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CheckMate 204

ASCO 2019: Durable responses in patients with melanoma brain metastases with nivolumab/ipilimumab

An update of the CheckMate 204 trial confirms efficacy and safety of first-line treatment with nivolumab/ipilimumab (NIVO + IPI) in patients with untreated asymptomatic melanoma brain metastases (MBM). It also demonstrates for the first time intracranial antitumor in patients with symptomatic MBM.

More than half of all patients with metastatic melanoma will have brain metastasis during the course of their disease. However, in past years, strategies for managing melanoma brain metastasis (MBM) have traditionally been limited to surgery and radiation therapy.

In this phase II trial, patients with ≥1 measurable, non-irradiated MBM sized 0.5–3.0 cm were enrolled into two cohorts: (A) those with no neurologic symptoms or steroid prescription (asymptomatic); and (B) those with neurologic symptoms, whether or not they were receiving steroids. In both cohorts, patients received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4, then NIVO 3 mg/kg Q2W until progression or toxicity.

The primary endpoint was intracranial clinical benefit rate (CBR, proportion of pts with complete response (CR), partial response (PR) and stable disease (SD) ≥6 mo). As of the clinical cutoff date, all treated patients (cohort A: 101; cohort B: 18) had been followed for a minimum of six months.

Responses both in patients with asymptomatic and symptomatic brain metastases

For cohort A, in this updated analysis with a median follow-up of 20.6 months, a total of 58.4% of patients reached a CBR.

In cohort B, patients received a median of one NIVO/IPI dose. Two of 18 patients (11%) received all four doses of the study drug combination. At a median follow-up of 5.2 months, the intracranial objective response rate was 16.7% and the CBR was 22.2%. The median time to intracranial response was 4.1 months, and the median duration of response has not yet been reached. Three out of four (75%) patients showed ongoing responses.

Grade 3/4 adverse events occurred in 54.5% of patients in cohort A and in 55.6% of patients in cohort B (with 6.9% and 16.7%, respectively, representing neurological side effects). One death related to treatment occurred in cohort A through immune-related myocarditis.

Spotlight on steroid role

»While symptomatic patients remain difficult to treat, some will definitely benefit from the immunotherapy treatment”, concluded first author MD PhD Hussein Abdul-Hassan Tawbi, MD Anderson Center, Texas, in his presentation. »Further study is needed to understand the biologic mechanisms of resistance to immunotherapy and to improve treatments in this challenging population.”

One of the factors that will need more detailed investigation seems to be the use of steroids at the time of treatment. »Clearly they are doing something”, stated MD Harriet M Kluger, Yale School of Medicine and Smilow Cancer Center, who discussed Dr. Tawbi’s presentation. »While only one out of four responders was on steroids at baseline, only one out of eleven patients on steroids responded. In contrast, three out of seven responders were off steroids during study treatment.”

Despite the lack of phase III data, Dr. Kluger argues that the available trial results support the use of NIVO + IPI in the treatment for patients with brain metastases. »Delays in access to trials for these patients are no longer justified.”


ASCO 2019
#9501 Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204).