1118P - Immunological alterations during neoadjuvant BRAF/MEK inhibition in patients with prior unresectable regionally advanced melanoma: Translational analysis from the REDUCTOR trial

Background

The REDUCTOR trial showed that neoadjuvant dabrafenib (D) plus trametinib (T) effectively reduced tumor size, enabling radical resection in 81% of patients (pts) with prior unresectable locally advanced melanoma. However, understanding of the immunological changes during BRAF/MEK inhibition and their correlation with responses remains limited. Here, we report translational research findings from the REDUCTOR trial, focusing on tumor immune infiltration changes.

Methods

In the REDUCTOR trial, 21 pts with unresectable, BRAF-mutated, locally advanced stage IIIC/oligometastatic stage IV melanoma received neoadjuvant D+T for 8 weeks, followed by surgery if sufficient downsizing was achieved. Pathologic responses were evaluated based on viable tumor cell percentage in the tumor bed. Tumor biopsies were collected at baseline, week 2, and surgery. Multiplex immunofluorescence staining was done on formalin-fixed, paraffin-embedded tumor samples to analyze SOX10 expression and the infiltration of CD3, CD8, CD20, CD68, and FOXP3 immune cells.

Results

All 21 pts were included in the analysis. Pathologic responses were evaluated in 18 pts, with 13 showing a pathologic response (PR) (4 partial, 3 near-complete, 6 complete) and 5 a non-response (pNR). Already from week 2 of treatment, an increase in overall immune infiltration compared to SOX10+ melanoma cells was observed. Immune infiltration at week 2 and at surgery was higher in pts with a PR compared to pts with a pNR (99.8% vs 55.4% [p=0.018], and 97.3% vs 48.0% [p=0.036] cells per mm2, respectively). A significant increase in CD20+ B cells was observed at surgery compared to baseline and 2 weeks (320 vs 36 [p=0.015], and vs 35 [p=0.046] cells per mm2, respectively). Pts with a PR had a significantly higher abundance of CD20+ B cells at surgery compared to pts with a pNR (614 vs 87 cells per mm2 [p=0.046]). No significant changes during treatment or associations with response were found in other immune cell subsets.

Conclusions

Our results demonstrate an increase in CD20+ B cells during neoadjuvant BRAF/MEK inhibition in prior unresectable locally advanced melanoma pts, especially in responders.

Clinical trial identification

EudraCT: 2013-002616-28.

Editorial acknowledgement

Legal entity responsible for the study

NKI-AVL.

Funding

NKI-AVL, Novartis.

Disclosure

W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen, Boehringer Ingelheim Ingelheim; Financial Interests, Institutional, Advisory Board: Belpharma, Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis; Financial Interests, Institutional, Local PI: BMS; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Funding: Sirius. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD - Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, Provectus; Financial Interests, Personal, Advisory Board: Neracare, SkylineDx; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Iovance Biotherapeutics, AstraZeneca; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Advisory Board: Third Rock Venture, CureVac, Imcyse; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio, Sastra Cell Therapy; Non-Financial Interests, Member: ASCO, AACR, SITC; Other, Other, Editor-in-Chief IOTECH: ESMO; Other, Other, Editorial Board ESMO Open: ESMO; Other, Other, Editorial Board: Kidney Cancer. All other authors have declared no conflicts of interest.