December 16, 2020 — The combination of nivolumab with ipilimumab demonstrated activity in patients with metastatic uveal melanoma with encouraging responses.
The combination of nivolumab (Opdivo) with ipilimumab (Yervoy) demonstrated activity in patients with metastatic uveal melanoma with encouraging responses, according to results of a phase 2 study published in the Journal of Clinical Oncology.
At a median follow-up of 13 months, the objective response rate (ORR) of 18% (95% CI, 7%-35.5%), with 1 (3%) complete response and 5 (15%) partial responses. Target lesion size was reduced from baseline in 41% of patients. The median progression-free survival (PFS) was 5.5 months (95% CI, 3.4-9.5).
“We were pleasantly surprised to see that dual checkpoint blockade could induce meaningful and durable responses,” study author Meredith Pelster, MD, a hematology-oncology fellow at The University of Texas MD Anderson Cancer Center said in an interview with OncLive®. “Specifically, the responses were not isolated to patients with extrahepatic disease, rather 83% of our responders had liver-predominant metastatic uveal melanoma. The duration of response was 12.1 months.”
The phase 2 clinical trial showed that there is potential for improved responses in patients for which there is no approved therapy by the FDA.
“Studies of single agent checkpoint inhibitors in metastatic uveal melanoma have shown minimal activity,” Pelster said. “Based on the efficacy of dual checkpoint inhibition in cutaneous melanoma, we questioned whether the combination of anti–CTLA-4 and anti–PD-1 would have meaningful antitumor activity in uveal melanoma as well.”
ORR was the primary endpoint as determined by RECIST v1.1 criteria, and progression-free survival (PFS), overall survival (OS), and adverse events were also examined.
The single-arm study included 35 patients, 33 of which were evaluable for efficacy. They were screened from July 7, 2015 through March 7, 2018. The median age at diagnosis was 62 years and 34% of patients were men. All patients were 18 years or older with a history of uveal melanoma with documented metastatic disease. They also had at least 1 measurable lesion measuring 1 cm or 1.5 cm in short axis, an ECOG performance status of 0 or 1, and acceptable end-organ function. Any number of prior treatments was permitted, with 15 patients (43%) having received 1 or more prior lines of therapy. Two of the 15 patients received prior pembrolizumab (Keytruda).
Identified tumor mutations were as follows: GNAQ (73%), GNA11 (23%), and wild type with a BAP1 mutation (3%). Most patients had stage IV M1a (49%) or M1b disease (40%). Nearly half (49%) of patients had both hepatic and extrahepatic metastases at the time of enrollment, with lung, bone, and soft tissue the most common extrahepatic sites of metastasis.
In the study, patients received nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg for 4 cycles, followed by nivolumab maintenance for up to 2 years. They were monitored via adverse event (AE) assessments, common laboratory tests, and liver function tests with each treatment during induction and every 4 weeks after until removed from study.
Additional data showed that the median OS was 19.1 months (95% CI, 9.6 months–not reached) and the 1-year OS rate was 56% (95% CI, 38%-71%).
“Even with an overall response rate of just 18%, the median survival for the entire study population is meaningful and represents an improvement over historical median overall survival,” Pelster said. “There may be an uncoupling effect here between response rate and survival, where generating a criteria-defined response is not critical for deriving survival benefit.”
Nearly all participants (91%) experienced an AE, with 14 patients (40%) experiencing a grade 3/4 treatment-related AE. The most common AEs included diarrhea, abnormal liver enzymes, pruritis, and hypothyroidism. Ten patients (29%) were removed from the study because of
AEs, and 7 patients required systemic steroids for the management of immune-related AEs.
“Nivolumab in combination with ipilimumab demonstrates antitumor activity in metastatic uveal melanoma,” the study authors wrote. “Results from this study and the Spanish GEM-1402 study indicate that this combination is active and should be considered for this patient population with otherwise limited options.”
When designing future clinical trials for metastatic uveal melanoma, oncologists can consider this combination as a control arm for randomized trials, Pelster explained.
“Oncologists now have clinical trial data to support the use of nivolumab and ipilimumab in metastatic uveal melanoma,” she said. “They can use the results of our study to counsel patients regarding the response rate, survival, and toxicities seen with the combination specifically in the uveal melanoma population.”