Georgina V. Long, BSc, PhD, MBBS
The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced an intracranial response of 46% in melanoma patients with asymptomatic, untreated brain metastases. The intracranial response rate (ICR) with nivolumab monotherapy was 20%.
Investigators observed a response in 16 of 35 evaluable patients treated with 1 mg/kg of nivolumab combined with 3 mg/kg of ipilimumab every 3 weeks for 4 doses, then 3 mg/kg of nivolumab every 2 weeks (cohort A). In contrast, only 5 of 25 evaluable patients randomly assigned to 3 mg/kg of intravenous nivolumab every 2 weeks (cohort B) showed a response.
At the August 2017 data cutoff, with a median follow up of 17 months (IQR, 8-25), 6 (17%) patients in cohort A had a complete response (CR) compared with 3 (12%) in cohort B.
“Given the increasing evidence of efficacy of immunotherapy across many solid tumors, these results might have marked implications for the management of active brain metastases in other solid tumors,” lead author Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney, and coauthors wrote.
“Patients with asymptomatic untreated melanoma brain metastases should be considered for combination nivolumab and ipilimumab in the first-line setting,” added Long et al.
Researchers conducting this multicenter open-label randomized phase II trial recruited 79 immunotherapy-naive adults with melanoma brain metastases at 4 sites in Australia from November 2014 to April 2017. Cohort A (n = 36) was assigned to the combination and cohort B (n = 27) was assigned to monotherapy.
Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in cohort C (n = 16) and assigned to monotherapy in a nonrandomized fashion. One (6%) patients in that group had a partial ICR and there were no complete ICRs.
Eligible patients had an ECOG performance status of 0 to 2, had at least one target intracranial lesion of 5 mm to 40 mm on Gadolinium-enhanced MRI, and had no history of severe autoimmune disease. Previous BRAF inhibitor therapy with or without MEK inhibitor therapy was allowed if intracranial RECIST 1.1 progression had occurred. The primary endpoint was ICR from week 12.
Intracranial progression was the best response for 14 (40%) patients in cohort A, 19 (76%) in cohort B, and 13 (81%) in cohort C.
At the cutoff, 15 (94%) of 16 responding patients in cohort A, and all 5 responding patients in cohort B remained in response.
The sole responder in cohort C had an investigator-assessed intracranial response that was ongoing at 22 months. This patient had BRAF
wild-type melanoma, no leptomeningeal melanoma, and neurological symptoms only.
Sixteen (46%) patients in cohort A and 20 (80%) in cohort B had experienced an intracranial progression event by the cutoff. The 6-month intracranial progression-free survival (PFS) was 53% (95% CI, 38-73) in cohort A, 20% (95% CI, 9-44) in cohort B, and 13% (95% CI, 3-46) in cohort C.
Median intracranial PFS was not reached in cohort A (95% CI, 2.9-not reached), 2.5 months (95% CI, 1.7-2.8) in cohort B, and 2.3 months (95% CI, 1.4-4.3) in cohort C. Thirteen (37%) patients had died in cohort A, 12 (48%) died in cohort B, and 13 (81%) in cohort C.
A lower baseline intracranial disease burden (sum of diameters, ≤19 mm) was associated with a longer PFS in cohort A compared with a baseline disease burden >19 mm. Median intracranial PFS increased from 2.1 months (95% CI, 1.3-2.9) in patients with progressive disease to not reached for those with a stable, partial, or complete responses in cohort A.
Patients from cohort A and B with baseline PD-L1 expression ≥1% had a numerically greater extracranial survival and overall PFS than patients with PD-L1 expression <1%. That was not true for intracranial PFS.
For patients with melanoma PD-L1 expression ≥1%, the extracranial and overall PFS were similar in cohorts A and B, but intracranial PFS was longer in cohort A. For PD-L1 expression <1%, the extracranial, intracranial, and overall PFS, were longer in cohort A than cohort B.
Thirty-four (97%) patients in cohort A, 17 (68%) in cohort B, and 8 (50%) in cohort C experienced treatment-related adverse events (TRAEs). Nineteen (54%) patients in cohort A, 4 (16%) in cohort B, and 2 (13%) in cohort C experienced grade 3 TRAEs. Three (9%) treatment-related grade 4 events (hepatitis, pulmonary edema, and hypopituitary) were reported in cohort A. There were none reported in cohorts B and C.
There were no deaths attributed to the study treatment. Nine (26%) patients in cohort A, one (4%) in cohort B, and 1 (6%) in cohort C discontinued study treatment due to AEs.
Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicenter randomised phase 2 study [published online March 27, 2018]. Lancet Oncol. doi: 10.1016/ S1470-2045(18)30139-6.