Nivolumab/Ipilimumab Yields Responses in Ovarian Clear Cell Carcinoma

Don Dizon, MD

The combination of 2 well-known immunotherapy agents, nivolumab (Opdivo) and ipilimumab (Yervoy), produced responses with a familiar safety profile in patients with clear cell carcinomas of the ovary and other sites, according to Don Dizon, MD.

The final readout of the phase 2 BrUOG 354 trial (NCT03355976), which had a median follow-up of 11.3 months (range, 1.6-46.4), revealed that patients with extra-renal clear cell cancers who received nivolumab plus ipilimumab (n = 30) achieved an overall response rate (ORR) of 33.3%, which included a complete response (CR) rate of 16.7%.1 These respective rates were 14.3% and 0% among patients who received nivolumab alone (n = 14).

“This represents a treatment option that should be more widely available,” Dizon, who is the director of women’s cancers at Lifespan Cancer Institute and an assistant professor of medicine at The Warren Alpert Medical School of Brown University, both in Providence, Rhode Island, said in an interview with OncLive^® during the 2024 ASCO Annual Meeting.

In the interview, Dizon discussed key updated findings from BrUOG 354, the potential future of immunotherapy for patients with ovarian and other gynecologic cancers, and the power of decentralized clinical trials.

OncLive: What was the rationale for the BrUOG 354 trial?

Dizon: When you think about ovarian cancer, there are different kinds of histologies. One of the more worrisome types is clear cell cancer. Clear cell histologies occur in the ovary approximately 10% of the time, in the uterus approximately 6% of the time, and in the cervix approximately 5% of the time. These are rare tumors that [present] across gynecologic sites but can happen anywhere outside of the kidney, as well.

The issue is that these clear cell cancers, especially of the gynecological tract, are also far more aggressive. They don’t tend to respond well to chemotherapy, and when they relapse or become metastatic, the prognosis is poorer compared with that of serous carcinomas. There’s a real need for innovative therapies.

The rationale for this specific trial of immunotherapy comes from anecdotal reports of CRs when people received immunotherapy on larger ovarian cancer trials. This has been consistently seen, however, the numbers of people enrolled in these trials were small, an average of less than 20 people. We devised BrUOG 354 to provide more of a definitive answer to the question: How well does immunotherapy work in people with clear cell cancers?

What patient population was enrolled in this study?

We enrolled people with ovarian or extra-renal clear cell cancers. The intent, when we started this trial, was [to enroll] anyone who was diagnosed with a clear cell cancer—whether it was [in] the stomach, colon, rectum, or anywhere [else]. Ultimately, we enrolled people with gynecological cancers. We had a cohort of people with ovarian cancer and a small proportion of people with uterine or other extra-renal sites. One person had disease, for example, in the abdominal wall. That was their presentation, and we assumed it was due to endometriosis-associated clear cell cancer.

What key findings have been previously presented from the study?

This study was presented [in 2022,] when we did the interim analysis. At the first stage, we enrolled 13 people [to receive] treatment with nivolumab [and 15 people to receive the] combination of nivolumab and ipilimumab. After we enrolled those people in both arms, we stopped the study and looked to see where we were.

We wanted to continue enrollment only if it made sense. If it appeared that the response rates were low, we were not planning to continue to study. However, if there was a hint that this [combination] could be good, we would continue. At that point, we closed the arm for nivolumab, because of those 13 [people enrolled], 2 people had a partial response, no one had a CR, and the ORR was 15.4%. At ASCO this year, [I presented findings from] the final analysis after the entire study was completed.

What were the efficacy findings from the final analysis?

The interesting findings is that [with] the combination of nivolumab and ipilimumab, you get a higher response rate, of 33.3%. That included 5 people who had a CR, which is unheard of in [people with] clear cell carcinoma who have seen prior chemotherapy and [have] advanced or metastatic [disease]. We also reported that the median progression-free survival was 2.2 months with nivolumab and 5.6 months with the combination. The median overall survival was 17.3 months with nivolumab and 24.7 months with the combination. Importantly, people who responded to the combination had a durable response. We had people staying on the study as they approached the 2-year mark, and even today, people are continuing on treatment.

What were the updated safety findings?

Encouragingly, treatment with immunotherapy in this group of people was not associated with any new safety signals. The adverse effect [AE] profile was consistent with what we know can happen and the AE profile of immunotherapy in general.

What are the clinical implications of these findings?

It’s going to be difficult to envision that we’re going to have a randomized trial of, say, standard-of-care chemotherapy vs immunotherapy. That would be ideal, because then we can definitively answer how well, compared with standard treatment, nivolumab and ipilimumab work, perhaps in a more tailored population of people with ovarian clear cell carcinoma. However, I don’t think we’re going to get there, because it took me approximately 5 years to enroll 44 people.

What I do think is that immunotherapy is [a treatment] that oncologists across the world are comfortable with. We’ve heard about its use in other settings, and for the most part, a lot of us have experience with these drugs. This dataset indicates that [nivolumab plus ipilimumab] is an important treatment option for people who have a very high-risk histology for ovarian, uterine, or even cervical cancer.

Is there anything else that you would like to add about the study?

This was a collaboration between 3 institutions in Illinois, as well as 1 institution in Providence, Rhode Island. We enrolled during the COVID-19 pandemic. We did not stop enrollment, and we didn’t stop anyone from being treated. However, a lesson learned from the pandemic is that you can do a therapeutic trial in a decentralized way. What that means for us is that we kept people on trial and prevented them from getting on a plane during the height of the pandemic by allowing shipments of study drugs for delivery close to home. They stayed on trial. All the regulatory follow-up was done centrally using telehealth, for example. However, this is a proof of concept that we can decentralize a therapeutic trial—especially when the drugs are familiar.

What ongoing research in this area are you looking forward to seeing?

There are 2 things that are going to be important. One is to try to see whether we can find predictive biomarkers that track with response or lack of response to immune checkpoint inhibitors and immunotherapy in general. We’re doing that analysis now to see whether we can find any biologic correlates.

The second is to think forward. If we presume that immunotherapy will be something that people with clear cell access, we’re going to need to try to figure out what else can be done. Continuing to explore options in the frontline setting, that first treatment paradigm for recurrent or metastatic disease, is still important. However, we’re going to see a larger proportion of patients who have received immunotherapy. What can we offer them in the immunotherapy-exposed setting?

I’ve just talked about how the activity of immunotherapy in clear cell cancers is important. As you scan a wider lens, it is likely that on the heels of the [phase 3] AGO-OVAR 2.29 trial [NCT03353831] of atezolizumab [Tecentriq] in platinum-resistant ovarian cancer, we are likely to abandon an approach where single-agent immunotherapy is evaluated for efficacy in ovarian cancer because it is unlikely it has a role to play in ovary cancer specifically.

Disclosures: Dr Dizon reports consulting roles with Glaxo SmithKline, Clovis/Pharma&, AstraZeneca, Pfizer, and Kronos Biotech; as well as ownership of stock options from Doximity and Midi.

Reference

Dizon DS, Mathews CA, David SM, et al. Final results of BrUOG 354: a randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas. J Clin Oncol. 2024;42(suppl 17):LBA5500. doi:10.1200/JCO.2024.42.17_suppl.LBA5500