A session at the Bladder Cancer Advocacy Network (BCAN) 2023 Think Tank is taking a deep dive into the evolving treatment paradigm in advanced urothelial carcinoma. The session, titled, “Defining treatment lines in metastatic urothelial cancer: Choosing the right targets and combinations is being co-chaired by Scott Tagawa MD, Weill Cornell Medicine, and Tracy Rose, MD, University of North Carolina. In this interview with Urology Times, Dr. Tagawa highlights key areas that will be covered in the BCAN session.
Tagawa: The nice thing for a physician in practice seeing patients who unfortunately have advanced urothelial carcinoma is that we now have a number of different options. That also leads to the complexity of having different treatment options without necessarily level 1 data supporting specific combinations or sequences. For a long time, there has been platinum chemotherapy in the first-line setting, and in the more recent era, that’s generally followed by maintenance avelumab (Bavencio). Now we hear that the first-line combination of cisplatin-based chemotherapy with nivolumab (Opdivo) may be better than chemotherapy alone. But that’s in a press release,1 so we will see what happens. We need to reconcile that [specific regimen] against the other combinations that weren't specifically cisplatin, or any platinum. But anyway, it's [typically] been platinum, followed by immunotherapy in the first line, and then single-agent enfortumab vedotin (Padcev) in the second-line setting.
But then we also have an accelerated approval of enfortumab vedotin plus pembrolizumab (Keytruda) [for the frontline treatment of patients with advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy].2 Additionally, we have sacituzumab govitecan (Trodelvy), [which has an accelerated approval for patients with locally advanced or metastatic urothelial cancer who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor].3 And then, findings from the phase 3 THOR trial (NCT03390504) presented during the 2023 ASCO Annual Meeting showed that erdafitinib (Balversa) [significantly improved overall survival compared with investigator’s choice of chemotherapy in patients with FGFR2/3-altered metastatic urothelial cancer who had previously received an PD-1 or PD-L1 therapy].4
So that’s a brief overview of some of the complexities for physicians and patients now in this setting, and that is the rationale for the BCAN session that I'm co-chairing with Dr. Tracy Rose. There will be 3 specific talks during the session. One on different ADCs, approved as well as investigational, and alone or with immune checkpoint inhibition. And that talk will be done by Dr. Vadim S. Koshkin from UCSF. There will be another session on FGFR targeted therapy that will be mostly on erdafitinib, alone or in combinations, by Dr. Arlene Siefker-Radtke from MD Anderson. And then Dr. Srikala Sridhar, from Princess Margaret Cancer Center, will talk about sequencing, patient selection, and the projected future landscape. And following those talks, there'll be a group discussion.
At this time, there’s really only one truly “prime-time” [level-1-evidence–supported] immunotherapy in the first-line setting and that is in a patient who has had first-line platinum-based chemotherapy and has had disease control, meaning a partial response or stable disease—we give those patients immunotherapy in the form of first-line avelumab maintenance. The major part of patient selection [for upfront avelumab maintenance] is that they have not had primary progression on platinum-based chemotherapy. And that would be kind of first-line switch maintenance therapy. The other part of patient selection would be is the patient a candidate for anti–PD-L1 immunotherapy; and that is generally a question of [whether or not they have very active autoimmune disease].
And then we’re about 3 months since the accelerated approval of enfortumab vedotin plus pembrolizumab in patients who are cisplatin unfit. In the recent ASCO recommendations about what to do in the setting of the cisplatin and carboplatin shortage, the nice thing is that enfortumab vedotin plus pembrolizumab was approved in this setting at the same time as the emergence of the severe carboplatin shortage. So, I think no one has a problem [using this regimen] provided that the patient is a candidate and doesn’t have, for instance, terrible neuropathy. The harder part is with cisplatin because we know that there’s a subset of patients—and it’s mostly those with soft tissue metastasis—that gets cisplatin-based combinations and are cured, even without maintenance immunotherapy. So that's a more difficult situation. But there’s a gray area about how much are we looking for cisplatin ineligibility? So, in the setting of cisplatin shortages, at least in this country, we may be offering enfortumab vedotin plus pembrolizumab while we’re still waiting for the head-to-head data of enfortumab vedotin/pembrolizumab vs platinum/gemcitabine from the phase 3 EV-302 study (NCT04223856). So we’ll see what happens, but it’s an exciting world in which we have all of these complications about what to do because it means we have a lot more choices for our patients.
