72MO - Concurrent BRAF targeted therapy (TT) with dabrafenib and trametinib and anti-PD-1 agent pembrolizumab (PD1) increased B cell signalling and inflammatory pathways more effectively than when given sequentially or with anti-PD-1 alone

Background

Long duration TT prior to immunotherapy(IO) is inferior to IO upfront for patients with advanced BRAF^V600 mutant melanoma while short duration TT continues to be investigated. The previously presented results of the neoadjuvant(NA) NeoTrio clinical trial (NCT02858921) demonstrated concurrent TT with PD1 yielded the highest pathologic response rates compared to 1 week of TT followed by PD1 or PD1 alone, although durability of pathological response was better with PD1 alone. We sought to characterise longitudinal changes to the tumour microenvironment induced by treatment.

Methods

In NeoTrio, 60 patients with BRAF^V600 mutant stage IIIB/C/D melanoma were randomised to 6 weeks of NA therapy in 1 of 3 arms: ALONE;PD1. Sequential(SEQ);1 week TT followed by PD1. Concurrent(CON);TT + PD1. We performed longitudinal RNA sequencing on 200 fresh frozen tumour samples across 4 timepoints(baseline-T0; week1-T1; week2-T2; week6 resection-T3) with matched haematoxylin and eosin (H&E) analysis.

Results

In RNA sequencing analysis, at T1 and T2, CON demonstrated significant increases in B cell receptor signalling over SEQ and ALONE (T1 p<0.001, T2 p=0.002). Inflammatory pathways (TNF, NF-Kappa B, IL-4 and IL-13, not IFN-γ) showed significant and sustained upregulation in CON compared to SEQ and ALONE at T1, 2 and 3. PI3K-Akt pathway was downregulated at T3 in CON when compared to SEQ (p=0.007). Matched H&E at T3 revealed CON held the highest number of tertiary lymphoid structures(TLS) and higher TLS and plasma cells(PC) were significantly associated with response (TLS p=0.01, PC p=0.02).

Conclusions

Concurrent TT with PD1 stimulates B cell signalling and inflammatory pathways beyond sequential TT and PD1 or PD1 alone. Analysis on peripheral blood mononuclear cells is ongoing and will be presented.

Clinical trial identification

NCT02858921.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Merck, Sharp Dohme. Dabrafenib and trametinib supply by Novartis.

Disclosure

A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre Fabre, QBiotics. M.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre Fabre, Eisai, Nektar, Regeneron. R.A. Scolyer: Financial Interests, Personal, Advisory Board: SkylineDx BV, IO Biotech ApS, MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol Myers Squibb, Myriad Genetics, GSK; Financial Interests, Personal, Full or part-time Employment: Sydney Local Health District; Financial Interests, Personal, Other, Co-Medical Director fee: Melanoma Institute Australia; Financial Interests, Personal, Officer: Bridport Pathology Pty Ltd; Financial Interests, Personal and Institutional, Coordinating PI, Investigator Grant (2022/GNT2018514): National Health and Medical Research Council of Australia. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L., IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V.; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. I. Pires da Silva: Financial Interests, Personal, Invited Speaker: BMS, MSD, Roche, Novartis; Financial Interests, Personal, Other, Travel Support: BMS, Roche; Financial Interests, Personal, Advisory Board: MSD. All other authors have declared no conflicts of interest.