LBA12 - Predictive value of gene-expression profiles (GEPs) and their dynamics during therapy in the NeoTRIPaPDL1 trial

Background

GEPs may reveal pathways associated with pathological complete response (pCR) in TNBC treated with neoadjuvant immunotherapy combination.

Methods

In NeoTRIP patients with TNBC were randomized to eight cycles of nab-paclitaxel/carbo (CT) with/without atezolizumab (CTA). 258 patients were evaluable for pCR. RNA-sequencing performed pre-treatment (n=242/258; 93.8%) and on treatment on day 1 of cycle 2 (excluding samples without tumor cells) (d1c2; n=161/258; 62.4%). We evaluated the association with pCR of the 27-gene IO score, TNBCtypes (BL1, BL2, LAR, M and MSL; Ring et al 2016), and selected tumor intrinsic and extrinsic gene-signatures. Within pCR group, super-responders were those with no tumor cells at d1c2 (33.3% in CTA; 16.5% in CT). Analyses were adjusted for baseline PD-L1 and sTILs.

Results

Pre-treatment, binary IO score was predictive of pCR in CTA (OR 3.64 [1.68-7.90], p=0.001), but not in the CT arm (1.31 [0.64-2.67] (p=0.46) (interaction p=0.029). Among TNBCtypes, the LAR subtype had the lowest pCR rate (CTA 22.2%, CT 18.8%), and BL1 had the highest (CTA 70.3%, CT 54.3%) (p=0.001) (Interactions not significant). High angiogenesis and fatty acid/cholesterol were independently linked to resistance in CTA, but not CT, arm (interaction p=0.005 and p=0.02, respectively). Only in CTA arm, super-responders were also characterized by high expression of some immune-signatures. At d1c2, high expression of several immune-related signatures were similarly predictive of pCR in both arms (p<0.01), whereas glutamine metabolism was linked to resistance in CTA arm only. For instance, high CD8 (above median) was associated with 58.6% and 61.7% pCR rate in CTA and CT arm, respectively, but low CD8 with only 22% and 23.1%. Combination of both baseline value and dynamic of some biomarkers was more informative than either one alone.

Conclusions

IO score, but not TNBCtype, is predictive of atezolizumab benefit over CT alone. Angiogenesis and lipid/glutamine metabolism were linked to resistance, suggesting new potential therapeutic targets. Super-responders in atezolizumab arm have a unique biology and represent ideal candidates to treatment de-escalation. Early biomarker dynamics provide additional predictive information.

Clinical trial identification

NCT02620280.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Michelangelo.

Funding

Roche.

