and other genomic signatures, these biomarkers represent promising mechanisms to better select and prognosticate for our patients.
Thus, the therapeutic role for avelumab monotherapy over others in metastatic urothelial carcinoma remains unclear. However, the prospect of use of avelumab in other settings—for example, in neoadjuvant regimens and as a component of novel combination strategies—is an important motivation for continued study of the role of this agent.
DISCLOSURE: Dr. Lalani reported no conflicts of interest. Dr. Choueiri has received honoraria from and consulted for Alligent, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Eisai, Exelixis, Foundation Medicine, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus, Roche/Genentech; and received institutional research funding/support from Pfizer, Exelixis, Bristol-Myers Squibb, Novartis, Peloton, AstraZeneca, Agensys, and TRACON.
REFERENCES
1. Patel MR, Ellerton J, Infante JR, et al: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): Pooled results from two expansion cohorts of the open-label, phase 1 trial. Lancet Oncol 19:51-64, 2018.
2. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 387:1909-1920, 2016.
3. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312-322, 2017.
4. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017.
5. Powles T, O’Donnell PH, Massard C, et al: Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncol 3:e172411, 2017.
6. Boyerinas B, Jochems C, Fantini M, et al: Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res 3:1148-1157, 2015.
7. Martini DJ, Lalani AA, Bossé D, et al: Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: A case series. J Immunother Cancer 5:66, 2017.
8. Petrylak DP, de Wit R, Chi KN, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomised, double-blind, phase 3 trial. Lancet 390:2266-2277, 2017.
9. Lalani AA, McGregor BA, Sonpavde GP, et al: JAVELIN: Avelumab another spear to fight urothelial carcinoma. Lancet Oncol 19:5-7, 2018.
10. Powles T: IMvigor211: A phase III randomized study examining atezolizumab versus chemotherapy for platinum-treated advanced urothelial carcinoma. EACR-AACR-SIC Special Conference 2017. Special Lecture. Presented June 27, 2017.
