Mecanismos de resistencia a terapias dirigidas e inmunoterapia

Mecanismos de resistencia a terapias dirigidas e inmunoterapia Noemi Reguart, MD, Ph. D Medical Oncology Department Translational Genomics and Targeted Therapeutics in Solid Tumors Hospita Clinic, IDIBAPS #SEOM 2019

Disclosure Information q Consultant or Advisory Role: Merck Sharp and Dohme, Roche, Boehringer Ingelheim, Pfizer, Takeda, Novartis, Astra-Zeneca, Lilly q Research Funding: Pfizer, Novartis q Speaking: Merck Sharp and Dohme, Roche, Boehringer Ingelheim, Pfizer, Takeda, Novartis, Astra-Zeneca q Other: Institutional financial interests: those related to clinical trials and patient recruitment #SEOM 2019

The ‘Game’ Theory WE ALWAYS MAKE THE `FIRST MOVE’ WE PLAY RATIONALLY Nash equilibrium ‘. . . . we need to change in game strategy, by anticipating the molecular mechanisms of resistance and incorporating dynamic strategies’ #SEOM 2019 Kateřina Staňková, JAMA Oncol 2019

FACTORS INFLUENCING THERAPIES in LUNG CANCER TARGETED THERAPIES: Tumor & Drug Original, N. Reguart #SEOM 2019 IO: Tumor, Drug, Environment, Microbiome & Host!!! Daniel S. Chen, et al, Nature 2017

MECHANISMS of RESISTANCES TARGETED THERAPIES: Tumor Dependent IO: Tumor & Host Dependent Intrinsic Factors Schrank Z, Cancer 2018 #SEOM 2019 Sharma P, Cell 2017

CLINICAL SCENARIOS FOR RESISTANCES TARGETED THERAPIES Acquired IMMUNOTHERAPY Primary Adaptive Selected by Pharmacologic Pressure Acquired Dagogo-Jack, Nature Reviews | Clinical Oncology 2018 #SEOM 2019 Padmanee Sharma, Cell 2017

THE PREDICTIVE BIOMARKERS in LUNG CANCER TARGETED THERAPIES ‘Cancer-agnostic’: NTRK fusion genes #SEOM 2019 IMMUNOTHERAPY

TWO CLINICAL SCENARIOS FOR RESISTANCES in LUNG CANCER TARGETED THERAPIES Intrinsic (primary) resistance IMMUNOTHERAPY Intrinsic (primary) resistance T 790 M+ AURA 3, Mok, NEJM 2017 #SEOM 2019 Champiat et al. NRCO 2018

PRIMARY RESISTANCE in LUNG CANCER TARGETED: INTRINSIC RESISTANCE Soria J-C, et al. N Engl J Med. 2018 #SEOM 2019 Hirokazu Taniguchi, Nature Communications 2019

RESISTANCES in LUNG CANCER IMMUNOTHERAPY Primary resistance to IO is worse than getting PD after SD or response (adaptive resistance) Response status 3 yr OS PD after CR/PR 29% PD after SD 12% PD as best response 3% Median OS post-progression according to best response Overcoming PRIMARY RESISTANCE is a therapeutic priority!!! Antonia Lancet Oncol 2019 #SEOM 2019 Antonia. Lancet Oncol 2019 Overcoming resistance- clinical results: Ross Soo

RESISTANCES in LUNG CANCER IMMUNOTHERAPY PD-L 1≥ 50% KN 024; Reck M. , NEJM 2016; JCO 2019; WCLC 2019 #SEOM 2019 38/154 (24%) completed 35 cycles ORR 82% Do. R ≥ 24 mo 25/38 (81%)

I ASEICA-ASPIC INTERNATIONAL MEETING PRIMARY/ADAPTIVE RESISTANCE in LUNG CANCER IMMUNOTHERAPY: INTRINSIC RESISTANCE, TUMOR INMUNOGENICITY Low Mutational Burden & Neoantigen Quality Clonal Neoantigens Smoking signature PD-L 1 expression Rizvi N, Science 2015 Mc. Granahan N, et al. Science 2016

PRIMARY/ADAPTIVE RESISTANCE in LUNG CANCER IMMUNOTHERAPY: EXTRINSEC & INTRINSIC RESISTANCE TIM-3 Upregulation Mc. Granahan N, et al. Cell 2017 #SEOM 2019 Koyama S, et al. Nat Commun 2016

I ASEICA-ASPIC INTERNATIONAL MEETING PRIMARY/ADAPTIVE RESISTANCE in LUNG CANCER IMMUNOTHERAPY: Cell Signaling Pathways Influencing Immune Response • INF�� signaling through JAK/STAT upregulates both antigen presentation and PD-L 1 expression. Loss of JAK/ STAT confers resistance to ICB. • Aberrant signaling through oncologic pathways leads to tumor formation and can be targeted to overcome immune checkpoint blockade resistance. Charlene M. Fares, ASCO Educational Book 2019

