Nivolumab plus ipilimumab active for melanoma brain metastases

Issue: July 10, 2017

CHICAGO — Nivolumab alone or with ipilimumab showed activity among patients with advanced melanoma and active brain metastases, according to results of the ABC clinical study presented at the ASCO Annual Meeting.

Perspective from Shailender Bhatia, MD

However, the combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) did not demonstrate the same efficacy in patients who had progressed on BRAF inhibitors.

Georgina V. Long

Previous studies have shown nivolumab alone or with ipilimumab improved response rates and PFS in patients with metastatic melanoma compared with ipilimumab alone. However, patients with brain metastases — a cause of morbidity and mortality in melanoma — were not included, so the impact of therapy on this patient population remained unknown.

Georgina V. Long, PhD, MBBS, FRACP, a clinical researcher from Melanoma Institute Australia, and colleagues evaluated the antitumor activity and safety of the addition of ipilimumab to nivolumab in 66 patients with melanoma and active brain metastases at least 5 mm in size but smaller than 40 mm.

Researchers enrolled patients treated with prior BRAF and MEK inhibitor therapy, but not with anti–CTLA-4, anti–PD-1 or anti–PD-L1 agents. The analysis included three cohorts: cohort A (n = 25) received 1 mg/kg nivolumab and 3 mg/kg ipilimumab every 3 weeks for four doses followed by 3 mg/kg nivolumab every 2 weeks; and cohorts B (n = 25) and C (n = 16) received 3 mg/kg nivolumab every 2 weeks.

Patients in cohorts A and B had not received local brain therapy; cohort C included patients with brain metastases who had failed local therapy, were neurologically symptomatic and/or had leptomeningeal disease.

Intracranial response after or at 12 weeks served as the primary endpoint. Secondary endpoints included extracranial response, best overall response, intracranial PFS, extracranial PFS, overall PFS, OS and safety.

The median follow-up was 16.4 months (range, 5-34).

Sixty-seven of 76 patients were included in the final analyses (77% men).

Among treatment-naive patients, median age was 61 years (range, 29-76) for cohort A and 62 years (range, 31-86) for cohort B. The previously treated patients from cohort C were younger (median age, 54 years; range, 28-73) due to the high number of patients with BRAF mutation in that cohort, Long said.

Rate of intracranial response appeared highest in patients treated with the combination (42%), followed by untreated patients who received nivolumab alone (20%) and previously treated patients who receive nivolumab alone (6%).

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“The median duration of intracranial response was not reached in any arm,” Long said.

The extracranial response rates were 48% in treatment-naive patients treated with combination therapy, 30% in treatment-naive patients treated with nivolumab alone and 25% in previously treated patients treated with nivolumab alone.

Treatment-related grade 3 and grade 4 toxicities occurred more frequently among treatment-naive patients who received combination therapy (96%) or nivolumab alone (68%) than previously treated patients who received nivolumab alone (56%). Four patients experienced a neurological adverse event; radionecrosis (n = 1), seizure (n = 1) and headache (n = 2). No treatment-related deaths were reported.

Elevated lactate dehydrogenase occurred in 42% of patients in cohort A, 58% in cohort B and 19% in cohort C.

“Nivolumab combined with ipilimumab has high activity in melanoma brain metastases and may be considered for upfront therapy in such patients,” Long said, adding that response is highest when given before other treatment. – by Melinda Stevens

Reference:

Long G, et al. Abstract 9508. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosure: Long reports a consultant or advisory role with Amgen, Array BioPharma; Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre and Roche/Genentech; honoraria from Bristol-Myers Squibb, Merck and Roche; and travel accommodations/expenses from Merck Sharp & Dohme and Roche/Genentech. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Shailender Bhatia, MD

This study answers an important question of whether systemic therapy upfront is appropriate for patients with melanoma who have active brain metastases. Traditionally, patients with active brain metastases would undergo surgery or radiotherapy first and then go on to receive systemic therapy. This study shows that upfront systemic therapy for patients with asymptomatic melanoma metastases to the brain is a reasonable option that can address the disease not only in the brain, but also outside the brain. Immunotherapy responses with combination immunotherapy can occur fairly quickly in the brain, which is important given the potential functional consequences of uncontrolled brain metastases.

Impressively, the responses are durable and systemic, which is not expected from local therapies such as radiation.

Other important considerations in using systemic immunotherapy in these patients include the chance of complications from immune-related inflammation around the tumors, which can lead to neurologic symptoms. The study shows that in carefully selected patients who have brain metastases, upfront systemic immunotherapy is safe to implement.

Overall, the study provides the melanoma oncologist proof-of-concept that systemic immunotherapy upfront can be used to treat patients with active brain metastases.

Shailender Bhatia, MD

Seattle Cancer Care Alliance

University of Washington

Disclosures: Bhatia reports institution research support from Bristol-Myers Squibb, EMD-Serono, Immune Design, Merck, NantKwest and Oncosec; an unpaid advisory board position for EMD-Serono; and honorarium from Genentech.