Case 2: Exciting New Treatment for Cis-Ineligible Bladder Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Arlene O. Siefker-Radtke, MD:Luckily, there are additional trials that have accrued looking at more of a maintenance type strategy, as well, following chemotherapy. So we will gain some important answers to this question at some point in the next few years, as soon as these trials read out.

Tian Zhang, MD:Matt Galsky, MD, presented the chemotherapy followed by pembrolizumab maintenance trial at ASCO [the American Society of Clinical Oncology] 2019 annual meeting, and I thought the data were compelling—to keep a patient in a response, use these agents sequentially more in a maintenance fashion rather than giving them all combination-wise up front.

Elizabeth R. Plimack, MD:I think 1 other point on that is chemotherapy, there’s a limit to how much we can give before building in a break or switching to something else. Immunotherapy seems to be if it’s working so far, we can continue it as long as it’s tolerated. And so thinking about those differences in terms of durability of response and ability to continue therapy are important. I think this underpins how we interpret these trials we just spoke about.

Arlene O. Siefker-Radtke, MD:I think it’s definitely exciting what we’ve seen with immunotherapy and the duration of response that we’ve seen with pembrolizumab showing a median duration of response second-line of over 2 years. With nivolumab, there are similar data. There was the landmark analysis of the CheckMate 275 data showing if you have a complete remission in the metastasis second-line state, you actually did extraordinarily well. So it’s very possible that durability and depth of response may matter. So giving chemotherapy to induce a response followed by something to maintain it, it feels a little bit like we’re treating leukemia now, or perhaps.

Tian Zhang, MD:The key question in that setting though, in my mind, is how long do we keep these patients on that because these immune-related adverse events can really occur any time, even years into treatment. And so there are still not enough prospective data, I think, to inform us on when we can stop therapy, particularly for those patients who have complete responses or very deep partial responses and who are 2, 3 years into treatment.

Arlene O. Siefker-Radtke, MD:It’s certainly very exciting. What do you think, Gordon, is it time to give this neoadjuvant?

Gordon Brown, DO:It’s interesting. As you know, based on Bart Grossman, MD’s initial data, which have changed our practice patterns as it relates to management surgically for patients with muscle invasive disease, the PURE-01 trial would suggest that we’re seeing complete pathologic responses that are superior to dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin, cisplatin] in some cases. So it would suggest potentially that yes, this might have a role there for the appropriately well selected patient in the neoadjuvant setting. That I think is not ready for prime time obviously, but it does raise some additional intellectual questions around which patient and at what time to institute this therapy. And it has really changed the landscape for how we manage bladder cancer.

Arlene O. Siefker-Radtke, MD:Certainly there are several clinical trials that are now open and accruing patients, studying the same idea, chemotherapy with immunotherapy as a neoadjuvant treatment to try to enhance the clinical benefit earlier in the disease space. But there are other options coming up as well. Tian, did you see any of the interesting ESMO [European Society for Medical Oncology] data on any other frontline combinations?

Tian Zhang, MD:Well, we were really impressed by the enfortumab vedotin with pembrolizumab trial that Chris Hoimes, DO, presented, the EV-103 study, where the objective response rate was somewhere around 70% in these frontline cisplatin-ineligible patients. And disease control; if you take everyone with stable disease or better, it was about 91%, 92%. So very impressive data early on for a single cohort phase II study, so we will need to see more patients and randomized to standard of care current controls. But I think it’s very promising for an active agent like enfortumab vedotin.

Arlene O. Siefker-Radtke, MD:It sounds like enfortumab is going to be a player in the future. What do you think, Betsy, anything else exciting coming up through the trials?

Elizabeth R. Plimack, MD:Sure. There are other metastatic trials looking at novel agents. I think sacituzumab govitecan, I hope I said that right, IMMU-132 showed again initial impressive data in terms of response. It’s an antibody drug conjugate targeting a different marker than enfortumab vedotin with a different linker toxin and a different toxicity profile. I think as we think about these agents, the question I’ll be asking is how different are they from one another? If one doesn’t work for a patient, can another one then have success or not? Kind of the same questions we were asking around the slew of PD-1 [programmed cell death protein 1] and PD-L1 [programmed death-ligand 1] inhibitors in this space when they all came at the same time. So I’m optimistic that these are different enough that we can have multiple treatment options for patients with urothelial cancer to look to.

Tian Zhang, MD:Yes. Maybe we can be a bit more precise about our definitions, too. So enfortumab vedotin targets Nectin-4. Antibody drug conjugate gets into the cell and acts via MMAE [monomethyl auristatin E], which targets microtubule proliferation and extension and so really helps in the cell cycle. And then as you say, sacituzumab is more TROP-2 targeting, gets in and acts as more of a irinotecan, sort of topoisomerase inhibitor. And so very different mechanisms, both by which they target the cell and then also by which they impact cell proliferation. I think we’re going to need to learn more about these agents and the differences in urothelial expression of these antigens on the cell surface, when it gets into the cell, how much that inhibits in urothelial cells and then also in normal tissues and the off-target effects. And they seem to be quite tolerable, but are there differences in their adverse effect profiles?

Transcript edited for clarity.