Clinical utility of precision medicine in oncology Prof. Christophe Le Tourneau, MD, PhD Institut Curie Paris & Saint-Cloud France Head, Department of Drug Development and Innovation (D 3 i) INSERM U900 Research unit Versailles Saint-Quentin-en-Yvelines University FEAM Geneva September 28, 2018
Treatment of cancer Primary tumor Metastases
à Aim = cure Treatment of cancer
Treatment of cancer Surgery Radiotherapy Local treatments Drugs For a limited time à Aim = cure
Treatment of cancer
Treatment of cancer Drugs Treatment for life Surgery Radiotherapy Curable situation in ~5% of cases (exception of germline tumors [95%]) Chronic disease
Treatment of cancer Surgery Radiotherapy Chemotherapy 20 th century 21 st century
Treatment of cancer Surgery Radiotherapy Chemotherapy Targeted therapy 20 th century 21 st century
Treatment of cancer Trastuzumab (Herceptin ) HER-2 Amplification Lapatinib (Tykerb ) 20%
Treatment of cancer Trastuzumab (Herceptin ) à Risk of recurrence decreased by 50% HER2+ breast cancer
Treatment of cancer Trastuzumab (Herceptin ) HER2+ metastasic breast cancer à Median overall survival increased from <2 to >6 years
Treatment of cancer Surgery Radiotherapy Chemotherapy Targeted therapy Immunotherapy 20 th century 21 st century
Treatment of cancer Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy
Treatment of cancer Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Targeted therapy Targeted therapy Targeted therapy Targeted therapy Targeted therapy Targeted therapy EGFR ALK ROS1 HER2 KRAS BRAF HER2
Treatment of cancer Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Targeted therapy Targeted therapy Targeted therapy Targeted therapy Targeted therapy Targeted therapy Immunotherapy Immunotherapy Immunotherapy PD-L1
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Utility of sequencing Prognostic value Predictive value
Utility of sequencing Prognostic value
Utility of sequencing Surgery Radiotherapy Chemotherapy Early breast cancer No chemotherapy
Utility of sequencing Sparano JA et al. NEJM [epub ahead of print on June 3, 2018]
Utility of sequencing Prognostic value Predictive value
Utility of sequencing What drugs? Surgery Radiotherapy Recurrent/metastatic cancer
SHIVA01
Patients with refractory cancer (all tumor types) Informed consent signed SHIVA01 Randomized proof-of-concept phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer Tumor biopsy NGS+ Cytoscan HD +IHC Therapy based on molecular profiling - Approved molecularly targeted agent Bioinformatics Informed consent signed R Non eligible patient Molecular biology board Eligible patient Conventional therapy based on oncologist s choice Cross-over NO Specific therapy available YES Le Tourneau et al. Lancet Oncol 2015;16:1324-34
SHIVA01 PFS WHOLE POPULATION Le Tourneau et al. Lancet Oncol 2015;16:1324-34
Challenges
Challenges Molecular = TREATMENT alteration ALGORITHM Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent
Challenges Treatment algorithm: - technology used to identify molecular alterations Le Tourneau et al. JNCI 2015;108:4
Challenges Ratan et al. Plos One 2013;8
Challenges Treatment algorithm: - technology used to identify molecular alterations - thresholds used Le Tourneau et al. JNCI 2015;108:4
Challenges O Rawe et al. Genomic Medicine 2013;5:28
Challenges Treatment algorithm: - technology used to identify molecular alterations - thresholds used - molecular alterations/drugs matching Le Tourneau et al. JNCI 2015;108:4
Challenges Treatment algorithm: - technology used to identify molecular alterations - thresholds used - molecular alterations/drugs matching - molecular alterations priorization Le Tourneau et al. JNCI 2015;108:4
Utility of sequencing
Utility of sequencing
Utility of sequencing MSI high Pembrolizumab
Utility of sequencing
Utility of sequencing
Utility of sequencing NTRK fusion Larotrectinib
Conclusions Sequencing has been demonstrated to successfully guide the need of adjuvant therapy in hormone-positive early breast cancer
Conclusions Sequencing has been demonstrated to successfully guide the need of adjuvant therapy in hormone-positive early breast cancer The predictive value of sequencing to guide therapy in cancer patients has not been demonstrated with a level 1 evidence
Conclusions All recurrent/metastatic cancer patients should be sequenced for MSI and NTRK fusions, and potential inclusion into clinical trials