133P - Neoadjuvant pembrolizumab plus lenvatinib in resectable stage III melanoma patients (pts) (NeoPele): Analysis of the peripheral immune profile correlated to pathological response

Background

Neoadjuvant immunotherapy (NeoIT) with anti-PD-1 (PD1) is associated with better event-free survival compared with adjuvant PD1 for pts with resectable stage IIIB-D melanoma, and patients with major pathological response (MPR, <=10% viable cells in the tumour bed) have a very low risk of recurrence. We have previously reported patients achieving MPR with NeoIT with PD1 and lenvatinib had a significant increase in CD21+ CXCR5+ B cells and number of lymphoid structures in the tumour microenvironment compared to non-MPR patients. Here, we sought to analyse peripheral immune profiles.

Methods

Pts with stage III melanoma treated with 6 weeks of PD1-based neoIT (PD1 + lenvatinib) were included (NeoPele clinical trial; NCT04207086). Cytometry by time of flight (CYTOF; 39-marker panel), was performed on peripheral blood mononuclear cells (PBMCs) at baseline (pre-op) and 6 weeks post-treatment prior to surgery (week 6).

Results

Of the 20 pts, 11 (55%) had MPR and 9 (45%) had a non-MPR. Pre-op, the % of Lag3+ CD4+ T cells was higher in MPR pts (p=0.0273), and there was a trend towards a higher % of CD8+ T cells (p=0.0549), particularly the % of TCF7+ CD8+ T cells (p=0.0722), compared to non-MPR pts. With treatment (from pre-op to week 6) and independent of pathological response, there was an increase in the % of TEMRA CD8+ T cells, of CD4+ Th1, Th17 and Tregs, of CD8+ and CD4+ T cells expressing inhibitory receptors (Lag-3, Tim-3 or TIGIT), of naïve and mature double negative (CD27- IgD-) B cells, and of classical (CD14+ CD16-) monocytes (p=0.0059). Peripheral immune responses from pre-op to week 6 that differed in MPR vs. non-MPR pts included; MPR pts had an increase in the % of CD4+ and CD8+ T effector memory cells (p=0.02) and of cytotoxic (CD56dim CD16+) NK cells (p=0.0059), but a decrease in the % of CD4+ Th2 (p=0.04); p=0.008), while non-MPR had an increase in the % of cytokine producers (CD56bright CD16-) NK cells (p=0.0328).

Conclusions

NeoIT induces a stronger peripheral anti-tumour immune response in MPR vs. non-MPR pts, including an increased pool of T effector memory cells, which may contribute to the better recurrence-free survival observed in MPR compared to non-MPR pts.

Clinical trial identification

NCT04207086.

Editorial acknowledgement

Legal entity responsible for the study

Melanoma Institute Australia.

Funding

Merck Sharp & Dohme.

Disclosure

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. R. Rawson: Financial Interests, Personal, Invited Speaker: MSD. A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre Fabre, QBiotics. R.A. Scolyer: Financial Interests, Personal, Advisory Role: 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. 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. All other authors have declared no conflicts of interest.