The results of the phase II trial examining combination immunotherapy were presented during the ASCO 2019 meeting.
A high rate of durable intracranial responses was observed in patients with asymptomatic melanoma brain metastases who received combination immunotherapy with nivolumab plus ipilimumab, leading the investigators to suggest that the combination should be used as first-line treatment in this population. Furthermore, intracranial antitumor activity was also observed in patients with symptomatic disease.
The results of the study, CheckMate 204 (abstract 9501), were presented by Hussein Tawbi, MD, PhD, of MD Anderson Cancer Center, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
“Brain metastases are a major cause of morbidity and mortality from melanoma. More than half of our patients with metastatic disease will have to deal with at least one brain metastasis during the course of their disease,” said Tawbi, who presented the results.
The investigators previously found that combination therapy with nivolumab plus ipilimumab was safe and effective in patients with untreated, asymptomatic melanoma brain metastases. In this study, they provided updated results for patients with asymptomatic disease and reported on the use of the combination therapy in patients with symptomatic disease.
The phase II trial (NCT02320058) included patients with at least one measurable, nonirradiated melanoma brain metastasis ranging from 0.5 to 3.0 cm. Two cohorts were assessed: patients with no neurologic symptoms or corticosteroid use (asymptomatic, n = 101; 67% male and 33% female) and patients with neurologic symptoms (symptomatic, n = 18; 72% male and 28%) female, irrespective of corticosteroid use (corticosteroid use, 11 of 18 patients).
In both cohorts, patients received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for 4 cycles, and then nivolumab (3 mg/kg) every 2 weeks until progression or toxicity occurred, up to 24 months. The primary endpoint was intracranial clinical benefit rate, which was defined as the proportion of patients with complete response, partial response, or stable disease for at least 6 months.
At a median follow-up duration of 20.6 months, the clinical benefit rate was 58.4% for the asymptomatic cohort. In this cohort, a majority of responders (87%) still had ongoing response at the time of data cutoff; thus, secondary endpoints, such as overall survival and median duration of response, have not yet been reached.
“Patients that are symptomatic are more challenging to treat,” said Tawbi. “A real concern is that steroids may actually reduce the effectiveness of immunotherapy.”
At the time of analysis, only 11% (2/18) patients in the symptomatic cohort had received all 4 doses of the combination treatment; all others received a median of 1 dose. Of responders, 75% (3 of 4) of responses are still ongoing; 1 responder was taking corticosteroids. At a median follow-up duration of 5.2 months, intracranial objective response rate was 16.7% and the clinical benefit rate was 22.2% in the symptomatic cohort.
Grade 3/4 adverse events occurred in 54.5% (54/101) of patients in the asymptomatic cohort and in 55.6% (10/18) of those in the symptomatic cohort. Adverse events in the nervous system (grade 3/4) occurred in 6.9% (7/101) of patients in the asymptomatic cohort compared with 16.7% (3/18) of patients in the symptomatic cohort. One treatment-related death (immune-related myocarditis in the asymptomatic cohort) occurred.
The investigators suggest that further studies are needed in patients with symptomatic brain metastases which, in addition to assessing other therapies, should improve the screening phase to enable rapid treatment of these patients.
“We have two phase II trials of IPI [ipilimumab] and NIVO [nivolumab] resulting in much higher response rates [than either nivolumab or pembrolizumab monotherapy], so I would go out and say that this should be the standard choice in this setting despite the added toxicity with this regimen,” said Harriet Kluger, MD, of Yale School of Medicine and Smilow Cancer Center at Yale New Haven Hospital, who was the discussant of the study at the meeting.