Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.

Abstract

9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]

Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+T cell trafficking

“…1C). Thus, the outcome of anti-PD-1/anti-CTLA-4 combination therapy was superior to the two monotherapies, which is in line with the reported intracranial response rate for anti-PD-1 monotherapy (21-25%) (12)(13)(14)(15) and anti-PD-1/anti-CTLA-4 combination therapy (50-55%) (15,16), as well as the 6 month progression-free survival rate of 28% and 46%, respectively (15). Due to these promising data, we focused on the anti-PD-1/anti-CTLA-4 combination therapy.…”

“…Pembrolizumab and nivolumab also showed efficacy in melanoma BrM with an ~21% response rate in the brain (12)(13)(14)(15). A very recent interim analyses from two clinical trials in drug-treatment naïve patients with melanoma BrM (ABC trial (15) and CheckMate 204 trial (16)) reported a 50% and 55%…”

Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial

“…The activity of nivolumab plus ipilimumab continues to be evaluated in phase 2 studies, including the anti–PD-1 Brain Collaboration Trial (NCT02374242) and the CheckMate 204 study of the combination in patients with melanoma brain metastases. 23,24 …”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…Relevant reduction in brain metastases was observed in 28% of patients, warranting further investigation of ICBs in this patient population [109]. In the phase 2 CheckMate 204 study, the combination of nivolumab and ipilimumab was administered to 75 patients with advanced melanoma and untreated brain metastases, and provided an intracranial ORR of 55% and an extracranial ORR of 49% [110].…”