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Nivolumab, ipilimumab combination effective for melanoma with brain metastases
The combination of nivolumab and ipilimumab had a clinically meaningful intracranial effect among patients with melanoma who had untreated brain metastases, according to results from the open-label, phase 2 CheckMate 204 trial.
The toxicities observed in the study appeared similar to those seen among patients without brain metastases treated with this immunotherapy combination.
“More than one-third of patients with advanced melanoma have brain metastases at diagnosis, and up to 75% have brain metastases at the time of death,” Hussein A. Tawbi, MD, PhD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues wrote.
“In phase 2 and phase 3 studies of advanced melanoma, ipilimumab [Yervoy, Bristol-Myers Squibb] combined with the anti-PD-1 agent nivolumab [Opdivo, Bristol-Myers Squibb] was shown to have efficacy superior to that of ipilimumab alone. However, these studies excluded patients with untreated brain metastases,” they added.
The CheckMate 204 trial included 94 patients from 28 U.S. sites with metastatic melanoma and at least one measurable, nonirradiated brain metastasis and no neurologic symptoms. Seventy-two patients (77%) had one or two intracranial target lesions and 21 (22%) had three or more intracranial target lesions.
Patients received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for up to four doses, followed by 3 mg/kg nivolumab every 2 weeks until disease progression or unacceptable toxicity.
Exclusion criteria included leptomeningeal involvement, autoimmune disease, or receiving systemic treatment with glucocorticoids or other immunosuppressive medication within 14 days before study therapy.
Rates of intercranial clinical benefit — defined as the proportion of patients with stable disease for at least 6 months — complete response or partial response served as the primary endpoints.
Median follow-up was 14 months.
Thirty-five percent (n = 33) of patients received all four scheduled doses of nivolumab and ipilimumab.
Researchers observed an intercranial clinical benefit rate of 57% (95% CI, 47-68). Twenty-six percent of patients achieved a complete response in the brain and 30% achieved a partial response, according to modified RECIST v1.1 criteria.
Results showed an extracranial clinical benefit of 56% (95% CI, 46-67).
Among patients with a minimum follow-up of 6 months, 64.2% achieved 6-month intracranial PFS and 59.5% achieved 9-month intracranial PFS. For extracranial assessments, results showed a 6-month PFS of 75.9% and a 9-month PFS of 70.4%. Global PFS rates were 61.1% at 6 months and 56.6% at 9 months.
Initial OS assessments showed a 6-month OS rate of 92.3% and 9-month OS rate of 82.8%. The estimated rate at 12 months was 81.5%
“The absence of progression for that long with brain metastases is huge,” Tawbi said in a press release. “Historically, the overall 1-year survival rate for patients with brain metastases is less than 20%, with the immunotherapy combination in this study, it’s 82%.”
The safety profile of nivolumab plus ipilimumab appeared similar to that reported among patients with melanoma who did not have brain metastases.
“We were quite concerned going into the study about immunotherapy causing inflammation and swelling in the brain, so this was closely monitored,” Tawbi said. “In the end, only 5% of patients had swelling in the brain.”
Treatment-related grade 3 or grade 4 adverse events occurred among 55% of patients. Twenty percent of patients discontinued treatment because of a grade 3 or grade 4 adverse event. Central nervous system treatment-related adverse events occurred among 36% of patients, with 7% of those events being grade 3 or grade 4.
The most common grade 3 or grade 4 neurologic adverse events included headache (3%), brain edema (2%), intercranial hemorrhage, peripheral moto neuropathy and syncope (all 1%).
One patient died from immune-related myocarditis.
“As treatment for stage 4 melanoma has improved greatly in recent years, our patients with metastases to the brain have remained the group most in need — they’ve had the worst prognosis — so we are very excited about these results,” Tawbi said. “This practice-changing study proved that you can start with immunotherapy first with these patients, tackling both brain and extracranial disease at the same time. It opens up new opportunities for development of systemic therapies for metastatic melanoma.” – by Cassie Homer
Disclosures: Bristol-Myers Squibb provided funding for this study. Tawbi reports nonfinancial support from Bristol-Myers Squibb during the conduct of the study; grant support and personal fees from Bristol-Myers Squibb, Merck and Genentech; and personal fees from Novartis outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
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Importantly, there was no apparent increase in neurological toxicities observed compared to previous studies conducted in patients without CNS involvement. The results clearly dispel the notion that the relatively immunoprotective microenvironment of the brain would prevent the efficacy of immunotherapy for brain metastases, or that the benefit of such treatments would be critically limited by cerebral inflammation.
The response rate is also quite similar to that reported in the COMBI-MB study, which evaluated the targeted therapy combination of dabrafenib and trametinib in metastatic melanoma patients with an activating BRAF V600 mutation and untreated or progressing brain metastases. However, while the durability of the responses in brain metastases achieved with dabrafenib and trametinib were much shorter than those achieved in non-CNS metastases, the overwhelming majority of responses to ipilimumab with nivolumab appear durable both within and outside of the brain.
Although it must be noted that the CheckMate 204 study excluded patients with brain metastases that required steroids to control neurological symptoms, and thus may not be applicable to all scenarios, the results suggest that ipilimumab plus nivolumab should be considered in all metastatic melanoma patients with asymptomatic brain metastases.
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