Three important studies presented at the 2017 American Society of Clinical Oncology (ASCO) annual meeting will likely impact initial management of patients with melanoma with asymptomatic brain metastases.
- In the prospective phase II CheckMate 204 trial (Abstract 9507), the combination of 4 cycles of nivolumab (1 mg/kg every 3 weeks) and ipilimumab (3 mg/kg every 3 weeks) followed by nivolumab maintenance (3 mg/kg every 2 weeks) resulted in a 55% intracranial objective response rate (ORR) in 75 patients with metastatic melanoma with asymptomatic brain metastases, including complete response (CR) in 21% of patients. The duration of response (DoR) has not been reached and responses are ongoing in 93% of responders. The estimated 6-month rate of progression-free survival (PFS) is 67%. The adverse event (AE) profile was consistent with previous studies of nivolumab and ipilimumab combination in metastatic patients without brain metastases. Nervous system AEs occurred in 37% of patients, with the most common being headache (25%). Brain edema, intracranial hemorrhage, peripheral neuropathy, and syncope occurred in 1 patient each.
- The Australian Phase II Anti-PD1 Brain Collaboration (ABC) trial (Abstract 9508) randomized 76 immune checkpoint inhibitor–naïve patients with metastatic melanoma with brain metastases to one of the three trial cohorts. Patients with asymptomatic brain metastases with no prior local therapy received either combination of ipilimumab and nivolumab or nivolumab alone. The combination of ipilimumab plus nivolumab was associated with higher intracranial ORR (42%), compared with nivolumab (20%). In a third small cohort with previously treated or symptomatic patients, the intracranial ORR to nivolumab was only 6%. In all cohorts, patients who did previously not receive BRAF and MEK inhibitors had better intracranial response rates (50%, 21%, and 25%, respectively). Of note, the intracranial response for the combination and nivolumab alone was only 16% in 12 patients who had received prior treatment with BRAF and MEK inhibitors. Median intracranial PFS was 4.8 months for the combination, compared with 2.7 months and 2.5 months for single-agent nivolumab. Patients receiving combination therapy had higher rates of AEs than patients receiving single-agent nivolumab.
Taken together, results from both Checkmate 2014 and ABC trial support the combined use of nivolumab and ipilimumab for melanoma patients with untreated asymptomatic brain metastases.
- Finally, results from the phase II COMBI-MB trial (Abstract 9506), which examined the combination of dabrafenib (150 mg twice daily) and trametinib (2 mg daily) in 125 patients with BRAF V600–mutant metastatic melanoma with brain metastases, showed that this combination was effective against melanoma brain metastases and was associated with intracranial ORR as high as 59%. Responses were similar regardless of prior local therapy and/or symptom status, but lower in patients with V600D/K/R mutations (44%). Interestingly, V600D/K/R mutations were associated with highest extracranial ORR (75% versus 41% to 55%). Estimated 12-month PFS was 19% in the entire treatment population, but higher in patients with V600E mutations who had received prior local therapy (47%). Preliminary overall survival (OS) results have shown a similar pattern, with a 12-month OS of 46% in the entire population and 69% in the V600E/prior local therapy group. No unexpected safety issues were observed with the combination. This study was simultaneously published in The Lancet Oncology.
The discussant of these abstracts, Lynn Schuchter, MD (University of Pennsylvania, Philadelphia, Pennsylvania, United States), called the results practice-changing, and said that initial systemic therapy should be seriously considered for all patients with melanoma with asymptomatic brain metastases. However, the best sequence of therapy and how to best combine systemic and local therapy remain as questions for future investigation.