Nivolumab Plus Ipilimumab May Offer Efficacious Therapeutic Approach in Rare GU Cancers

Novel approaches with immunotherapy combination regimens have displayed the potential to augment the treatment arsenal for patients with rare genitourinary (GU) malignancies, according to Bradley McGregor, MD.

In a phase 2 study (NCT03333616), McGregor et al examined the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of patients with advanced rare GU malignancies who had not received prior immunotherapy.1 Patients with bladder cancer with variant histologies (BCVH) who received the combination (n = 49) achieved an objective response rate (ORR) of 37% (80% CI, 27%-47%); the median duration of response was not yet reached and 9 patients experienced a response lasting over 12 months. The median progression-free survival was 6.2 months (95% CI, 2.7-9.2) and the 12-month overall survival rate was 58% (95% CI, 42%-71%).

“What I find remarkable about this [research] is that we [often consider] these rare tumors, and think, ‘This is a really challenging trial and we can’t enroll [patients]’. We showed that it can be done. We enrolled [49] patients with [BCVH] in less than 3 to 4 years and that’s with the COVID-19 pandemic and delays in enrollment.” McGregor said. “When we work together and have a novel trial design, patients are interested. Patients with these rare tumors come to an academic center and want something different. They want to try a novel, rational approach. We have shown that it can be done, and through collaboration with the patients, patient advocacy [groups], and other sites, we can truly advance care for patients with these rare tumors.”

In an interview with OncLive®, McGregor discussed the study’s rationale and findings as well as the process of implementing the regimen into the GU treatment paradigm at his institution. McGregor is director of clinical research at the Lank Center for Genitourinary Oncology, a senior physician, and a Marra Lochiatto Investigator at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts.

OncLive: What was the rationale and process that led to the implementation of this protocol?

McGregor: [We began] the development of [this program] years ago and the idea was that we have a lot of patients who [present] with rare tumors or a rare variety of a common tumor, [such as] variants of bladders tumors [including] small cell or squamous cell [cancer] of the bladder or urinary tract. As immunotherapy was being developed, the idea was that immunotherapy is sort of a tumor agnostic approach that is approved across a variety of tumors.

Very early on we recognized that this could potentially be a niche where we could think about these rare tumors. In what we call the rare GU protocol, we studied the combination of nivolumab and ipilimumab in those patients who were generally excluded from traditional trials in a variety of cohorts. We looked at cohorts of patients with diverse [tumor] histologies of the urinary tract, adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and small cell prostate [cancer]. We looked to study [this combination] across this spectrum of tumor types.

What were the logistics of getting this program off of the ground?

If we were to do a trial just looking at adrenal or penile tumors, that would be very hard and take a lot of effort to enroll patients in a timely fashion. But because we looked at a wide variety of tumors, we were able to open sites across the US. Although each individual tumor type is rare, by grouping all these [tumor types] together we were able to enroll [patients in the trial] at a reasonable rate.

We saw some signals early on in terms of efficacy, and because we were able to include so many different histologies there was interest in other sites to enroll. From a logistic standpoint, when you open this trial, you would hope to enroll not just 1 or 2 but 3 or 4 of these tumor types. Therefore, it made sense to invest in this trial.

Where have the strongest efficacy signals been observed so far?

There is always a give-and-take with these approaches. With trials [such as this one] you’re able to accrue patients relatively faster than if you [studied] something specifically, but the idea behind this is that you can’t stop here. We enrolled patients into 3 cohorts: urinary tract [tumors], adrenal tumors, and other tumors. In the other tumors [cohort], the results were relatively disappointing. There were no responses in platinum-refractory germ cell tumors, which we’ve seen in other trials, [and there were] very few responses in penile carcinoma.

In adrenal tumors, we had a small number of responses. We need to look at those data a bit further because sometimes response rate alone doesn’t tell you the efficacy. But, in those patients with divergent histology of the urinary tract, we saw 2 things. We saw a response rate that was close to 40%. Then, in those patients with small cell carcinoma of the bladder, we [initially] saw 2 out of 3 patients with impressive responses.

We took those numbers and [determined that] we can do more. Therefore, we [performed] a first expansion cohort looking at patients with small cell carcinoma anywhere in the urinary tract or the prostate. With more patients we saw an ORR of 50% which was often very durable or [we saw] progression; there was really no stability. [These are] exciting numbers. Then we did a further expansion. Now we have over 50 patients with divergent histology of the urinary tract, and that 40% ORR has been confirmed.

Starting with this small trial of 19 patients [with bladder cancers], we found the signal of where the regimen seems to be effective and then we took the next step. Now, as we work to publish the manuscript, we’re trying to look at biomarker response, including with PD-L1. We hope to have that analysis done [soon] so we can get these data out there. [Approximately] 50 patients with diverse histologies of the urinary tract will be one of the largest subsets of patients available [for trial enrollment and] that hopefully can help us guide therapy for these patients.

Reference

1. McGregor BA, Campbell MY, Huan J, et al. Phase II study of nivolumab (nivo) and ipilimumab (ipi) for advanced bladder cancer with variant histologies (BCVH). Ann Oncol. 2023;34(suppl 2):S1205-S1206. doi:10.1016/j.annonc.2023.09.1018