Durable complete response in a patient with leptomeningeal melanoma after treatment with dabrafenib, trametinib, and nivolumab.

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple-drug regimen may be considered a viable option in fit patients. This case highlights the potential for long-term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies.

Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

PURPOSE: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. PATIENTS AND METHODS: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. RESULTS: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months. CONCLUSIONS: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response.