Colorectal Cancer in the Coming Years: What Can We Expect?

Colorectal Cancer in the Coming Years: What Can We Expect? Clara Montagut, MD, PhD Hospital Universitari del Mar, Barcelona, Spain Memorial Sloan Kettering Cancer Center, New York, United States

What Are the Key Questions? CONCEPT 1 - Novel oncogenic targets CONCEPT 2 - Targeting tumor evolution CONCEPT 3 - Multi-OMICS: Integration of genomic, transcriptomic, immune and stromal data

Understanding Colorectal Cancer Comprehensive Analysis of Genome Data Cancer Genome Atlas Network. Nature. 2012;487(7407):330-337. Walther A, et al. Nat Rev Cancer. 2009;9(7):489-499.

Novel Targets HER2 HERACLES Project HER2 amplification, RAS wildtype Trastuzumab + lapatinib 78% disease control Sartore-Bianchi A, et al. Lancet Oncol. 2016;17(6):738-746. Siena S, et al. J Clin Oncol. 2015;33(suppl): Abstract 3508.

Improving Targeted Therapies in mcrc CONCEPT 1 - Novel oncogenic targets CONCEPT 2 - Targeting tumor evolution CONCEPT 3 - Multi-OMICS: Integration of genomic, transcriptomic, immune and stromal data

Tumor Spatial Heterogeneity Inter-patient variation Intra-patient variation Intra-tumor variation Gerlinger M, et al. N Engl J Med. 2012;366(10):883-892.

Improving Targeted Therapy in mcrc PAST Single gene single marker single drug Companion Diagnostics 1 test alteration A 1 drug PRESENT Multi gene multi marker multi drug FUTURE Multi OMICS systems biomedicine adaptive (immune) drug mcrc, metastatic colorectal cancer

Improving Targeted Therapy in mcrc PAST Single gene single marker single drug Companion Diagnostics 1 test alteration A 1 drug PRESENT Multi gene multi marker multi drug FUTURE Multi OMICS systems biomedicine adaptive (immune) drug mcrc, metastatic colorectal cancer

Kopetz S, et al. J Clin Oncol. 2015;33(34):4032-4038. Progression-free survival (PFS) 2.1 months Response rate 5%

Dynamics of BRAF Inhibition Alpelisib Panitumumab EGFR RAS sos grb2 PI3K PiP2 PiP3 Encorafenib MEK BRAF EGFR upregulation following BRAF inhibition AKT mtor ERK Prahallad A, et al. Nature. 2012;483(7387):100-103. Corcoran RB, et al. Cancer Discov. 2012;2(3):227-235. Misale S, et al. Sci Transl Med. 2014;6(224):224ra26.

SINGLE DOUBLET From Single Targeting to Multi Targeting: Increasing Clinical Benefit in BRAF+ mcrc Vemurafenib + Panitumumab 3 13% Yaeger et al CCR 15 Vemurafenib + Cetuximab 4 20% Tabernero et al ASCO 14 Encorafenib + Cetuximab 5 22% Tabernero et al ESMO 16 Dabrafenib + Panitumumab 6 10% Atreya, ASCO 15 TRIPLET Response Rate Vemurafenib 1 5% Kopetz, JCO 15 Dabrafenib 2 11% Falchook, Lancet 08 Vemurafenib (BRAFi) + Cetuximab + Irinotecan 7 35% Hong, ASCO 15 Dabrafenib (BRAFi) + Panitumumab + Trametinib (MEKi) 6 26% Atreya, ASCO 15 Encorafenib (BRAFi) + Cetuximab + PI3Ki 5 32% Tabernero, ESMO 16 BEACON TRIAL: Encorafenib (BRAFi)+ 48% Cetuximab + Binimetinib (MEKi) 8,9 (+31% SD) Kopetz, ESMO 17 VanCutsem, ASCO-GI `18 Greater efficacy SD, stable disease 1. Kopetz S, et al. J Clin Oncol. 2015;33(34):4032-4038. 2. Falchook et al. Lancet. 2008. 3. Yaeger R, et al. Clin Cancer Res. 2015;21(6):1313-1320. 4. Tabernero J, et al. J Clin Oncol. 2014;32(5s): Abstract 3518. 5. Tabernero J, et al. Ann Oncol. 2016;27(suppl_2): Abstract O-026. 6. Atreya CE, et al. J Clin Oncol. 2015;33(suppl): Abstract 103. 7. Hong DS, et al. J Clin Oncol. 2015;33(suppl): Abstract 3511. 8. Huijberts S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 517P. 9. Van Cutsem E, et al. J Clin Oncol. 2018;36(4S): Abstract 627.

BEACON Trial Schema Patients with BRAF V600E -mutant mcrc Safety Lead-In Completed Binimetinib + encorafenib + cetuximab Dosedetermining cohort n = 9 Dose expansion cohort n = 21 Randomization 1:1:1 Phase III Currently Enrolling Triplet Therapy: Binimetinib + encorafenib + cetuximab n = 205 Doublet Therapy: Encorafenib + cetuximab n = 205 Control Arm: FOLFIRI + cetuximab or irinotecan + cetuximab n = 205 Disease progression Disease progression Disease progression Continued follow-up for evaluation of OS National Institutes of Health. https://clinicaltrials.gov/ct2/show/nct02928224. Accessed May 1, 2018. Huijberts S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 517P. Van Cutsem E, et al. J Clin Oncol. 2018;36(4S): Abstract 627.

