531MO - VHIO immune gene-expression signature (VIGex) to enrich patient selection in immunotherapy (IT) phase I clinical trials

Background

While the number of phase I clinical trials testing IT agents continues to increase exponentially, few trials include an enrichment strategy to optimize response. We have developed the VIGex test, a gene expression panel using RNA data, developed from a pan-cancer cohort of 649 tumor samples and a set of 51 immune-related genes (including genes related to interferon-γ signalling, T-cell exhaustion, Tregs, tumor associated macrophages (TAM) and antiinflammatory cytokines) (submitted ESMO2020).

Methods

We conducted a retrospective review of the pts treated with IT at VHIOś Phase 1 Unit from 2018-2019 who had VIGex performed prior to IT. 2 clusters (hot (HT) and cold (CT)) were defined by VIGex and correlated with clinical benefit rate (CBR) and progression free survival (PFS). A subset of CT enriched for TGFb signaling and TAMs associated genes was identified. CBR was defined as the sum of partial responses and stable disease (SD) for ≥4 months (m). The primary objective was to describe preliminary signs of predictive value from VIGex.

Results

Overall, 61 pts were identified, median age was 60 years, all ECOG ≤1, 30 treated with single IT agents (49%) and 31 with IT combinations (51%). Median prior lines were 2 (1-3) and median follow-up was 5.8 m. VIGex was performed on primary tumor (59%) or metastases (41%). In the whole cohort, CBR was 25% (5 pts (8%) achieved a partial response (PR) and 10 pts (17%) achieved a prolonged SD). Median PFS and OS were 1.7 m (CI95% 1.4 – 2.3) and 6.7 m (CI95% 4.5 – 9.5) respectively. VIGex algorithm classified 20 pts as HT and 41 pts as CT. CBR was 55% in the HT group and 18% for CT group (p= 0.016 Fisherś exact test). Interestingly, CT subgroup enriched for TGFb signaling and TAMs had a 0% CBR. Significantly longer progression free survival (PFS) was also observed for HT vs. CT clusters (HR: 0.5; 0.28 – 0.89; p = 0.02). Of note, significance was maintained after adjustment in a multivariate model for other prognostic variables (age, ECOG and single vs. combination IO treatments).

Conclusions

Our results suggest that VIGex may be a predictive marker of IT benefit in phase I clinical trials. With upcoming early phase IT treatments, VIGex could become a promising tool to enrich patientś selection and improve clinical outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vall d'Hebron Institute of Oncology.

Funding

Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI) supported by the Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation) (grant 89/2017). La Caixa Foundation (LCF/PR/CEO7/50610001). Cellex Foundation providing research facilities and equipment.

Disclosure

A. Hernando-Calvo: Travel/Accommodation/Expenses: Kyowa Kirin. I. Braña: Advisory/Consultancy: Orion Pharma; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: AstraZenca ; Speaker Bureau/Expert testimony: Merck Serono; Advisory/Consultancy: Rakutan Pharma; Speaker Bureau/Expert testimony: Roche. O. Saavedra Santa Gadea: Travel/Accommodation/Expenses: Kyowa Kirin; Travel/Accommodation/Expenses: MSD. M. Vieito: Advisory/Consultancy: Debio; Advisory/Consultancy: Roche; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Merck Serono. A.B. Azaro Pedrazzoli: Advisory/Consultancy: Orion Pharma; Advisory/Consultancy: Ambcure GmbH; Research grant/Funding (self): Ambcure GmbH. I. Matos: Research grant/Funding (self), ESMO Research Fellowship: Roche. C. Saura: Advisory/Consultancy: AstraZenca; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: F-Hoffmann La Roche Ltd; Advisory/Consultancy: Genomic Health; Advisory/Consultancy, Research grant/Funding (institution): Merck, Sharp and Dhome España S.A; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Odonate Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Philips Healthwork; Advisory/Consultancy: Pierre Fabre ; Advisory/Consultancy: priME Oncology; Advisory/Consultancy, Research grant/Funding (institution): Puma; Advisory/Consultancy: Synthon ; Advisory/Consultancy: Sanofi Aventis; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eli Lilly and Company; Research grant/Funding (institution): Genetech; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Piqur Therapeutics; Research grant/Funding (institution): Zenith Pharma; Research grant/Funding (institution): Roche. G. Argiles Martinez: Advisory/Consultancy, Research grant/Funding (institution): Hoffman La-Roche; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Servier; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Menarini; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Boston Pharmaceuticals; Research grant/Funding (institution): Genentech. E. Elez: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Hoffman La-Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Servier; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Array; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (institution): MSD; Honoraria (institution): AbbVie; Honoraria (institution): GSK; Honoraria (institution): AstraZeneca; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution): Boehringer Ingelheim. E. Munoz Couselo: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self): Sanofi. E. Felip: Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Janssen; Speaker Bureau/Expert testimony: Medscape; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: Merck Sharp and Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: priME; Advisory/Consultancy: Roche; Advisory/Consultancy: Samsung; Advisory/Consultancy: Takeda; Speaker Bureau/Expert testimony: Touchime; Advisory/Consultancy: GSK; Advisory/Consultancy: Bayer; Research grant/Funding (institution): Grant for Oncology Innovation; Research grant/Funding (institution): Fundación Merck Salud. J. Seoane: Leadership role, Research grant/Funding (institution): Mosaic Biomedical; Research grant/Funding (institution): Northern Biologics; Research grant/Funding (institution): Roche/Glycart; Research grant/Funding (institution): Hoffmann La Roche. J. Tabernero: Advisory/Consultancy: Array Biopharma ; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Genentech; Advisory/Consultancy: Genmab A/S; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Imugene Limited; Advisory/Consultancy: Inflection Biosciences Limited; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Kura Oncology; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Menarini; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Merus; Advisory/Consultancy: Molecular Partners; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pectomyc; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy: ProteoDesign SL; Advisory/Consultancy: Rafael Pharmaceuticals; Advisory/Consultancy: F. Hoffmann-La Roche Ltd; Advisory/Consultancy: Sanofi; Advisory/Consultancy: SeaGen; Advisory/Consultancy: Seattle Genetics. A. Vivancos: Advisory/Consultancy: Sysmex; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Merck; Advisory/Consultancy: Roche; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Bayer; Licensing/Royalties: Ferrer; Research grant/Funding (institution): Debio; Advisory/Consultancy: Sysmex; Research grant/Funding (institution): Cellestia Biotech; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Chittern. E. Garralda: Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Thermo Fisher; Advisory/Consultancy: Hoffmann La Roche; Research grant/Funding (institution): Ellipses Pharma; Advisory/Consultancy: Neomed Therapeutics; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: SeaGen; Advisory/Consultancy: TFS; Research grant/Funding (institution): Alkermes; Advisory/Consultancy, Research grant/Funding (institution): Bristol Mayers Squibb; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Sharp and Dohme; Travel/Accommodation/Expenses: Menarini; Travel/Accommodation/Expenses: Glycotope. All other authors have declared no conflicts of interest.