164P - A spatially informed transcriptomic model to forecast early resistance to front-line osimertinib in advanced EGFR-mutant NSCLC

Background

Single-agent osimertinib effectively controls EGFR-mutant disease. However, some patients experience early progression and might require more intensive front-line treatment strategies. In this work, we aimed to develop a transcriptomic model to predict early osimertinib resistance.

Methods

We analyzed baseline FFPE tumor samples from a multi-institutional retrospective cohort of 105 EGFR-mutant NSCLC patients treated with first-line osimertinib. Thirty-two patients (30.5%) had early resistance (PFS<=10 months). We utilized GeoMx^TM DSP to perform multi-region transcriptomic analysis separately from the tumor (panCK+) and stromal compartments. We used adaptive Elastic Net logistic regression to develop the models, and assessed their predictive performance with repeated 5-fold cross-validation. Additionally, we performed WES in 33 cases to assess chromosomal instability signatures.

Results

Baseline CNS metastases and ECOG PS were clinical variables associated with early resistance, which together had a modest predictive performance (AUC=0.71). Considering compartment-specific gene expression levels alone, the tumor compartment showed a higher prediction accuracy (18 genes; AUC=0.74) than the stroma (34 genes; AUC=0.61). Combining tumor and stroma did not improve the predictive performance. A final forecasting model incorporating two clinical variables plus 19 genes measured in the tumor compartment showed the highest capacity to predict early resistance (AUC=0.84). The signature contained genes related to cancer cell hallmarks and innate and adaptive immunity. This model had a higher discrimination capacity than a simulated pseudo-bulk RNA model (AUC=0.72). Of the 12 early resistant cases with WES data, 6 had genomic profiles indicative of sensitivity to platinum-based chemotherapy, 4 of which were also predicted as high risk of acquiring MET amplification.

Conclusions

We have developed a spatially informed transcriptomic model to forecast early osimertinib resistance that outperforms clinical variables and a pseudo-bulk RNA model. With further validation, it could be used to guide front-line combinatorial treatment strategies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Fundacion OncoSur.

Funding

AstraZeneca (Externally Sponsored Research: ESR-20-20709).

Disclosure

J. Zugazagoitia: Financial Interests, Personal, Invited Speaker: Takeda, BMS, AstraZeneca, NanoString, Guardant Health; Financial Interests, Personal, Advisory Board: Roche, Sanofi, BMS, Pfizer, Novartis, Janssen; Financial Interests, Personal and Institutional, Funding, Research Grant: AstraZeneca, Roche, BMS. B. Roch: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, AstraZeneca, Amgen, MSD, Roche, Chugai, Lilly, Takeda, Novartis. P. Garrido Lopez: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Janssen, MSD, Touch Expert, Medscape; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Janssen, Lilly, MSD, Novartis, Roche, Takeda, Daiichi Sankyo, Sanofi, Amgen; Financial Interests, Personal, Advisory Board, Spouse: Gebro, Janssen, Nordic; Financial Interests, Personal, Invited Speaker, Spouse: Janssen, Boehringer Ingelheim, Pfizer, Amgen, Nordic; Financial Interests, Personal, Other, Data monitoring committee for INC280I12201 trial in 2020: Novartis; Financial Interests, Personal, Steering Committee Member, CACZ885V2201C_CANOPY-N trial: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Local PI: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Steering Committee Member, IO102-012/KN-764 trial: IO Biotech; Financial Interests, Personal, Steering Committee Member, JNJ-61186372 (JNJ-372) Clinical Development Program: Janssen; Financial Interests, Institutional, Other, Spouse: Mitsubishi, AbbVie; Financial Interests, Institutional, Other, Spouse, clinical trial team: Janssen, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member, JDQ443G12301 trial, Steering Committee member: Novartis; Non-Financial Interests, Leadership Role, Past Council member as Women for Oncology Committee ChairPast Fellowship and Award Committee and Press CommitteeFaculty for lung and other thoracic tumors: ESMO; Non-Financial Interests, Leadership Role, President of the Spanish Federation of Medical Societies (FACME) 2020-2022Past President 2023-2024: FACME; Non-Financial Interests, Leadership Role, Former President of Spanish Medical Oncology Society: SEOM; Non-Financial Interests, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Board member: AECC; Non-Financial Interests, Leadership Role, IASLC Women in Thoracic Oncology Working Group Member, Educational Committee member, Academy member: IASLC; Non-Financial Interests, Advisory Role, Member of the Spanish National Health Advisory Board: Spanish Minister of Health; Non-Financial Interests, Advisory Role, Assessment for lung cancer screening evaluation: EUnetHTA; Non-Financial Interests, Advisory Role: Spanish National Evaluation network (RedETS), member of the King Hussein Award’s Board of Directors; Non-Financial Interests, Advisory Role, scientific advisory group member for clinical immunological, oncology and lung cancer areas: EMA; Other, My son is working with the pharma company TEVA as an engineer. I do not have any relationship with TEVA: TEVA. M.D. Isla Casado: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Johnson & Johnson, MSD, Amgen, Pfizer, Sanofi, BMS, GSK; Financial Interests, Personal, Invited Speaker: Pfizer, Roche, Johnson & Johnson, MSD, Lilly, Sanofi, Novartis, BMS, AstraZeneca, Merck. C. Aguado: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, Novartis, AstraZeneca, Sanofi, Pfizer, Roche, Pierre Fabre, Takeda, BMS. A. Callejo Perez: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Pfizer, BMS; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Travel accommodation: MSD; Financial Interests, Personal, Other, Travel accommodation: Takeda. R. Marse Fabregat: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, MSD, BMS, Pfizer, Takeda, Lilly, Amgen; Financial Interests, Personal, Funding: AstraZeneca, Lilly, Takeda, Pfizer, Roche, MSD, BMS. M.R. García Campelo: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, BMS, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Financial Interests, Personal, Other, Co-founder: Trialing Health S.L.. K. Syrigos: Financial Interests, Institutional, Speaker’s Bureau: MSD, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: BMS. O.J. Juan Vidal: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Roche/Genentech, Lilly, Takeda, AstraZeneca, Janssen; Financial Interests, Personal, Other, Travel expenses: MSD; Financial Interests, Personal, Invited Speaker: Bristol Myers Squib, Amgen, Roche/Genetech, Pfizer; Financial Interests, Institutional, Funding: AstraZeneca. E. Conde Gallego: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Lilly, Pfizer, AstraZeneca, Janssen; Financial Interests, Personal, Funding: Roche, Thermofisher. G. Macintyre: Financial Interests, Personal, Other, Co-founder, director, shareholder: Tailor Bio Ltd.. L.G. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati, Boehringer Ingelheim; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Other, lectures: AICME; Financial Interests, Personal, Other, Lectures: CCO; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Personal, Other, spin off (I have around 8% of stocks): Altum sequencing; Financial Interests, Personal, Ownership Interest, spin-off (10%): Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-Cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President. ASEICA ( Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group; Non-Financial Interests, Other, Board member of this anti-cancer Charity: AECC; Non-Financial Interests, Member, Past-President: ASEICA (Spanish Cancer Research Association); Non-Financial Interests, Leadership Role, President: Oncosur Foundation. All other authors have declared no conflicts of interest.