Abstract 1010P
Background
Osimertinib has shown robust survival benefit in advanced EGFR-mutant NSCLC. However, ≈ 15% of these patients experience disease progression within 6 months of therapy, and there is a need to identify targetable resistance mechanisms.
Methods
We used baseline FFPE tumor samples from a retrospective cohort of 86 EGFR-mutant NSCLC patients treated with first-line osimertinib at 14 Spanish institutions. Patients were equality distributed between EGFR-del19 and EGFR-L858R mutations. We used Digital Spatial Profiling (GeoMxTM) to quantify 1800 genes separately from the tumor (panCK+) and stromal compartments. SpatialDecon was employed to infer the abundance of stromal and immune cell types. We compared spatially resolved transcriptomic profiles between patients with early resistance (PFS<6 months) and durable responders. Comprehensive genomic characterization and resistance prediction analyses are ongoing.
Results
The median PFS was 25.9 months and 11 patients (13%) had early resistance. MET was the most prominent gene significantly overexpressed in early resistant patients. Gene sets related to cell cycle progression and transcriptional regulation were highly enriched in these patients. Tumor compartment transcriptomic profiles of patients with early resistance differed according to main EGFR mutations. Seven genes were prominently upregulated (fold-change>1.5; FDR-adjusted p<0.05) in early resistant patients with EGFR-del19 cases (MET, HDAC1, NSD2, KMT2D, POLR2A, NDUFB4 and ATP2A2), whereas no genes or pathways were significantly enriched in early resistant EGFR-L858R cases after adjusting for multiple comparisons. Instead, EGFR-L858R cases had significantly higher levels of CD4 naïve T cells in the tumor compartment. Multiple gene sets related to immune activation, particularly MHC-class II antigen presentation, were overexpressed in patients with durable benefit, regardless of compartment or EGFR mutation.
Conclusions
We identified novel spatially resolved transcriptomic profiles associated with early osimertinib resistance in human NSCLC. In addition, our data suggest that pre-existing anti-tumor immunity might be required to achieve durable benefit from first-line osimertinib.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Fundación Oncosur. Hospital 12 de Octubre.
Funding
AstraZeneca.
Disclosure
P. Garrido Lopez: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Sanofi; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda, Novartis, IO Biotech; Financial Interests, Personal, Advisory Board, Spouse: Boehringer Ingelheim, Gebro, Janssen, Nordic; Financial Interests, Personal, Invited Speaker, Spouse: Boehringer Ingelheim, Janssen; Financial Interests, Personal, Other, Data monitoring committee for a clinical trial in 2020: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Invited Speaker: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Invited Speaker, study entitled JNJ-372: Janssen; Non-Financial Interests, Leadership Role, Council member as Women for Oncology Committee Chair Fellowship and Award Committee and Press Committee, Faculty for lung and other thoracic tumours: ESMO; Non-Financial Interests, Leadership Role, President of the Spanish Federation of Medical Societies (FACME): FACME; Non-Financial Interests, Leadership Role, Former President of Spanish Medical Oncology Society Member of the Spanish National Health Advisory Board: 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: IASLC; Other, My son is working in the pharma company Teva as an engineer. I do not have any kind of relationship with Teva. C. Aguado: Financial Interests, Personal, Invited Speaker: Roche, MSD, AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Board: BMS, Sanofi; Non-Financial Interests, Institutional, Principal Investigator: Lilly, Mirati. A. Callejo Perez: Non-Financial Interests, Institutional, Advisory Board: Bristol-Myers Squibb Bristol-Myers Squibb Recipient, F. Hoffmann La Roche AG, Boehringer Ingelheim, MSD Oncology, Kyowa Kirin ; Non-Financial Interests, Institutional, Other: F. Hoffmann La Roche AG, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, MSD Oncology. M.R. Garcia Campelo: Financial Interests, Personal, Invited Speaker: MSD, Bristol-Meyer, Roche, Boehringer Ingelheim, Medscape, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi. O.J. Juan Vidal: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, Takeda, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Institutional, Funding: AstraZeneca. J. De Castro Carpeno: Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer, BMS, MSD Oncology, Roche, Pfizer, Takeda, Gsk, Janssen, Sanofi, Bayer, Lilly. E. Conde Gallego: Financial Interests, Personal, Research Grant: Lilly, Roche, Thermo Fischer; Financial Interests, Personal, Other: AstraZeneca, BMS, Lilly, MSD, Pfizer, Takeda. S. Ponce Aix: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD. 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, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: 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); Financial Interests, Other, Foundation President: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. J. Zugazagoitia: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Roche, Pfizer, Novartis, Guardant Health, Nanostring; Financial Interests, Personal, Research Grant: AstraZeneca, Roche. All other authors have declared no conflicts of interest.