Emerging Therapeutic Strategies in Colorectal Cancers in The Genomic Era Ahmad Awada, MD, PhD Head Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) 06/2015
Colorectal Tumors: Available Active Therapies Chemotherapy Bevacizumab, Aflibercet, RAS mutated regorafenib TAS-102 Colorectal Chemotherapy Bevacizumab, Aflibercet, RAS non-mutated Regorafenib Cetuximab, panitumumab TAS-102
Colorectal Tumors: Emerging Cytotoxic Agents Etirinotecan: A polymer-conjugate of irinotecan? Antibody-drugs conjugate: • Several agents in clinical trials • Better therapeutic index?
Molecular mechanisms of primary and secondary resistance to anti-EGFR therapies in mCRC Misale S et al., Cancer Discovery 2014
A patient with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab Montagut et al. Nature Medicine 18, 2, 2012
RAS Non-Mutated Colorectal Cancer: Beyond Cetuximab and Panitumumab • More efficient anti-EGFR MoAbs • MoAbs directed to other members of the HER family (e.g., HER2 and HER3) • MoAbs directed to other receptors than HER family (e.g ., MET, …) • Combination with downstream effector inhibitors Adapted from Tabernero J et al., ESMO 2014
Sym004: A novel synergistic anti-EGFR Ab mixture directed against distinct epitopes of EGFR
MEHD7945A (dual EGFR & HER-3 MoAb)
New therapeutic approaches • Emerging druggable targets based on genomics • Immunotherapy Steward W et al., ESMO 2014
Genomic classification of CRC Di Nicolantonio et al., ESMO 2014
HER2 and MET are actionable targets that emerge in case of resistance to EGFR therapies in CRC Bertotti A et al., Cancer Discov. 2011 Nov;1(6):508-23 Bardelli A et al., Cancer Discov. 2013 Jun;3(6):658-73
c-MET axis inhibition Sattler & Salgia, Update Cancer Ther 2009
Anti MET + Anti EGFR therapies are active in the preclinical setting Bardelli A et al., Cancer Discov. 2013
Correlation between HER2 amplification and therapeutic resistance to cetuximab in (xeno)patients Bertotti A et al., Cancer Discov 2011; 1: 508-23
Anti-EGFR and anti-HER2 therapies in cetuximab- resistant HER2-amplified xenopatients with mCRC Bertotti et al. Cancer Discovery 2011
Heracles Studies Di Nicolantonio et al., ESMO 2014
Therapeutic Dual Inhibition of HER2 Pathway<br />in Metastatic Colorectal Cancer <br />The HERACLES Trial * Presented By Salvatore Siena at 2015 ASCO Annual Meeting
HERACLES CONSORT diagram Presented By Salvatore Siena at 2015 ASCO Annual Meeting
HERACLES treatment and assessments Presented By Salvatore Siena at 2015 ASCO Annual Meeting
Patients characteristics Presented By Salvatore Siena at 2015 ASCO Annual Meeting
Safety and tolerability Presented By Salvatore Siena at 2015 ASCO Annual Meeting
Response Presented By Salvatore Siena at 2015 ASCO Annual Meeting
Representative CE-CT scans of 2 responders Presented By Salvatore Siena at 2015 ASCO Annual Meeting
Time to Progression by HER2 score Presented By Salvatore Siena at 2015 ASCO Annual Meeting
Studies in RAS mutant mCRC: MEK inhibitors are the basis of these studies Dienstmann R et al. ASCO Educ Book 2014
BRAF (V600E) mutated CRC 1 Di Nicolantonio F. J Clin Oncol 2018; 2 De Roock et al. Lancet Oncol 2010; 3 Van Cutsem et al., J Clin Oncol 2011; 4 Seymour MT et al. Lancet Oncol 2013
Differential response of BRAF inhibition in BRAF mutant melanoma versus colon cancer Bernards R et al., ESMO 2014 N Engl J Med. 2010 363:809-19 Kopetz et al., ASCO 2010
EGFR and BRAF inhibition synergize to suppress BRAF mutant colon cancer growth Bernards R et al., ESMO 2014 Prahallad et al., Nature 2012
Early efficacy comparison of BRAFi / EGFRi / MEKi combinations in CRC Dienstmann R et al., ASCO Educ Book 2014
Phase 1/2 Study of the MEK Inhibitor Trametinib, BRAF Inhibitor Dabrafenib, and Anti-EGFR Antibody Panitumumab in Patients With BRAF V600E-Mutated Metastatic Colorectal Cancer Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Dabrafenib (D) + Trametinib (T):<br />Limited Activity in BRAFm CRC Presented By Chloe Atreya at 2015 ASCO Annual Meeting
MEK116833 Phase 1/2 Study Design Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Demographics Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Safety Profile Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Dermatologic Toxicity Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Duration on Study Presented By Chloe Atreya at 2015 ASCO Annual Meeting
Prevalence of other RTK overexpression in CRC specimens (1%) (2%) TCGA CRC dataset (195 complete tumors) interrogated through http://www.cbioportal.org/ Cerami E et al., Cancer Discov. 2012 May:2(5):401-4 Gao J et al., Sci Signal. 2013 Apr 2;6(269):pl1
ALK translocation in CRC cells is associated with tumour sensitivity to ALK kinase inhibition Di Nicolantonio et al., ESMO 2014
Prevalence of NTRK1 rearrangements in CRC is 1.5% De Braud F et al., 2014 ASCO Annual Meeting, J Clin Oncol 32:5s, 2014 (suppl; absr 2502)
Immune modulating agents Tabernero J et al., ESMO 2014
Druggable immune check-points Tabernero J et al., ESMO 2014
Anti-PD1/PDL1 in mCRC Lipson, Clin Cancer Res 2013
PD-1 blockade (Pembrolizumab) in colorectal cancers previously treated MMR-deficient MMR-proficient (n=11) (n=21) WES 1782 73 (somatic mutations) Ir ORR (at 20w) 40% 0% Ir PFS (at 20w) 78% 11% ORR (RECIST) 40% 0% DCR (RECIST) 90% 11% Median PFS Not reached 2.2 mo Median OS Not reached 5 mo Dung T. Le, ASCO 2015 (LBA100)
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