The Next Step in Bladder Cancer Immune-Oncology Therapy? Combination Therapy!

Back in May 2017, I wrote an article for this column in response to the press release that atezolizumab did not offer a survival benefit over taxane chemotherapy in the IMvigor 211 randomized, phase 3 trial, for patients in the post-platinum locally-advanced or metastatic urothelial carcinoma setting.1  At the time, we didn’t understand what had happened to lead to this negative result, especially since the phase 12 and 23 atezolizumab data had been so promising.  Additionally, we had just seen survival benefit with pembrolizumab in the same clinical disease state.4  Eventually, we learned the problem…clinical trial design. 

The Ventana SP142 antibody detects tumor-infiltrating immune cells, and hierarchical testing was used for the statistical primary endpoint analysis for this trial.  The IHC 2/3 population, where ≥5% of the tumor-infiltrating immune cells stained positive, was first analyzed and overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11.1 months [95% CI 8.6-15.5; n=116] vs 10.6 months [8.4-12.2; n=118]; stratified hazard ratio [HR] 0.87, 95% CI 0.63-1.21; p=0.41).5  This precluded the ability for further formal statistical analysis.  The problem became apparent after identifying that response rates were essentially identical between the two IHC 2/3 treatment groups, noted at 23% in the atezolizumab arm and 22% in the chemotherapy arm.  This randomized trial proved the Ventana SP142 antibody to be a prognostic, not predictive biomarker, as IHC 2/3 patients had better outcomes in both arms than those who were IHC 0/1, but it did not provide a selection for better response to atezolizumab. 

The article I wrote in May 20171 was directly in response to the fact that there was an ongoing adjuvant treatment trial with atezolizumab, and I was seeing patients call in with concerns about enrollment on that trial.  Fortunately, enrollment was completed and we await results from that and other randomized, phase 3 adjuvant trials.  The current issue at hand is that we have 4 approved agents that do not have proven survival benefit and one agent, pembrolizumab, with a proven survival benefit.  However, one must ask if one truly believes that pembrolizumab is truly superior to atezolizumab, nivolumab, durvalumab or avelumab?  There are no direct comparative randomized control trials and the mechanism of action of these 5 drugs are similar.  If there is a difference, it is not noticeable, and it has not and should not deter ongoing clinical trial accruals.

Ultimately, it may all be a moot point as we have pending results from front line metastatic disease trials with the KEYNOTE 361, gemcitabine/platinum vs. gemcitabine/platinum plus pembrolizumab vs. pembrolizumab alone, and IMvigor 130, gemcitabine/platinum vs. gemcitabine/platinum plus atezolizumab vs. atezolizumab alone trials.  I have previously discussed these and other front-line metastatic urothelial disease trials in another Urotoday Clinical Trials Portal article.6  It is possible that combination chemotherapy plus PD-(L)1 antibody therapy could be a new standard of care in the near future.

However, there is still much rationale to study other combinations beyond chemotherapy with PD-(L)1 antibodies.  Given the large number of ongoing trials, I will highlight, in this article, combination trials of atezolizumab with other novel agents.  These include combinations with other immunotherapeutic agents, for instance, cytokine, vaccine and combination checkpoint therapy.  Of course, there are other targets of interest as well.  Multiple growth factors, such as HER2 and fibroblast growth factor receptors (FGFR), also offer services as important therapeutic targets.  Finally, there have been many early attempts to introduce antiangiogenic agents into the urothelial carcinoma treatment paradigm.  Combinations with PD-(L)1 therapy make logical sense given that antiangiogenic agents have the potential to increase vascular permeability and facilitate T cell infiltration into the tumor microenvironment.

See below for more specific details on some of these ongoing combination therapy trials that are actively accruing patients.

Ongoing combination trials of Atezolizumab with other immunotherapy agents
Ongoing combination trials of Atezolizumab with growth factor-targeting agents
Ongoing combination trials of Atezolizumab with antiangiogenic agents

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center.

1. Yu, E. (May 2017). From the Desk of Evan Yu: “No…the ball game is not over...adjuvant trials of PD-1 and PD-L1 antibodies in urothelial carcinoma must go on!”. [online] [Accessed 17 Apr. 2019].
2. Powles T et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer." Nature, 515 (Nov 2014): 563-7.
3. Rosenberg JE 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 (May 2016):1909-20. doi: 10.1016/S0140-6736(16)00561-4. Epub 2016 Mar 4.
4. Bellmunt J et al. "Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma." New England Journal of Medicine, 376 (Mar 2017):1015-26.
5. Powles T et al "Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial." Lancet, 391 (Feb 2018):748-57. doi: 10.1016/S0140-6736(17)33297-X. Epub 2017 Dec 18.
6. Yu E. (Apr 2017) 
From the Desk of Evan Yu: PD-1 or PD-L1 Inhibition for Front-Line Metastatic Urothelial Cancer. [online] [Accessed 17 Apr. 2019]