1079MO - Progression of BRAF mutant CNS metastases are associated with a transcriptional network bearing similarities with the innate PD-1 resistant signature (IPRES)

Background

Melanoma CNS metastases are a common problem that causes high morbidity and mortality. Although first line dabrafenib-trametinib and ipilimumab-nivolumab (I-N) have similar intracranial response rates (50-55%), durable responses are only seen with combination immunotherapy and CNS resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs within 6 months. We sought to investigate the utility of I-N after BRAF-MEKi CNS progression and identify resistance mechanisms.

Methods

All patients receiving second/third line I-N for CNS metastases from 1/3/15 to 1/8/18 with prior progression on BRAF-MEKi and MRI brain staging were included. Modified intracranial RECIST was used to assess response. Formalin fixed paraffin embedded samples of BRAF V600 mutant CNS metastases naïve to treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of CNS samples naïve to systemic treatment versus BRAF-MEKi progression was performed.

Results

Thirty patients received second/third line I-N with median CNS diameter of 21 mm. Modest efficacy of I-N after BRAF-MEKi progression was observed with an intracranial response rate of 4.8% (1/21) and median PFS of 5.5 weeks. Given the poor activity of I-N after BRAF-MEKi CNS progression we investigated the mechanisms that also conferred resistance to immunotherapy. We identified 179 differentially expressed genes (DEG) between naïve and BRAF-MEKi progression CNS metastases (p < 0.05, false discovery rate [FDR] < 0.1). Gene set enrichment analysis with KEGG, GO or Hallmark libraries did not identify distinct pathways. Enrichment of DEG from the Innate anti-PD1 Resistance Signature (IPRES) was identified (p < 0.01, FDR = 0.03). Macrophage associated chemokines and myeloid activation genes were upregulated in CNS progression samples. Histological assessment showed increased macrophage grading in BRAF-MEKi progression samples (mean 1.45 vs 0.45, p=0.009).

Conclusions

I-N after CNS BRAF-MEKi progression has modest intracranial activity. CNS metastases resistant to BRAF-MEKi showed expression of the IPRES gene signature and upregulation of myeloid cell activation markers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

P.K.H. Lau: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Pfizer. D. Kee: Honoraria (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Novartis. P. Neeson: Research grant/Funding (self): Bristol-Myers Squibb. S. Sandhu: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Amgen; Honoraria (self): Merk Sharp & Dohme; Honoraria (self): Janssen. G. McArthur: Research grant/Funding (institution), Principal Investigator of clinical trials with the following commercial entities (all revenues payed to my institution as reimbursement for trial- costs): Bristol-Myers Squibb; Research grant/Funding (institution), Principal Investigator of clinical trials with the following commercial entities (all revenues payed to my institution as reimbursement for trial- costs): Array BioPharm; Research grant/Funding (institution), Principal Investigator of clinical trials with the following commercial entities (all revenues payed to my institution as reimbursement for trial- costs): Amgen; Research grant/Funding (institution), Principal Investigator of clinical trials with the following commercial entities (all revenues payed to my institution as reimbursement for trial- costs): Pfizer. All other authors have declared no conflicts of interest.