Despite Efforts Made With Immunotherapy in Metastatic Urothelial Cancer, Chemotherapy Remains King in Frontline

Partner | Cancer Centers | <b>Cleveland Clinic</b>

Shilpa Gupta, MD, discusses ongoing research with immunotherapy in bladder cancer, where research efforts should focus with regard to biomarkers, and other emerging agents that might move the needle forward.

Platinum-based chemotherapy continues to serve as the standard of care for the frontline treatment of patients with metastatic urothelial cancer, despite many efforts made to examine immunotherapy and chemoimmunotherapy in this setting, according to Shilpa Gupta, MD. However, for those who are ineligible for cisplatin, immunotherapy options are available.

“The only time single-agent immunotherapy should be considered is in patients who are not eligible to receive cisplatin; [these patients can be treated] with pembrolizumab [Keytruda] or atezolizumab [Tecentriq],” Gupta explained. “Moreover, no available data support the use of chemotherapy with immunotherapy for the treatment of patients with urothelial cancer, thus, platinum-based chemotherapy remains the standard.”

In patients who do not experience disease progression after first-line platinum-based chemotherapy, avelumab (Bavencio) maintenance has become the standard of care, based on data from the JAVELIN Bladder 100 trial, added Gupta. Results from the trial showed that the addition of avelumab to best supportive care improved the median overall survival (OS) by over 7 months in patients with locally advanced or metastatic disease. The addition of the PD-L1 inhibitor reduced the risk of death by 31%.

“This research provides information that sequential use probably leads to a better therapeutic index than when used in combination up front,” noted Gupta.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Bladder Cancer, Gupta, a medical oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic, discussed ongoing research with immunotherapy in bladder cancer, where research efforts should focus with regard to biomarkers, and other emerging agents that might move the needle forward.

OncLive®: How did the KEYNOTE-361 and IMvigor130 trials set the stage for the role of immunotherapy in bladder cancer?

Gupta: These trials evaluated the role of chemoimmunotherapy in the treatment of patients with metastatic urothelial cancer in the frontline setting and compared it with chemotherapy alone. There were also arms comparing single-agent immunotherapy with standard chemotherapy.

The results from the IMvigor130 trial demonstrated that the combination of chemotherapy and immunotherapy slightly improved progression-free survival [PFS]; however, the overall survival [OS] data are not yet mature. Moreover, results from the KEYNOTE-361 trial were negative in terms of both PFS and OS. As such, platinum-based chemotherapy continues to be the standard of care in the frontline setting.

What was learned from the phase 3 DANUBE trial?

The DANUBE trial looked at an immunotherapy doublet, which consisted of a PD-L1 inhibitor and CTLA-4 inhibitor, as well as a PD-L1 inhibitor alone compared with standard platinum-based chemotherapy. Neither the immunotherapy doublet nor the single agent proved to be better than chemotherapy. Thus, this trial was also negative and reinforced previously reported data. Ultimately, chemotherapy remains the standard of care. We now understand that immunotherapy is not better than chemotherapy in this space, and neither is the combination of immunotherapy and chemotherapy.

Conversely, analyses from JAVELIN Bladder 100 demonstrated a benefit with immunotherapy. Do these results suggest that immunotherapy is best served in the maintenance setting?

For urothelial cancer, unlike lung cancer, we are seeing that the up-front use of chemotherapy and immunotherapy is not better than chemotherapy alone, but when used sequentially in the maintenance setting.

Immunotherapy is already approved in the platinum-refractory setting, but when used early on for patients who do not progress after platinum-based chemotherapy, it leads to a tremendous survival benefit; this was demonstrated in the JAVELIN Bladder 100 analyses.

How helpful have biomarkers of response been?

In the platinum-refractory setting, there was no requirement to look for PD-L1 expression; however, patients who expressed high levels of PD-L1 derived a greater benefit [from immunotherapy]. Even so, the indication was for anyone who progresses on platinum-based chemotherapy. We are still trying to learn how to best select patients who may or may not benefit from these approaches.

Do you believe the field would be better off utilizing biomarkers that suggest a lack of response, rather than response?

This is a very important question. We are currently trying to find biomarkers in this space that suggest lack of response. Notably, only about 25% of patients actually respond to immunotherapy; the vast majority do not. This is especially true for patients who rapidly progress on immunotherapy, thus, we need to understand what is driving their resistance to this approach. Some early data suggest that epidermal growth factor beta may be a mediator of resistance, but we are still trying to understand the biomarker aspect.

Could you highlight the role of enfortumab vedotin-ejfv (Padcev)in metastatic urothelial cancer?

Right now, enfortumab vedotinis approved for patients with metastatic urothelial cancer who have previously received platinum-based chemotherapy and immunotherapy. The agent showed significant and favorable results. Updated OS data were recently presented during the 2020 ESMO Virtual Congress and these data look very promising. However, once this agent is approved, we are looking forward to learning more about its use when combined with immunotherapy in the first-line cisplatin-ineligible space.

The role of enfortumab vedotin is probably going to move up to the frontline setting, to see whether combination immunotherapy will be better than chemotherapy. The ongoing, randomized, phase 3 EV-103 trial is trying to answer this question.

Are there any other emerging agents that you are excited about?

Antibody-drug conjugates (ADCs), such as sacituzumab govitecan [Trodelvy], are being studied. The toxicity profile and mechanism of action of this agent is different than enfortumab vedotin. In the future, we believe most patients will receive 1 of these ADCs agents at some point, in some sequence. We are anticipating data from the ongoing, randomized trials.


Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial cancer (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1