12P - Spatially preserved multi-region transcriptomic subtyping and biomarkers associated with long-term benefit with chemoimmunotherapy in extensive-stage small cell lung cancer (ES-SCLC)

Background

Transcriptomic subtyping holds promise for personalized therapy in SCLC, but intratumoral transcriptomic heterogeneity and its clinical significance remain poorly defined. In this study, we aimed to assess transcription factor-defined subtypes within multiple regions of intact tissues and identify gene sets associated with long-term chemoimmunotherapy benefit.

Methods

We assessed baseline FFPE tumors from 26 ES-SCLC patients enrolled in the CANTABRICO clinical trial (EudraCT: 2020-002328-35). We used GeoMx^TM DSP to perform transcriptomic analysis from multiple intratumoral regions of interest (ROIs). We used an assay with +1800 genes (GeoMx^TM CTA) plus custom-designed and subsequently validated mRNA probes targeting subtype-defining transcription factors.

Results

We profiled 121 ROIs from 26 tumors. Cluster analysis based on ASCL1, NEUROD1, POU2F3 and YAP1 showed that all samples clustered within 3 groups: SCLC-A (58 ROIs, 47.93 %), SCLC-N (37 ROIs, 30.58 %) and SCLC-Y/I (26 ROIs, 21.49 %). SCLC-P subtype was not identified in this cohort. Gene set enrichment analysis (GSEA) using linear mixed models revealed that SCLC-A subtype was enriched in cell cycle and DNA damage repair genes and showed repression of multiple gene sets associated with anti-tumor immune response. SCLC-Y/I subtype showed the opposite pattern. Six patients (23%) had tumors with co-existence of more than one subtype, not evident through morphological inspection. Predominant subtype or the presence of subtype heterogeneity were not associated with outcomes. Tumors from patients with sustained benefit (time to progression >= 12 months) had mRNA profiles characterized by upregulation of interferon gamma (IFNg)-related genes and down-regulation of gen sets involved in glycolysis and aberrant metabolism.

Conclusions

This study reveals substantial intratumoral subtype heterogeneity in SCLC. In this limited cohort, we did not observe outcome significance for transcriptional subtypes. Our findings related to long-term treatment benefit require validation in independent cohorts.

Clinical trial identification

Data from patients enrolled in the CANTABRICO study (phase IIIb clinical trial, EudraCT 2020-002328-35).

Legal entity responsible for the study

Fundación OncoSur.

Funding

AstraZeneca.

Disclosure

C. Martí Cubells: Financial Interests, Personal, Invited Speaker: MSD, BMS, AstraZeneca; Financial Interests, Personal, Other, Reimbursement of conference attendance: MSD, BMS, Merck. B. Massuti Sureda: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: MSD, Roche; Financial Interests, Institutional, Funding, Research on Tumor Board: BMS; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, MSD; Non-Financial Interests, Personal, Advisory Board: ASCO; Non-Financial Interests, Personal, Member: IASLC, SEOM; Non-Financial Interests, Personal, Leadership Role: SLCG. M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Takeda, Janssen, Cassen Recordati, BMS; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn; Financial Interests, Institutional, Funding: BMS, AstraZeneca, Roche. M.R. García-Campelo: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche, Boehringer Ingelheim, Medscape Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi; Financial Interests, Personal, Invited Speaker: MSD, BMS, Roche, Boehringer Ingelheim, Medscape Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi; Financial Interests, Personal, Principal Investigator: MSD, BMS, Roche, Boehringer Ingelheim, Medscape Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi. P. Diz Tain: Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD, Takeda, Pfizer, Amgen; Financial Interests, Personal, Advisory Role: BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD; Financial Interests, Personal, Training: BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD, Takeda, Pfizer; Financial Interests, Institutional, Principal Investigator: AstraZeneca, Roche, Mirati; Financial Interests, Personal, Advisory Board: Takeda. M.D. Isla Casado: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultation and speaker honoraria: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, F. Hoffmann-La Roche, Janssen, MSD, Pfizer, Takeda; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultation honoraria: Lilly, Merck, Sanofi; Financial Interests, Personal, Speaker, Consultant, Advisor, Speaker honoraria: Novartis; Financial Interests, Institutional, Other, Clinical trial: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, F. Hoffmann-La Roche, GSK, Janssen, Lilly, Merck, Mirati Therapeutics, MSD, Novartis, Pfizer, Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, F. Hoffmann-La Roche, GSK; Other, Personal, Member of Board of Directors, Executive board member: Commission for the Approval of New Drugs, Regional Health Care Department (Spain). A. Moreno Paul: Financial Interests, Personal, Invited Speaker: Roche, MSD, Bristol; Financial Interests, Personal, Other, Reimbursement of conference attendance: Roche, MSD. E. Conde Gallego: Financial Interests, Personal, Research Funding: Roche, ThermoFisher; Financial Interests, Personal, Other, Honoraria: Roche, Lilly, Pfizer, AstraZeneca, Janssen. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daichii, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: 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, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President: ASEICA (Spanish Association of Cancer Research); Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. J. Zugazagoitia: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultant: Sanofi, AstraZeneca, BMS, Roche, Pfizer, Novartis, Guardant Health; Financial Interests, Personal, Invited Speaker: Sanofi, Takeda, BMS, Pfizer, Roche, AstraZeneca, NanoString, Guardant Health; Financial Interests, Personal, Other, Travel honoraria: Sanofi, Takeda, BMS, Pfizer, Roche, AstraZeneca, NanoString; Financial Interests, Institutional, Research Funding: BMS, AstraZeneca, Roche. All other authors have declared no conflicts of interest.