Disclosure

G. Bianchini: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Neopharm Israel; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: EISAI; Financial Interests, Personal, Training: MSD; Financial Interests, Personal, Training: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Other, travel grants: Roche; Financial Interests, Personal, Other, travel grants: Pfizer; Financial Interests, Personal, Other, travel grants: AstraZeneca; Financial Interests, Personal, Other, travel grants: Eisai. C. Huang: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: EirGenix; Financial Interests, Institutional, Research Grant: OBI Pharma; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Personal, Advisory Role: Roche; Non-Financial Interests, Personal, Advisory Role: Eli Lilly; Non-Financial Interests, Personal, Advisory Role: EirGenix; Non-Financial Interests, Personal, Advisory Role: OBI trials; Non-Financial Interests, Personal, Leadership Role: Taiwan Breast Cancer Consortium. D. Egle: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, travel grant: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Myriad. B. Bermejo: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Invited Speaker: Palex; Financial Interests, Personal, Invited Speaker: AstraZeneca; Other, Personal, Member of the Board of Directors: Geicam. R.S. Seitz: Financial Interests, Personal, Full or part-time Employment: OncoCyte; Financial Interests, Personal, Stocks/Shares: OncoCyte. T.J.J. Nielsen: Financial Interests, Personal, Full or part-time Employment: OncoCyte; Financial Interests, Personal, Stocks/Shares: OncoCyte. C. Zamagni: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, travel accommodation: Roche; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, travel accommodation: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, travel accommodation: Pfizer; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Other, travel accommodation: PharmaMar; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Other, travel accommodation: Tesaro; Financial Interests, Personal, Advisory Board: QuintilesIMS; Financial Interests, Personal, Other, travel accommodation: Pierre Fabre; Financial Interests, Personal, Other, travel accommodation: Istituto Gentili; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Other, travel accommodation: Celgene; Financial Interests, Institutional, Funding, research funding: Roche; Financial Interests, Institutional, Funding, research funding: Novartis; Financial Interests, Institutional, Funding, research funding: AstraZeneca; Financial Interests, Institutional, Funding, research funding: Pfizer; Financial Interests, Institutional, Funding, research funding: SeattleGenetics; Financial Interests, Institutional, Funding, research funding: Tesaro; Financial Interests, Institutional, Funding, research funding: PierreFabre; Financial Interests, Institutional, Funding, research funding: Istituto Gentili; Financial Interests, Institutional, Funding, research funding: Takeda; Financial Interests, Institutional, Funding, research funding: TEVA; Financial Interests, Institutional, Funding, research funding: Medivation; Financial Interests, Institutional, Funding, research funding: AbbVie; Financial Interests, Institutional, Funding, research funding: Array BioPharma; Financial Interests, Institutional, Funding, research funding: Morphotek; Financial Interests, Institutional, Funding, research funding: Synthon; Non-Financial Interests, Personal, Leadership Role: Europa Donna italy, Susan J Komen Emilia-Romagna, LOTO Onlus, Mamazone Sudtirol; Non-Financial Interests, Personal, Member: Europa Donna italy, Susan J Komen Emilia-Romagna, LOTO Onlus, Mamazone Sudtirol. M. Thill: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Other, travel expenses: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, travel expenses: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Other, travel expenses: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, travel expenses: Eisai; Financial Interests, Personal, Invited Speaker: Exact Sciences; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Funding: Exact Sciences; Financial Interests, Personal, Other, travel expenses: Exact Sciences; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Other, travel expenses: Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, travel expenses: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, travel expenses: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, travel expenses: Pfizer; Financial Interests, Personal, Advisory Board: Pierre-Fabre; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Writing Engagements: Roche; Financial Interests, Personal, Other, travel expenses: Roche; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Invited Speaker: Hexal; Financial Interests, Personal, Other, travel expenses: Hexal; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Invited Speaker: Vifor; Financial Interests, Personal, Advisory Board: Vifor; Financial Interests, Personal, Other, travel expenses: Vifor; Financial Interests, Personal, Advisory Board: Biom'Up; Financial Interests, Personal, Advisory Board: ClearCut; Financial Interests, Personal, Writing Engagements: ClearCut; Financial Interests, Personal, Advisory Board: pfm medical; Financial Interests, Personal, Invited Speaker: pfm medical; Financial Interests, Personal, Writing Engagements: pfm medical; Financial Interests, Personal, Other, travel expenses: pfm medical; Financial Interests, Personal, Invited Speaker: Celgene; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Other, travel expenses: Celgene; Financial Interests, Personal, Invited Speaker: Clovis; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Other, travel expenses: Clovis; Financial Interests, Personal, Project Lead, trial funding: Exact Sciences; Non-Financial Interests, Personal, Leadership Role: Scientific Subboard German Breast Group; Non-Financial Interests, Personal, Member of the Board of Directors: AWOgyn; Non-Financial Interests, Personal, Leadership Role: BLFG; Non-Financial Interests, Personal, Leadership Role: OncoNet Rhein-Main. A. Anton: Financial Interests, Personal, Advisory Board: Bayer Spain; Financial Interests, Personal, Expert Testimony: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Personal, Member: GEICAM; Non-Financial Interests, Personal, Member: TTD group (Spanish Digestive Tumor Treatment Group); Non-Financial Interests, Personal, Member: ECO Foundation . E.M. Ciruelos: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: PUMA; Financial Interests, Institutional, Funding: Roche; Non-Financial Interests, Personal, Member of the Board of Directors: SOLTI Cooperative Group; Non-Financial Interests, Personal, Advisory Role: Instituto de Salud Carlos III. B.L. Schweitzer: Financial Interests, Personal, Full or part-time Employment: OncoCyte; Financial Interests, Personal, Stocks/Shares: OncoCyte. R. Greil: Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Sandoz; Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Funding, Research Funding: Celgene; Financial Interests, Institutional, Funding, Research Funding: Roche; Financial Interests, Institutional, Funding, Research Funding: Merck; Financial Interests, Institutional, Funding, Research Funding: Takeda; Financial Interests, Institutional, Funding, Research Funding: AstraZeneca; Financial Interests, Institutional, Funding, Research Funding: Novartis; Financial Interests, Institutional, Funding, Research Funding: Amgen; Financial Interests, Institutional, Funding, Research Funding: BMS; Financial Interests, Institutional, Funding, Research Funding: MSD; Financial Interests, Institutional, Funding, Research Funding: Sandoz; Financial Interests, Institutional, Funding, Research Funding: AbbVie; Financial Interests, Institutional, Funding, Research Funding: Gilead; Financial Interests, Institutional, Funding, Research Funding: Daiichi Sankyo; Other, Personal, Other, Travel expenses, accomodations: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo. G. Viale: Financial Interests, Personal, Advisory Board: Roche Genetech; Financial Interests, Personal, Advisory Board: MSD Oncology; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daichii Sankyo; Financial Interests, Personal, Advisory Board: Ventana; Financial Interests, Personal, Advisory Board: Dako Agilent; Financial Interests, Personal, Advisory Role: Menarini; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Other, Research contract: Roche; Financial Interests, Institutional, Other, Research contract: Cepheid; Financial Interests, Institutional, Other, Research contract: Dako Agilent; Financial Interests, Institutional, Other, Research contract: Ventana. M. Callari: Financial Interests, Personal, Advisory Role: Novartis. L. Gianni: Financial Interests, Personal, Advisory Board: ADC Therapeutics; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Oncolytics Biotech; Financial Interests, Personal, Advisory Board: Odonate Therapeutics; Financial Interests, Personal, Advisory Role: Odonate Therapeutics; Financial Interests, Personal, Advisory Board: Onkaido Therapeutics; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, travel support: Pfizer; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Hexal Sandoz; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Synthon; Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Advisory Role: Zymeworks; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Advisory Role: Forty Seven (CD47); Financial Interests, Personal, Advisory Role: Genenta; Financial Interests, Personal, Advisory Role: METIS Precision Medicine; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Revolution Medicines; Financial Interests, Personal, Advisory Role: Synaffix; Financial Interests, Personal, Advisory Role: Menarini Ricerche; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Biomedical Insights Inc; Financial Interests, Institutional, Funding, Support for research projects: Zymeworks; Financial Interests, Institutional, Funding, Support for research projects: Revolution Medicines; Other, Personal, Other, Co-Inventor of “European Patent Application N. 12195182.6 and 12196177.5” titled “PDL-1 expression in anti-HER2 therapy”- Roche - Issued- No compensation provided: Roche. All other authors have declared no conflicts of interest.