in Colorectal Cancers in The Genomic Era Ahmad Awada, MD, PhD Head - - PowerPoint PPT Presentation

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in colorectal cancers in the

in Colorectal Cancers in The Genomic Era Ahmad Awada, MD, PhD Head - - PowerPoint PPT Presentation

Dec 21, 2022 826 likes •1.3k views

Emerging Therapeutic Strategies in Colorectal Cancers in The Genomic Era Ahmad Awada, MD, PhD Head Medical Oncology Clinic Institut Jules Bordet Universit Libre de Bruxelles (U.L.B.) 06/2015 Colorectal Tumors: Available Active Therapies

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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

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Colorectal Tumors: Available Active Therapies

Colorectal

RAS mutated

Chemotherapy Bevacizumab, Aflibercet, regorafenib TAS-102

RAS non-mutated

Chemotherapy Bevacizumab, Aflibercet, Regorafenib Cetuximab, panitumumab TAS-102

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Colorectal Tumors: Emerging Cytotoxic Agents

Etirinotecan: A polymer-conjugate of irinotecan? Antibody-drugs conjugate: • Several agents in clinical trials

Better therapeutic index?

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Molecular mechanisms of primary and secondary resistance to anti-EGFR therapies in mCRC

Misale S et al., Cancer Discovery 2014

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Montagut et al. Nature Medicine 18, 2, 2012

A patient with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab

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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

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Sym004: A novel synergistic anti-EGFR Ab mixture directed against distinct epitopes of EGFR

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MEHD7945A (dual EGFR & HER-3 MoAb)

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New therapeutic approaches

Steward W et al., ESMO 2014

Emerging druggable targets based on

genomics

Immunotherapy

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Di Nicolantonio et al., ESMO 2014

Genomic classification of CRC

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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

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c-MET axis inhibition

Sattler & Salgia, Update Cancer Ther 2009

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Anti MET + Anti EGFR therapies are active in the preclinical setting

Bardelli A et al., Cancer Discov. 2013

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Correlation between HER2 amplification and therapeutic resistance to cetuximab in (xeno)patients

Bertotti A et al., Cancer Discov 2011; 1: 508-23

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Anti-EGFR and anti-HER2 therapies in cetuximab- resistant HER2-amplified xenopatients with mCRC

Bertotti et al. Cancer Discovery 2011

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Di Nicolantonio et al., ESMO 2014

Heracles Studies

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Therapeutic Dual Inhibition of HER2 Pathway<br />in Metastatic Colorectal Cancer <br />The HERACLES Trial *

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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HERACLES CONSORT diagram

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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HERACLES treatment and assessments

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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Patients characteristics

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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Safety and tolerability

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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Response

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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Representative CE-CT scans of 2 responders

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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Time to Progression by HER2 score

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

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Studies in RAS mutant mCRC: MEK inhibitors are the basis of these studies

Dienstmann R et al. ASCO Educ Book 2014

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BRAF (V600E) mutated CRC

1Di Nicolantonio F. J Clin Oncol 2018; 2De Roock et al. Lancet Oncol 2010; 3Van Cutsem et al., J Clin Oncol 2011; 4Seymour MT et al. Lancet Oncol 2013

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Bernards R et al., ESMO 2014 N Engl J Med. 2010 363:809-19 Kopetz et al., ASCO 2010

Differential response of BRAF inhibition in BRAF mutant melanoma versus colon cancer

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Bernards R et al., ESMO 2014 Prahallad et al., Nature 2012

EGFR and BRAF inhibition synergize to suppress BRAF mutant colon cancer growth

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Early efficacy comparison of BRAFi / EGFRi / MEKi combinations in CRC

Dienstmann R et al., ASCO Educ Book 2014

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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

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Dabrafenib (D) + Trametinib (T):<br />Limited Activity in BRAFm CRC

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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MEK116833 Phase 1/2 Study Design

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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Demographics

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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Safety Profile

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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Dermatologic Toxicity

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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Duration on Study

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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Prevalence of other RTK overexpression in CRC specimens

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

(1%) (2%)

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Di Nicolantonio et al., ESMO 2014

ALK translocation in CRC cells is associated with tumour sensitivity to ALK kinase inhibition

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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)

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Tabernero J et al., ESMO 2014

Immune modulating agents

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Tabernero J et al., ESMO 2014

Druggable immune check-points

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Anti-PD1/PDL1 in mCRC

Lipson, Clin Cancer Res 2013

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PD-1 blockade (Pembrolizumab) in colorectal cancers previously treated

Dung T. Le, ASCO 2015 (LBA100)

MMR-deficient (n=11) MMR-proficient (n=21) WES (somatic mutations) 1782 73 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

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THANK YOU