170P - Targeting myeloid cells in non-small cell lung cancer and hepatocellular carcinoma: a window-of-opportunity trial of nivolumab with BMS-813160 (CCR2/5i) or BMS-986253 (anti-IL8)

Background

Monocyte-derived macrophages (mo-macs) and polymorphonuclear leukocytes (PMNs) are abundant in non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), limiting response to immune checkpoint blockade (ICB) by promoting an immunosuppressive tumor microenvironment (TME). Preclinical work shows that tumor-derived CCR2 ligands and IL8 play a key role in recruiting mo-macs and PMNs, respectively, to the TME. Disrupting these signaling pathways augments ICB in mouse models, but clinical benefit has yet to be observed.

Methods

This phase IIa trial assessed the efficacy of BMS-813160 (CCR2/5i) or BMS-986253 (anti-IL8) administered with nivolumab (NIVO) over 4 weeks prior to resection. NSCLC patients were treated with NIVO and CCR2/5i (arm A) or NIVO and anti-IL8 (arm B). HCC patients were treated with NIVO (arm C), NIVO and CCR2/5i (arm D), or NIVO and anti-IL8 (arm E). Primary endpoints were major pathologic response (≤10% viable tumor) for NSCLC and significant tumor necrosis (>70% necrosis) for HCC. Secondary endpoints were safety/tolerability, time to surgery (TTS), and radiographic response.

Results

36 patients were enrolled from March 2020-August 2023; 14 were treated with NIVO and CCR2/5i, 16 with NIVO and anti-IL8, and 6 with NIVO. CCR2/5i and anti-IL8 were safe/tolerated (dose-limiting toxicities or grade 3/4 treatment-related adverse events). 32 of 36 patients underwent resection (mean TTS of 34.8 days). 3 patients met the primary endpoints: 2 in arm B and 1 in arm D. In patients treated with CCR2/5i, serum concentration of CCR2/5 ligands increased, and number of circulating monocytes decreased, after treatment. In patients treated with anti-IL8, serum concentration of IL8 decreased after treatment; however, number of circulating PMNs was not affected. Tissue analysis with scRNA-seq and multiplex imaging is ongoing to elucidate the biologic effects of these agents.

Conclusions

Although CCR2/5i and anti-IL8 appear to be biologically active and exert effects on chemokine levels, they fail to significantly augment the role of ICB in the preoperative setting, contrary to preclinical evidence.

Clinical trial identification

NCT04123379.

Legal entity responsible for the study

The authors.

Funding

CIMAC-CIDC, PACT.

Disclosure

S. Gnjatic: Financial Interests, Personal and Institutional, Funding, Unrelated to Current Work: Regeneron Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, EMD Serono, Pfizer, and Takeda. M. Merad: Financial Interests, Personal, Advisory Board: Compugen Inc., Myeloid Therapeutics Inc., Morphic Therapeutic Inc., Asher Bio Inc., Dren Bio Inc., Nirogy Inc., Oncoresponse Inc., Owkin Inc., Larkspur Inc., Innate Pharma Inc., DBV Inc., Pionyr Inc., OSE Inc., Genenta Inc.; Financial Interests, Personal, Stocks/Shares: Compugen Inc., Myeloid Therapeutics Inc., Morphic Therapeutic Inc., Asher Bio Inc., Dren Bio Inc., Nirogy Inc., Oncoresponse Inc., Owkin Inc., and Larkspur Inc.; Financial Interests, Personal and Institutional, Funding: Regeneron Inc. and Boehringer Ingelheim Inc. T.U. Marron: Financial Interests, Personal, Advisory Board: Rockefeller University, Regeneron Pharmaceuticals, AbbVie, Bristol Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, and Astellas; Financial Interests, Personal and Institutional, Funding: Regeneron, Bristol Myers Squibb, Merck, and Boehringer Ingelheim. All other authors have declared no conflicts of interest.