Is the current design of precision medicine studies the right one: lessons from the SHIVA trial PRO Christophe Le Tourneau, MD, PhD Institut Curie – Paris & Saint-Cloud – France Department of Medical Oncology Head of Early Phase Clinical Trials Versailles-Saint-Quentin-en-Yvelines University WIN symposium – Paris – June 27, 2016
Conflicts of interest • Nothing to disclose
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Introduction • CUSTOM trial (Advanced thoracic malignancies) Lopez-Chavez et al . JCO 2015;33:1000-7
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Introduction • WINTHER
Introduction • M-PACT
Informed Patients with refractory consent cancer (all tumor types) signed Imatinib Everolimus Sorafenib Erlotinib Dasatinib Tumor biopsy Lapatinib Trastuzumab Vemurafenib Tamoxifen Letrozole Abiraterone NGS+ Cytoscan HD +IHC Targeted therapy based on molecular profiling Informed R Bioinformatics consent signed Conventional therapy at physicians‘ choice Molecular Non eligible Eligible biology patient patient board Cross-over Specific NO therapy YES available Le Tourneau et al . Lancet Oncol 2015;16:1324-34
Introduction Le Tourneau et al . Lancet Oncol 2015;16:1324-34
Introduction Precision medicine trials Stratified trials Algorithm-testing trials Molecularly- Histology- Non- Randomized stratified stratified randomized Tumor types 1 N 1 or N Was the design of the SHIVA trial the right one? Molecular N 1 or N N Alterations Treatments N 1 N Test Test drugs efficacy Test algorithm efficiency Le Tourneau et al . Chin Clin Oncol 2014;3:13
Outline Is the current design of precision medicine studies the right one? PRO
Outline Is the current design of precision medicine studies the right one? PRO 1) The SHIVA trial asked a real-life question
Real-life question Ciriello et al . Nature Genet 2013;45:1127-33
Real-life question • Pilot study by von Hoff et al . von Hoff et al . JCO 2010;28:4877-83
Real-life question • 18/66 patients (27%): PFS ratio>1.3 von Hoff et al . JCO 2010;28:4877-83
Real-life question Patients receiving matched targeted therapy Patients receiving no matched targeted therapy Tsimberidou et al . CCR 2012;18:6373-83
Real-life question Failure-free survival Overall survival Patients receiving matched targeted therapy Patients receiving matched targeted therapy Patients receiving no matched targeted therapy Tsimberidou et al . CCR 2012;18:6373-83
Real-life question ? >
Outline Is the current design of precision medicine studies the right one? PRO 1) The SHIVA trial asked a real-life question 2) The SHIVA trial was designed to evaluate a specific prespecified treatment algorithm
Treatment algorithm Molecular profile Molecular = TREATMENT ALGORITHM alteration Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm Targets Molecular alterations MTAs ER, PR Protein expression >10% IHC Tamoxifen or Letrozole HORMONE RECEPTOR PATHWAY AR Protein expression >10% IHC Abiraterone PI3KCA, AKT1 Mutation/Amplification AKT2/3, mTOR, RICTOR, RAPTOR Amplification PTEN Homozygous deletion Heterozygous deletion + mutation or IHC Everolimus PI3K/AKT/mTOR STK11 Homozygous deletion PATHWAY Heterozygous deletion + mutation INPP4B Homozygous deletion BRAF Mutation/Amplification Vemurafenib KIT, ABL1/2, RET Mutation/Amplification Imatinib PDGFRA/B, FLT3 Mutation/Amplification Sorafenib EGFR Mutation/Amplification Erlotinib RAF/MEK HER-2 PATHWAY Mutation/Amplification Lapatinib + Trastuzumab SRC Mutation/Amplification Dasatinib EPHA2, LCK, YES1 Amplification
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm • Variants of interest: - validated hotspots mutations * frequency: >4% for SNVs and >5% for indels * coverage: >30X for SNVs and >100X for indels - non targeted variants * outside a hotspot * frequency >10% * no synonymous mutations * no polymorphisms
Treatment algorithm • Amplifications: - Gene copy number * diploid tumor: >6 * tetraploid tumor: >7 - Amplicon size * <1 Mb * <10 Mb if protein overexpression/or loss of expression is validated in IHC
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm Le Tourneau et al . JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm Targets Molecular alterations MTAs ER, PR Protein expression >10% IHC Tamoxifen or Letrozole AR Protein expression >10% IHC Abiraterone PI3KCA, AKT1 Mutation/Amplification AKT2/3, mTOR, RICTOR, RAPTOR Amplification PTEN Homozygous deletion Heterozygous deletion + mutation or IHC Everolimus STK11 Homozygous deletion Heterozygous deletion + mutation INPP4B Homozygous deletion BRAF Mutation/Amplification Vemurafenib KIT, ABL1/2, RET Mutation/Amplification Imatinib PDGFRA/B, FLT3 Mutation/Amplification Sorafenib EGFR Mutation/Amplification Erlotinib HER-2 Mutation/Amplification Lapatinib + Trastuzumab SRC Mutation/Amplification Dasatinib EPHA2, LCK, YES1 Amplification
Treatment algorithm PFS – Hormone receptor pathway Le Tourneau et al . Lancet Oncol 2015;16:1324-34
Treatment algorithm • 72 yo female AR+ breast cancer M0 Abiraterone M14
Treatment algorithm Targets Molecular alterations MTAs ER, PR Protein expression >10% IHC Tamoxifen or Letrozole AR Protein expression >10% IHC Abiraterone PI3KCA, AKT1 Mutation/Amplification AKT2/3, mTOR, RICTOR, RAPTOR Amplification PTEN Homozygous deletion Heterozygous deletion + mutation or IHC Everolimus STK11 Homozygous deletion Heterozygous deletion + mutation INPP4B Homozygous deletion BRAF Mutation/Amplification Vemurafenib KIT, ABL1/2, RET Mutation/Amplification Imatinib PDGFRA/B, FLT3 Mutation/Amplification Sorafenib EGFR Mutation/Amplification Erlotinib HER-2 Mutation/Amplification Lapatinib + Trastuzumab SRC Mutation/Amplification Dasatinib EPHA2, LCK, YES1 Amplification
Treatment algorithm
Treatment algorithm PFS – PI3K/AKT/mTOR pathway Le Tourneau et al . Lancet Oncol 2015;16:1324-34
Treatment algorithm • 41 yo female PI3KCA-mutated cervical ca M0 Everolimus M3
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