Regarding how serious the issue is, it depends on your region. There are certain regions that, I hear, had no carboplatin a couple of months ago, with some availability of cisplatin. And then sometimes a new batch will come out, and the people will be covered for a period of time. I would refer people, essentially on a daily/weekly basis—because they are being updated in real time—to the FDA website or the ASCO website, that will have updates, both in terms of availability—so when there's a new lot that comes out—and in terms of guidance since there are about 10 different disease settings for which there is more specific guidance, including bladder cancer.
The basic guidance is when the goal is cure, we really need certain drugs; and for urothelial cancer that is cisplatin….So, [for the most part] we are kind of stuck [in a situation] when there is no cisplatin. At that point, the patient travels to another region to get it or we just go with upfront surgery and then kind of re-evaluate at [that point] and see if there is platinum available for adjuvant therapy or do adjuvant immunotherapy if that’s applicable for that particular patient. For metastatic disease, like I said, luckily there’s enfortumab vedotin plus pembrolizumab if that’s appropriate for the patients, but that’s on a case-by-case basis. As the updates come in terms of availability and as the evidence changes, then I would expect that ASCO website to be updated.
We have some biomarkers; however, whether or not they are truly predictive still needs to be determined. Many people will accept FGFR3 gene mutations or FGFR2/3 fusions as predictive for drugs such as erdafitinib. But we haven’t fully tested treating patients who are negative for these abnormalities, so I would say the biomarkers have not been fully established as predictive, but FGFR status it is still one of the most accepted markers. There are also different ways of splitting the patient populations by genomics…but it’s not ready for prime time. And then there are other biomarkers that are being looked at in the field.
I would like to stress that even though FGFR3 is only expressed in about 15% to 20% of advanced urothelial carcinomas, it’s 0% if we don’t check. And so especially now that we have a specific drug for these patients, we should be checking all of the patients [for this biomarker].
I'll just put in a plug that there are many ongoing clinical trials. Even when we have good options, we're always trying to do better. We’re also aiming to improve outcomes in terms of efficacy, whether it’s overall survival or patient-reported outcomes, and especially in settings where there are fewer treatment options. For example, when a patient has already received 2 or 3 of these agents and there is not much left. For these patients, there are earlier phase clinical trials out there exploring additional promising agents. So I would say to everyone, be on the lookout for those clinical trials.
1. Opdivo (nivolumab) in Combination with Cisplatin-Based Chemotherapy Shows Overall Survival and Progression-Free Survival Benefit for Cisplatin-Eligible Patients with Unresectable or Metastatic Urothelial Carcinoma in the Phase 3 CheckMate -901 Trial. Published online and accessed July 11, 2023. https://investors.bms.com/iframes/press-releases/press-release-details/2023/Opdivo-nivolumab-in-Combination-with-Cisplatin-Based-Chemotherapy-Shows-Overall-Survival-and-Progression-Free-Survival-Benefit-for-Cisplatin-Eligible-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma-in-the-Phase-3-CheckMate--901-Trial/default.aspx
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. Published online and accessed April 3, 2023. https://bit.ly/3MdWuAJ
3. 1. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. Posted online April 13, 2021. Accessed April 13, 2021. https://bit.ly/3mI4xap
4. Loriot Y, Matsubara N, Park SH, et al. Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). J Clin Oncol. 2023;41(suppl 17):LBA4619.