PRIMARY/ADAPTIVE RESISTANCE in LUNG CANCER IMMUNOTHERAPY: INTRINSIC RESISTANCE Prevalent (~25%) subgroup STK 11/KEAP 1 mut mediate a cold microenvironment Arbour KC, CCR 2018; Skoulidis F, Cancer Discovery 2018 #SEOM 2019 Ferdinatos S, WCLC 2019

PRIMARY RESISTANCE in LUNG CANCER IMMUNOTHERAPY: HYPERGROGRESSION Tumour Kinetics (TGR): Dynamic and Quantitative assesment ~14 -20% NSCLC Besse B, WCLC 2019; ; Kim, Annals Oncol 2019; L. Giaconne, H Clínic, ESMO 19;

PRIMARY RESISTANCE in LUNG CANCER IMMUNOTHERAPY: HYPERGROGRESSION PD-1 • NO consistent predictors (clinicopathologic or molecular) reported thus far. • Tumour biopsy samples at the time of HPD are key to understand underlying biology. Champiat S et al. Nat Rev / Clin Oncol 2018; Champiat et al. Clin. Cancer Research 2016; Kato et al. CCR 2017; Saa da-Bouzid et al. Annals of Oncology 2017; Ferrara R et al. JAMA Oncol 2018; Kim CG et al. Ann Oncol 2019; Lo Russo G, CCR 2019 #SEOM 2019 PD-1

TWO CLINICAL SCENARIOS FOR RESISTANCES in LUNG CANCER TARGETED THERAPIES T 790 M+ Acquired (secondary) resistance AURA 3, Mok, NEJM 2017 #SEOM 2019 IMMUNOTHERAPY Acquired (secondary) resistance Champiat et al. NRCO 2018

ADQUIRED RESISTANCE in LUNG CANCER IMMUNOTHERAPY: INTRINSIC RESISTANCE Silenced HLA Class I Antigen Gettinger S, et al. Cancer Discovery 2017 #SEOM 2019 Evolution of Neoantigens Anagnostou V, et al. Cancer Discovery 2017

ADQUIRED RESISTANCE in LUNG CANCER TARGETED RESISTANCE: A MORE ‘BASIC’ SCENARIO (1) On-target resistances (EGFR T 790 M, ALK, ROS 1, NTRK mutations) (2) Activation of alternative pathways (MET amplification, KRAS mutations) (3) Phenotype transformation (SCLC, EMT) #SEOM 2019

ADQUIRED RESISTANCE in LUNG CANCER ‘ON-TARGET’ and ALTERNATIVE PATHWAY RESISTANCES EGFR MUTATIONS ALK FUSIONS First/Second Generation EGFR inh Third Generation Osimertinib Ramalingam et al. ESMO 2018. Abstract LBA 50 #SEOM 2019 Justin F. Gainor , Cancer Discovery 2016

ADQUIRED RESISTANCE in LUNG CANCER DIFFERENTIAL ACTIVITY OF TARGETED THERAPIES ACCORDING TO RESISTANCES Gainor JF, et al. Cancer Discov. 2016 #SEOM 2019

NEXT STEP: OVERCOMING IO RESISTANCES IN LUNG CANCER IO-Landscape of Novel Combination Strategies J Tang, Annals of Oncology 2018

OVERCOMING IO RESISTANCES IN LUNG CANCER Landscape of Novel Combination Strategies: + Anti-PD-1/L 1 Overcome T-Cell Exhaustion: TIM 3/LAG 3/TIGIT Increase Tumor Immunogenicity and T-Cell Priming: vaccines/virus Upregulate cytokine production and antigen presentation: epigenetic modifiers #SEOM 2019

IDENTIFYING RESPONDERS IMMUNOTHERAPY RESISTANCE TIDE, transcriptomic evaluation of two primary mechanisms of tumor immune evasion: • signatures of T cell dysfunction • signatures of T cell exclussion Peng Jiang, Nature Medicine 2018 #SEOM 2019

OVERCOMING IO RESISTANCES Checkpoint Targets: Novel combinations in IO-naïve setting Bemcentinib (AXL) + Pembrolizumab (NSCLC) AXL+: ORR 40%, m. OS 12 mo Krebs MG, WCLC 2019 #SEOM 2019

NEW DRUG STRATEGIES NTRK RESISTANCES and LOXO-195 Hyman, AACR 2019 #SEOM 2019

NEW APPROACHES TUMOR RE-BIOPSIES: TREATMENT ACCORDING TO RESISTANCES Progression on First-Line Osimertinib: ORCHARD Study #SEOM 2019

ANTICIPATING RESISTANCES LIQUID BIOPSIES: ANTICIPATING THE ONSET OF RESISTANCES Justin F. Gainor , Cancer Discovery 2019 #SEOM 2019

I ASEICA-ASPIC INTERNATIONAL MEETING MY FINAL TAKE AWAY MESSAGES • Cancer cells are active “players” in the game • Longitudinal and dynamic evaluation of tumor specimens required to anticipate subsequent cancer cell ‘movements’ • Understanding mechanisms of resistance in the tumor and its microenvironment is a major priority in the field, BUT NOT only at ACQUIRED but also in PRIMARY RESISTANCE #SEOM 2019