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CHICAGO -- Clinical activity and survival outcomes improved with the addition of ipilimumab (Yervoy) to nivolumab (Opdivo) in patients with ovarian or other gynecologic clear cell carcinomas, according to results from the non-comparative phase II BrUOG 354 study.

At a median follow-up of 11.3 months, the overall response rate (ORR) among the 30 patients who received the combination was 33.3%, with five complete and five partial responses, and an additional 10 patients had stable disease, reported Don Dizon, MD, of Lifespan Cancer Institute and Rhode Island Hospital in Providence, at the American Society of Clinical Oncology (ASCO) annual meeting.

Among 14 patients who received nivolumab alone, there were two partial responses and no complete responses, for an ORR of 14.3%, while five patients had stable disease.

The median duration of response was 22.4 months with the immunotherapy combination and 30.6 months with single-agent nivolumab.

Median progression-free survival was 5.6 months for patients who received the combination and 2.2 months for those treated with nivolumab alone, while median overall survival was 24.7 months and 17.3 months, respectively.

"We can conclude based on prior studies and this one, which is the largest in CCC [clear cell carcinoma], that immunotherapy represents an important and available treatment option for our patients with these rare and aggressive malignancies," said Dizon.

Though rare, extra-renal clear cell carcinomas can occur in any organ of the body. "About 10% of ovarian cancers, 3 to 4% of cervical cancers, and up to 6% of uterine cancers are clear cell," said Dizon. "It's important because compared to serous carcinomas, CCCs are associated with a lower overall response rate to chemotherapy, inclusive of all of our standard treatment options, and as such, when they relapse or metastasize, patients face a worse overall and progression-free survival."

Across gynecologic clear cell cancers, the most frequently altered genes are those involving TP53, ARID1A, PIK3CA.

Prior studies in ovarian clear cell carcinoma have shown much higher response rates with nivolumab and ipilimumab versus single-agent nivolumab, as in BrUOG 354. In , the ORR was 31.4% (with a complete response rate of 5.8%) compared with 12.2% with nivolumab alone. Those investigators suggested that clear cell carcinoma was associated with up to a fivefold higher chance of a response with the immunotherapy doublet versus other histologies.

In , among 19 patients with ovarian clear cell carcinoma who were treated with nivolumab and ipilimumab for up to 2 years, followed by nivolumab alone, the overall response rate was 21%. There were no responses among eight patients enrolled with endometrial clear cell carcinoma and three with cervical clear cell carcinoma.

A predominance of complete or partial responses has been observed with dual immunotherapy, noted ASCO-invited discussant Bradley Corr, MD, of the University of Colorado in Aurora. "Taken together, we might think that clear cell histology is what yields the super response we see in these trials," he said.

However, "it is unclear whether these patients were platinum-resistant or -sensitive," given that the median number of prior lines of therapy was one in BrUOG 354, whereas in NRG GY003, 20% of patients had one, 43% had two, and 37% had three prior lines of therapy. "This begs the question: did patients [in BrUOG 354] do better because of the histology or because they were earlier in their disease course?" he asked.

was a two-stage, randomized, non-comparative study in which nivolumab 240 mg IV every 2 weeks with and without ipilimumab 1 mg/kg every 6 weeks were evaluated in patients with extra-renal clear cell carcinoma after at least one prior therapy, which could not include prior immunotherapy.

In the first stage of the study, patients were randomly assigned to nivolumab or nivolumab plus ipilimumab with stratification by tumor site (ovarian vs extra-ovarian). Treatment continued until disease progression or unacceptable toxicity. Each arm was evaluated for ORR separately during the first stage using Response Evaluation Criteria in Solid Tumors (RECIST) and iRECIST (for cancer immunotherapy trials) criteria.

The nivolumab arm was closed after the first stage, and patients were subsequently treated with nivolumab plus ipilimumab.

Median patient age was 57 years, 75% were white, 11.4% were Hispanic, and 9% were Black. Of the patients, 81.2% had ovarian cancer, 13.6% had uterine cancer, and 4.5% had "other" cancer. The median number of prior lines of therapy was 1 to 1.5, with up to 7 lines given.

Four patients on combination nivolumab and ipilimumab remained on treatment. No new responses occurred after 1 year of therapy.

"We saw no new signals of toxicity," said Dizon. "The major toxicity of note was hypothyroidism," which occurred in 35.7% of patients taking nivolumab alone and 20% taking the combination.

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