Nivolumab plus ipilimumab demonstrated an intracranial response (ICR) rate of 42% in asymptomatic patients with melanoma brain metastases who had not received prior local therapy to the brain.
In the phase II Anti-PD1 Brain Collaboration (ABC) trial, the 6-month intracranial PFS rate was 46% with the anti–PD-1/CTLA-4 combination.
“The combination of nivolumab and ipilimumab has high activity in melanoma brain metastases and may be considered for upfront therapy in such patients,” said lead author Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney.
Brain metastases are detected in about 20% to 25% of patients at diagnosis for stage IV melanoma, and in autopsy series, they have been detected in about 50% to 70% of patients.
The ABC trial was an Australian trial that included 76 patients with active melanoma brain metastases who had to have at least 1 brain metastasis that was greater than or equal to 5 mm but less than 40 mm. Prior anti–PD-1/PD-L1 or anti–CTLA-4 therapy was not allowed; however, prior BRAF and MEK inhibitors were allowed. Patients had and ECOG performance status of 0 to 2.
The study had 3 cohorts: (A) 33 asymptomatic patients with no prior local therapy to the brain randomized to nivolumab (Opdivo; 1 mg/kg) plus ipilimumab (Yervoy; 3 mg/kg) every 3 weeks for 4 cycles, followed by nivolumab at 3 mg/kg every 2 weeks; (B) 27 asymptomatic patients with no prior local therapy to the brain randomized to nivolumab at 3 mg/kg every 2 weeks; and (C) 16 patients with previous local treatment to the brain, or had symptoms, or had leptomeningeal disease and had progression in 2 consecutive MRI brain scans randomized to receive nivolumab at 3 mg/kg every 2 weeks.
Long presented results at ASCO for 67 of the 76 recruited patients who had more than 18 weeks’ follow-up at the May 8, 2017, data cutoff. This included 26 patients in each of cohorts A and B, and all 16 patients from cohort C. The median follow-up was 16.4 months (95% CI, 13.8-19.5). The range of follow-up was 5 months to 34 months.
The median age for cohorts A and B was approximately 60. Patients in cohort C were younger, with a median age of 54. Most patients were male and had an ECOG performance status of 0; however, 50% of patients in cohort C had an ECOG performance status of 1 or 2. Elevated LDH occurred in about 40% of patients in cohorts A and C; however, 58% of patients in cohort B had elevated LDH.
Approximately 50% of patients in cohorts A and B had BRAF V600 mutations, compared with 81% in cohort C. About one-fourth of patients in cohorts A and B had received prior BRAF plus MEK inhibitor therapy, compared with 75% in cohort C. In cohorts A and C, approximately 50% of patients had at least 4 brain metastases, compared with 20% in cohort B.
The primary endpoint was the ICR rate at or after 12 weeks. Secondary endpoints included extracranial response rate (ERR), overall response rate, progression-free survival (PFS), overall survival, and safety.
The 42% ICR rate in cohort A included a complete response (CR) rate of 15% and a partial response rate of 27%. Eight percent of patients in the cohort had stable disease (SD), 46% of patients had progressive disease (PD), and 4% of patients were not evaluable.
The ICR rate in cohort B was 20%, including a CR rate of 12% and a PR rate of 8%. Four percent of patients had SD, 72% had PD, and 4% were not evaluable.
The ICR rate in cohort C was 6%, including a CR rate of 0 and a PR rate of 6%. Twenty-five percent of patients had SD and 69% had PD.
The median duration of ICR has not been reached in any of the 3 arms.
Among patients who had not received prior BRAF/MEK inhibitors, the ICR rate was 50% (15% CR, 35% PR) in cohort A, 21% (10.5% CR, 10.5% PR) in cohort B, and 25% (1 PR in 4 patients) in cohort C. The PD rates were 35%, 68%, and 50% in the 3 arms, respectively.
The median intracranial PFS was 4.8 months in cohort A, 2.7 months in cohort B, and 2.5 months in cohort C. The 6-month PFS rates were 46%, 28%, and 13%, respectively.
An analysis of intracranial PFS by response status showed that, “Among the complete responders, not 1 had yet progressed. There have been minor progressions in the group that had a partial response in the brain, and more progressions in those who had stable disease,” said Long.
The ERR was 48% in cohort A, including a 10% CR rate and a 38% PR rate. The ERR was 30% in cohort B, comprising a 10% CR rate and a 20% PR rate. In cohort C, the ERR was 25%, including a CR rate of 8% and a PR rate of 17%.
The median extracranial PFS was 5.3 months in cohort A, 2.7 months in cohort B, and 2.7 months in cohort C. The 6-month PFS rates were 47%, 40%, and 10%, respectively.
“There were no new or unexpected adverse events (AEs) in the trial,” said Long. All-grade treatment-related AEs occurred at rates of 96% in cohort A, 68% in cohort B, and 56% in cohort C. The rates of grade 3/4 treatment-related AEs were 46%, 24%, and 19%, respectively.
Serious treatment-related AEs occurred in 46% of cohort A, 12% of cohort B, and 25% of cohort C. Discontinuations due to AEs occurred in 27%, 4%, and 6% of the 3 cohorts, respectively.
“Neurological adverse events were not frequent, occurring in only 4 of 67 analyzed patients, including 1 radionecrosis, 1 seizure, and 2 headaches, presumably due to swelling,” noted Long.
Long GV, Atkinson V, Menzies AM, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). J Clin Oncol 35, 2017 (suppl; abstr 9508).
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