Expert perspectives on optimal treatment approaches in patients with newly diagnosed metastatic urothelial carcinoma.
Thomas Powles, MBBS, MRCP, MD: The treatment options for first-line cancer metastatic urothelial cancer have changed a lot over the past 10 years. They’re still not as complicated or as dynamic as [options for] breast cancer or even lung cancer, but we have made some progress. I think the first thing to say is that frontline chemotherapy, GEM/CIS [gemcitabine/cisplatin] or GEM/CARBO [gemcitabine/carboplatin], is the standard of care. There are other options, accelerated AMVAC [accelerated methotrexate, vinblastine, doxorubicin, and cisplatin] and maybe some other chemotherapy regimens too, but essentially, I think it’s reasonable to say that GEM/CIS and GEM/CARBO are the standards. Cisplatin eligibility remains an important first decision, and most patients are cisplatin ineligible because of either performance status or poor renal function. There are other factors such as hearing loss that we need to think about, too. Most patients get 4 to 6 cycles of chemotherapy initially.
The time at progression, historically, if you stop chemotherapy, the median progression-free survival is [approximately] 4 months. And most patients don’t get second-line therapy. Thus, it’s really important to pick the first line of therapy correctly. There [are] robust data looking at maintenance avelumab associated with 31% reduction in the risk of death versus placebo. Hence, it’s fair to say a standard of care as it currently stands is GEM/CIS or GEM/CARBO and then maintenance avelumab.
Now, there are some caveats. We know that atezolizumab [ATEZO] and pembrolizumab [PEMBRO] both have frontline data, particularly in the biomarker-high population; that’s the PD-L1 biomarker. But I think there are 2 components to that. Firstly, it appears that that PD-L1 biomarker is not particularly active and effective. And what I mean by that is we’ve done a lot of trials testing that biomarker prospectively even in the frontline setting and it has not been successful. And the other issue is ATEZO and PEMBRO are approved in the cisplatin-ineligible population, and we know that even GEM/CARBO has higher response rates than atezolizumab or pembrolizumab. And we know that in frontline immune therapy, progression of disease occurs really quickly in a high proportion of patients. Thus, even in that PD-L1 biomarker–high, cisplatin-ineligible population, it’s still actually easier to give GEM/CARBO and maintenance avelumab.
Now, would I like that to change in the future? Are there exciting drugs coming forward in the future? The answer is yes, there are, and we would like to replace chemotherapy altogether. But going back to what I said previously, chemotherapy actually has disease control rates of [approximately] 70%, response rates of [approximately] 45%, and quite impressive initial control of disease. Therefore, getting that initial control and trying to maintain it with avelumab is more attractive than the alternatives, which are giving frontline immune therapy and taking a risk that the cancer will grow quickly or waiting for the cancer to come back after chemotherapy and giving second-line pembrolizumab or atezolizumab, which actually is too late for most patients.
Transcript edited for clarity.