Targeting Trop-2 in Advanced Urothelial Carcinoma - Episode 11

Novel Sequencing Strategies for Advanced Urothelial Carcinoma

Recommendations regarding how to best integrate newer therapies, including antibody-drug conjugates, into treatment plans for patients with advanced urothelial carcinoma.

Petros Grivas, MD, PhD: It’s great to see that antibody-drug conjugates have entered the treatment armamentarium. Both are very important and can be used in sequence, 1 after the other. I don’t see any cross-resistance. They’re different drugs, so it’s important to take into account the toxicity profile of those agents, which can be different, along with the patient comorbidities, preferences, level of evidence, and data to help us sequence these drugs in the clinic. But it’s exciting to have options for the patients. Neeraj, do you have any comments on that from your experience?

Neeraj Agarwal, MD: I’ve had a very similar experience. Relatively speaking, they’re overall much better-tolerated drugs. Most of my patients will be eligible for these antibody-drug conjugates compared with my experience with cisplatin-based chemotherapy. That’s definitely exciting news. I’d like to highlight 1 very important point you raised, which is that these 2 antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan, are exclusive of each other. They carry different chemotherapy payloads: MMAE [monomethyl auristatin E] in the context of enfortumab vedotin and SN-38 in the context of sacituzumab govitecan. There are different targets, nectin-4 vs trop-2.

These are entirely different drugs, unlike what we think about with PD-1 or PD-L1 inhibitors. If I’ve used 1, I don’t have much enthusiasm or data for the use of other. But in this case, they’re completely different drugs. They’re in the same class of drug. That’s the only similarity they have. If my patient was progressing on enfortumab vedotin, I’m doing the preauthorization for sacituzumab govitecan, because I know there’s no overlapping mechanism of action. That’s the best news for our patients.

Second, they have nonoverlapping toxicities. If the toxicities were overlapping, I’d have much less enthusiasm. But because of neuropathy with enfortumab vedotin, which could be because of the use of enfortumab vedotin after platinum-based chemotherapy in the majority of patients, that could be happening from that perspective also. Having said that, neuropathy, hyperglycemia, and skin rash with enfortumab vedotin are nonoverlapping toxicities compared with sacituzumab govitecan, which is associated with diarrhea and neutropenia. That’s all great news for our patients.

Petros Grivas, MD, PhD: I totally agree. You summarized very well the different mechanisms of action and toxicity profile that allow us to use both agents in sequence. Dr [Guru] Sonpavde at Dana-Farber [Cancer Institute] is doing a study combining the 2 antibody-drug conjugates. I’ll be interested to see the efficacy and safety data. It’s important to point out that both enfortumab vedotin against nectin-4 and sacituzumab govitecan against trop-2 are being used in patients without needing to check the biomarker. This is because we’ve seen data that nectin-4 and trop-2, these different targets, are expressed in very high proportion in urothelial cancer cells, so there was no need to check for the biomarker expression, which is different from erdafitinib, with FGFR2 or FGFR3 mutation or fusion. That makes it even easier for the patients, right?

Neeraj Agarwal, MD: Absolutely. Especially the small, simple study we published together, when we saw that in the United States until 2018. The study was focused on how many patients with newly diagnosed metastatic bladder cancer were receiving chemotherapy or any systemic therapy and how they went on to receive subsequent lines of therapies. That study was basically the Medicaid databases and utilization from SEER [Surveillance, Epidemiology, and End Results] datasets. One of the studies we included was by Dr [Matthew] Galsky. The findings were quite surprising in that only 48% patients received first-line chemotherapy or systemic therapy. Less than 25% of patients received second-line therapy, and only around 7% or 8% patients received third-line therapy.

That’s happening because of the requirement of using cisplatin-based or platinum-based chemotherapy in the first line. Many of my surgeon colleagues don’t think their patients are eligible for these therapies. Sometimes we don’t even get referral at the community level. With these antibody-drug conjugates, I wanted to add 1 point: why I may give that background. I’m waiting for antibody-drug conjugates to move to the first-line therapy setting. Once that happens, we’re going to show a more meaningful improvement in overall survival and a more drastic change in the treatment paradigm in our patients with metastatic bladder cancer. What do you think about that, Petros?

Petros Grivas, MD, PhD: Neeraj, those are great points. The paper you quoted is very impressive. Both you and I were shocked by the data. Only 15% to 20% of patients get second-line therapy with advanced urothelial cancer, which raises the issues. We’re losing patients along the way. Only 6% are getting third-line therapy, and this is because of clinical deterioration, decline of the status of the patient, performance status deterioration, access to care, and potentially some health care disparities. We have to figure out the reasons. But a significant part is the aggressive nature of urothelial cancer, and that’s something we need to keep in mind. That’s why the argument about maintenance therapy is very important with the JAVELIN Bladder 100 trial, which shows overall survival benefit and less attrition because you keep patients without progression a longer time.

But to your point, there’s a lot of enthusiasm about getting antibody-drug conjugates, either sacituzumab govitecan or enfortumab vedotin early on in the frontline setting. Now trials are combining, for example, pembrolizumab with enfortumab vedotin or sacituzumab govitecan. More recently, we’re looking at a combination of chemotherapy with an antibody-drug conjugate. We have to see where these trials take us and how they’re looking in the future. For now, chemotherapy retains its role. But with a further evaluation of antibody-drug conjugates earlier on, we may be able to keep transforming the treatment landscape, keep more patients on therapy, delay progression or death, and prolong the lives of those patients.

Neeraj Agarwal, MD: Definitely. We’re hoping that more than 17% of patients will receive second-line systemic therapy, and more than 6% of patients will receive third-line systemic therapy for their metastatic bladder cancer. But with the data we saw, as you summarized, of 100 patients in the United States, 48% received first-line therapy, 17% received second-line therapy, and 6% received third-line therapy until 2018. Since then, antibody-drug conjugates have arrived. It will be very interesting to repeat this study and see how things have changed after 3 years.

Petros Grivas, MD, PhD: It’s very exciting to see the trend. Neeraj, I agree with you. We should do this study again a few years from now and see how things evolve. I share the hope with you that we’re going to keep increasing the longevity and the quality of life of our patients. These are both important points, and you’ve led studies in prostate cancer with quality-of-life and patient-reported outcomes. These are also relevant in urothelial cancer.

Transcript edited for clarity.