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Nivolumab/Ipilimumab Combination Active Upfront in Melanoma Brain Metastases

Published Online:8:42 PM, Tue June 6, 2017

Georgina Long, BSc, PhD, MBBS
More than 40% of patients with melanoma brain metastases achieved objective intracranial responses to combination treatment with nivolumab (Opdivo) and ipilimumab (Yervoy), results of a randomized phase II trial showed.
The response rate increased to 50% for patients with previously untreated melanoma. One-fifth of patients with untreated disease had intracranial responses to nivolumab alone.
In general, intracranial and extracranial response rates were similar in patients with no prior therapy, as reported at the 2017 American Society of Clinical Oncology annual meeting in Chicago.
“Nivolumab, combined with ipilimumab or nivolumab alone, has activity in asymptomatic brain metastases without prior local therapy,” said Georgina Long, BSc, PhD, MBBS, chair of melanoma medical oncology and translational research at the Melanoma Institute of Australia in Sydney. “Activity is high when nivolumab and ipilimumab are given upfront. The activity is low following treatment with the combination of a BRAF inhibitor and MEK inhibitor. The activity of nivolumab monotherapy is low after multiple modality therapy or in leptomeningeal melanoma.”
The data suggest that nivolumab, alone or in combination with ipilimumab, warrants consideration as upfront therapy for patients with melanoma brain metastases, she added.
As many as one-fourth of patients with advanced melanoma have brain metastases at diagnosis, and as many as 70% have brain metastases at autopsy. Systemic therapies have some activity against melanoma brain metastases, but a need for more effective options persists, said Long.
Australian researchers conducted a randomized clinical trial to evaluate nivolumab, alone or in combination with ipilimumab, in patients with asymptomatic melanoma brain metastases and no prior local therapy for brain lesions. A third arm of the trial evaluated nivolumab monotherapy in patients with symptomatic, previously treated, or leptomeningeal brain lesions and evidence of progression on MRI.
Data cutoff on May 8, 2017 included all patients treated for more than 18 weeks (n = 67). The study population had a median follow-up of 16.4 months and a range of 5 to 34 months. Eligible patients had brain lesions ≥5 mm but <40 mm.
The patients with previously untreated brain metastases had a median age of 61 to 62, median ECOG performance status of 0 in 65% to 70% of cases, LDH exceeding the upper limit of normal in about half the cases, 2 or more target brain lesions in about 80% of cases, and half had BRAF V600 mutations. One-fourth of the patients had received prior BRAF/MEK inhibitor combination therapy for extracranial lesions.    
The group with previously treated intracranial lesions (n = 16) had a median age of 54. Half had an ECOG performance status of 1 to 2, 94% had multiple target lesions in the brain, and three-fourths had received a BRAF/MEK inhibitor combination.
Overall, 11 of 26 (42%) patients untreated brain lesions responded to the combination of nivolumab and ipilimumab (4 complete responses), as did 5 of 25 (20%) in the nivolumab monotherapy arm (3 complete responses). In contrast, 1 of 16 (6%) patients with previously treated intracranial lesions responded to nivolumab.
Excluding patients with prior systemic therapy, 10 of 20 patients with untreated brain lesions responded to the nivolumab/ipilimumab combination, and 4 of 19 (21%) responded to nivolumab monotherapy. One of 4 patients with treated brain lesions but no systemic therapy responded to nivolumab.
Intracranial responses were similar to extracranial responses to combination therapy and to nivolumab monotherapy, said Long. The nivolumab/ipilimumab arm had an overall response rate for extracranial lesions of 48% (10 of 21 evaluable patients) and 30% with nivolumab alone (6 of 20). Among patients with previously treated brain lesions, the extracranial response rate was 25% (3 of 12 patients).
The median intracranial progression-fee survival (PFS) was 4.8 months with nivolumab/ipilimumab, 2.7 months with nivolumab alone, and 2.5 months for the patients with previously treated intracranial lesions. The 6-month PFS was 46%, 28%, and 13%, respectively.
Extracranial PFS in the patients with untreated brain lesions was 5.3 months with the combination and 2.7 months with nivolumab alone. The patients with treated brain lesions had an extracranial PFS of 2.7 months. The 6-month PFS was 47%, 40%, and 10% across the 3 groups of patients. 
The frequency, type, and severity of treatment-related adverse events were consistent with prior experience with the study drugs, and no patients developed new or unexpected adverse events, Long said.
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. 2017;35 (suppl; abstr 9508).

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