1661MO - Genomic somatic copy number alterations drive adaptive tumor immune suppression and primary resistance to anti-PD1 + anti-angiogenics in pleural mesothelioma

Background

In patients with advanced pleural malignant mesothelioma (MM), Pembrolizumab [P] in combination with Nintedanib [N] synergize with a response rate of 24% (PEMBIB trial initial results reported at ESMO Congress 2021), superior to [P] alone (8% in MM in the KN158 trial). Here we report new data from the biomarker analysis performed in this trial (NCT02856425).

Methods

30 MM patients were treated with [N] (150mg bid) & [P] (200mg IV Q3W). Fresh tumor biopsies were collected in media and immediately processed at baseline and at C2D1 for measuring proteins released in the biopsy supernatant and immune cell infiltrates (by Flow Cytometry). Frozen and fixed tumor biopsies were also analyzed by WES, FISH, RNAseq and IHC. Circulating cytokines & immune cells were measured on plasma and fresh whole blood at baseline and on-treatment. At 6 months, patients remaining in stable disease or objective tumor response per RECIST1.1 were categorized as having Durable Clinical Benefit (DCB). All differences reported here are statistically significant with a p value at least <0,05.

Results

Higher PD-L1 on tumor cells, higher tumor CD45+, CD3+ & CD8+ T-cells characterized the DCB group at baseline. Unexpectedly, active recruitment of CD8+ T-cells, with higher gene expression of EOMES, T-BET, IFNg, & GzmB, occurred in No DCB tumors upon treatment. At C2D1, same levels of tumor infiltrating CD8+ T-cells were found in DCB & No DCB tumors. This tumor T-cell recruitment occurred in a context of high blood and tumor CXCL9 increases upon [N]+[P] treatment. However, No DCB patients presented more IL6, VEGF, IL8, in their blood & tumor secretome and they increased their tumor content in CD4+ CD25+ Tregs compared to DCB patients upon treatment. Tumor somatic copy number alterations (SCNA) were higher in tumors with no DCB and correlated with higher plasmatic IL-6 rate levels in MM patients.

Conclusions

MM primary resistance to anti-PD1+antiangiogenics is not due to a lack of CD8+ T-cell tumor response but to an adaptive secretion of IL6 by tumors, driven by genomic SCNA, leading to VEGF and IL8 secretion, and recruitment of tumor infiltrating Tregs.

Clinical trial identification

NCT02856425.

Editorial acknowledgement

Legal entity responsible for the study

Gustave Roussy.

Funding

Funding: Boehringer Ingelheim; Drug supply: Boehringer Ingelheim & MSD;Sponsor: Gustave Roussy.

Disclosure

C. Baldini: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Expert Testimony: MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Invited Speaker: iTeos, AZ, Janssen, Amgen, Bicycle Therapeutics, MSD, Seattle Genetics, Tahio; Non-Financial Interests, Member: ASCO, SIOG, SOFOG, AACR. N. Chaput-Gras: Financial Interests, Personal, Advisory Board, Strong-Iopredi Scientific Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Educational Session On Immune Cell Death: Servier; Financial Interests, Institutional, Expert Testimony, Expertise On Immune Cell Death Biomarkers: Servier; Financial Interests, Personal, Invited Speaker: Cytune Pharma; Financial Interests, Institutional, Research Grant, Research grant to identify immune biomarkers associated to clinical response in patients treated with agonistic mAbs: GSK; Financial Interests, Institutional, Research Grant, Preclinical studies in mice: GSK; Financial Interests, Institutional, Research Grant, Immune profiling of Head & Neck tumors: Sanofi. C. Massard: Non-Financial Interests, Personal, Advisory Board: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm Group, Genentech/Roche, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, Orion, Taiho Pharmaceuticals, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals. J. Soria: Financial Interests, Personal, Full or part-time Employment, From Sept 2017 to Dec 2019: AstraZeneca; Financial Interests, Personal, Invited Speaker, 2019-2021: Hookipa Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment, SVP Amgen since August 2021: Amgen; Financial Interests, Personal, Stocks/Shares: Gritstone, Hookipa Pharmaceuticals. G. Zalcman: Financial Interests, Personal, Invited Speaker, outside the submitted work: BMS, MSD, AstraZeneca, Boehringer Ingelheim; Non-Financial Interests, Personal, Advisory Board, outside the submitted work: Roche, Takeda, AstraZeneca. A. Marabelle: Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS, Merck Serono, AstraZeneca, Amgen, Sanofi, Servier; Financial Interests, Personal, Stocks/Shares: Pegascy SAS, Centessa Pharmaceuticals, HiFiBio, Shattuck Labs; Financial Interests, Institutional, Research Grant: Merus, BMS, Boehringer Ingelheim, Transgene, Foundation MSD Avenir, Sanofi. All other authors have declared no conflicts of interest.