Although immunotherapy is not an approved treatment for muscle-invasive bladder cancer (MIBC), many recent trials are producing promising results that could lead to approval in the future.
At the 2022 ASCO Genitourinary Cancers Symposium, for instance, a study assessed the safety and efficacy of neoadjuvant nivolumab (Opdivo) in combination with gemcitabine-cisplatin in a population of patients with MIBC.1 Shilpa Gupta, MD, discusses the favorable outcomes of this trial in a recent interview with Urology Times®. Gupta is the director of genitourinary oncology at Cleveland Clinic in Ohio.
This was an investigator-initiated study, BLASST-1 [NCT03294304], [which] is [the] Bladder Cancer Signal Seeking trial of adding nivolumab to the standard of care gemcitabine and cisplatin in patients with muscle-invasive bladder cancer undergoing cystectomy. I led this trial across 3 institutions, and we enrolled 41 patients to see if the combination of immunotherapy and chemotherapy can lead to improved pathologic downstaging compared to historical controls.
In this study, we enrolled 41 patients who were scheduled to receive 4 cycles of gem-cis [(gemcitabine plus cisplatin)] and nivolumab. All [of] the patients underwent surgery. There were no delays to surgery [and] there were no long-term complications related to treatment. The pathologic downstaging was pretty impressive at 66%. The complete response rates were 49%, which is quite impressive compared to historical controls. I think these findings were very reassuring. Now, we are doing a phase 3 trial comparing just chemotherapy with chemotherapy and nivolumab. That's called the ENERGIZE trial, which is currently accruing [NCT03661320].2
There have been several trials now that have proved that immunotherapy is effective in neoadjuvant settings, whether used by itself or in combination with chemotherapy. It's generally deemed to be safe and [improves] outcomes. Because these are all [mostly] single-arm trials, now the combination or single-agent immunotherapy, or a combination with antibody drug conjugate, or with chemotherapy, is being evaluated in phase 3 trials with the comparator arms of chemotherapy. So, apart from enrolling on the clinical trial, we are still offering the standard-of-care chemotherapy to patients when eligible and immunotherapy is not yet approved in this setting.
In our trial, we saw really encouraging downstaging and complete responses. When we looked at the RNA analysis, looking at the responses by molecular subtype, we found that patients with basal type tumors had more favorable responses in our study compared to responses in the luminal type. When we look at a comparative cohort of patients who received only chemotherapy in another cohort, the responses in both basal type and luminal type are similar, so this tells us that bladder cancer is not just a very simple disease, and being a molecularly heterogeneous disease, we should be able to tailor therapies. In this case, adding immunotherapy showed that the basal type tumors were responding even better. The future of this is to lead a biomarker-based study, which is currently being planned in the cooperative groups. But from our study, we are further trying to evaluate the biomarkers of responses and resistance to immunotherapy by looking at the pre- and post-treatment tissues available from our study and comparing [them] to another neoadjuvant study utilizing just immunotherapy and another cohort utilizing just chemotherapy, so we can eventually come up with some guidance as to which patients may be able to do better just with chemo or just with immunotherapy, or with combination approaches. So, we currently have a Department-of-Defense-funded grant. We are looking at that for this purpose.
The take-home message for the practicing urologist is to always refer patients to their medical oncologist for consideration of innovative trials. Most of them [are] now incorporating immunotherapy in some way or another, and even in patients who are not eligible to receive cisplatin. Historically, those patients went directly for surgery. Now, we have trials utilizing immunotherapy and antibody drug conjugates prior to surgery, so I think the key here is to enroll patients in these novel trials to better answer this question of, what is the role of these agents in patients who are planning for surgery?
I think the audience would be encouraged to know that in the future, it seems like immunotherapy would become the standard of care. Right now, since it is not approved, the goal should be to try to enroll in trials that offer that opportunity.
1.Gupta S, Sonpavde G, Weight CJ, et al. Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #439
2. Sonpavde G, Necchi A, Gupta S, et al. ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. Future Oncol. 2020 Jan;16(2):4359-4368. doi:10.2217/fon-2019-0611