Subgroup Analyses and Progression After EV-302

With the new EV-302 readout, how does the OS data look for patients across race, metastatic disease site, and renal function subgroups?

Dr. Powles: Drs. Michiel Van Der Heijden and Shilpa Gupta, along with other colleagues presenting these datasets, have done a fabulous job. Firstly, I find the datasets very clean, and we have made significant efforts over a prolonged period to surpass platinum-based chemotherapy. Because of that, EV-302 stands as a very robust study in my opinion.

Consequently, in every subset we examine, EV/pembro outperforms platinum-based chemotherapy. We have demonstrated favorable data from a response perspective, as well as from both PFS and OS standpoints across different patient groups. It is fair to say that the issue of which patients should still receive platinum-based chemotherapy and the relevance of platinum eligibility is almost negligible. I do not believe it holds much significance in the first-line setting anymore.

If a patient were to present at a hospital in the United States with access to the combination as it currently stands, I would not hesitate to recommend EV/pembro. However, I would advise patients extensively regarding potential adverse events such as rash during the initial 12 weeks, transaminitis, immune-related early toxicity, cumulative peripheral neuropathy, and other uncommon side effects associated with immune therapy, which we have not discussed extensively yet.

It is noteworthy that immune therapy can induce unusual side effects. In previous trials, the antagonistic relationship between chemotherapy and immune checkpoint inhibition somewhat mitigated the spike in immune-related toxicities. However, in the frontline setting with EV/pembro combination therapy, I believe there is less antagonism between the drugs. Rather, what we observe is a potent immune response, which is more characteristic of immune therapy and its associated toxicity. Thus, I do not consider the EV/pembro regimen more challenging than platinum-based chemotherapy, which is notoriously difficult.

Currently, I have a patient who experienced renal failure, sepsis, and neutropenic sepsis after just 2 cycles of gem-carbo, with the cancer progressing. Hence, the story of platinum-based chemotherapy has never been favorable. Replacing it has been a significant advancement both in terms of efficacy and toxicity. Unlike before, where I might have considered giving gem-carbo to certain patients, now I lean towards EV/pembro. However, it is crucial to discuss, educate, and train regarding these adverse events, particularly focusing on skin rash and transaminitis during the initial 3 cycles.

It is truly an exciting time in urothelial cancer research.

What do you project will be the preferred treatment after progression on EV/pembro – sacituzumab govitecan or chemotherapy?

Dr. Powles: The vast majority of patients typically receive platinum-based chemotherapy in the second-line. We presented this data at ESMO, and it appears quite rational. Notably, although the median progression-free survival is 12 months, the overall survival extends to 30 months, indicating that patients generally fare well after progression. Some patients may continue with EV/pembro if they have had a deep response to therapy. However, relapse is possible even after such a response. For instance, a patient’s cancer might decrease from 10 centimeters to 1 centimeter, but if it subsequently increases from 1 centimeter to 2 centimeters, that is considered disease progression, even though it is not back to the original size.

Many patients may do well but eventually progress, leading to questions about whether to change therapy and when to do so. Should therapy be changed only when the cancer returns to its initial state, or should we consider changing at the first sign of progression? Additionally, for patients who received EV/pembro, peripheral neuropathy may affect the feasibility of administering platinum-based chemotherapy.

It is uncertain whether sacituzumab govitecan will definitively outperform platinum-based chemotherapy. We require further trials to ascertain that. This entire domain remains undefined, and I am eager to participate in further exploration in this area.