BEACON Trial: Safety Lead-In Efficacy 1 Previous regimen 2 Previous regimens Van Cutsem E, et al. J Clin Oncol. 2018;36(4S): Abstract 627.

Temporal Heterogeneity: Clonal Dynamics KRAS KRAS wt Basal RAS-wt tumor wt KRAS Response to anti-egfr treatment wt RAS-mutant tumor at progression to treatment Anti-EGFR treatment wt, wildtype

Clonal Dynamics in mcrc Patients Treated With Anti-EGFR mab in mcrc CT, computed tomography; mab, monoclonal antibody; PR, partial response Van Emburgh BO, et al. Nat Commun. 2016;7:13665.

Acquired Resistance to Anti-EGFR Therapy in CRC 2. Mutations in extracellular domain of EGFR Cell membrane S492R G465R/E G464L K467T I491M EGFR HER2 ampl MET ampl PI3-K AKT KRAS NRAS BRAF MEK 1. Downstream mutations or activation of alternative receptors that converge in MEK activation ERK Yonesaka K, et al. Sci Transl Med. 2011;3(99):99ra86. Montagut C, et al. Nat Med. 2012;18(2):221-223. Misale S, et al. Nature. 2012;486(7404):532-536. Diaz LA Jr, et al. Nature. 2012;486(7404):537-540. Bardelli A, et al. Cancer Discov. 2013;3(6):658-673. Troiani T, et al. Clin Cancer Res. 2013;19(24):6751-6765. Misale S, et al. Sci Transl Med. 2014;6(224):224ra26. Hobor S, et al. Clin Cancer Res. 2014;20(24):6429-6438. Arena S, et al. Clin Cancer Res. 2015;21(9):2157-2166. Siravegna G, et al. Nat Med. 2015;21(7):795-801. Russo M, et al. Cancer Discov. 2016;6(2):147-153.

Liquid Biopsy to Guide Biomarker-Based Treatment After Cetuximab/Panitumumab: Ongoing Trials Liquid biopsy Basal RAS wt tumor First-line chemo + anti- EGFR PD Biomarker Treatment Clinical Trial HER2 ampl Trastuzumab + lapatinib Heracles trial (phase II) BRAF mut BRAFi + antiegfr+ MEKi BEACON study RAS mut Rechallenge CHRONOS; FIRE-4 EGFR ECD ctdna genotyping - Panitumumab - 2 nd generation antiegfr: Sym004 PAN-HER NCT02083653 (phase II) NCT01520389 (phase I)

Cetuximab Rechallenge Mutations in RAS emerge during anti-egfr treatment RAS RAS wt wt RAS wt Basal RAS wt tumor Response to treatment Progression to treatment

Cetuximab Rechallenge Mutations in RAS emerge during anti-egfr treatment and decline when treatment is suspended RAS RAS wt wt RAS wt Basal RAS wt tumor Response to treatment Progression to treatment Off treatment

Liquid Biopsy for Longitudinal Monitoring of RAS Mutations in Blood of Patients: Rechallenge with Cetuximab Siravegna G, et al. Nat Med. 2015;21(7):795-801.

Ongoing Clinical Trials Evaluating Anti-EGFR Rechallenge in mcrc Study (Study ID) Anti-EGFR Agent or Combination Main Selection Criteria CRICKET (NT02296203) Cetuximab RAS and BRAF wildtype First-line irinotecan-based (FOLFIRI or FOLFOXIRI) cetuximab-containing therapy producing at least a PR REGAIN (NCT02316496) Cetuximab + irinotecan RAS and BRAF wildtype First-line chemotherapy regimen with a fluoropyrimidine and irinotecan (FOLFIRI) + cetuximab with initial PR/complete response (CR) and progressive disease (PD) with PD >6 weeks after the last administration of cetuximab FIRE-4 (EudraCT 2014-003787-21) Cetuximab RAS wildtype First-line FOLFIRI + cetuximab therapy producing at least a PR A phase II Trial of Rechallenge With Panitumumab Driven by RAS Clonal- Mediated Dynamic of Resistance: CHRONOS (EudraCT 2016-002597-12) Panitumumab RAS and BRAF wildtype First-line anti-egfr-containing therapy producing at least a PR Predefined criteria of RAS mutational load measured on plasma ctdna at progression of firstline and before rechallenge

PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug Co-ocurring alterations spatial heterogenity Clonal selection temporal heterogenity FUTURE Multi OMICS systems biomedicine adaptive immune / stromal drug

The Consensus Molecular Subtype (CMS) Classification Gene Expression CMS1 MSI Immune CMS2 Canonical CMS3 Metabolic CMS4 Mesenchymal 14% 37% 13% 23% MSI, CIMP high, hypermutation SCNA high Mixed MSI status, SCNA low, CIMP low SCNA high BRAF mutations KRAS mutations Immune infiltration and activation WNT and MYC activation Metabolic deregulation Stromal infiltration, TGFb activation, angiogenesis Worse survival after relapse Worse relapse-free and overall survival CIMP, cytosine-guanosine (CpG) island methylation phenotype; MSI, microsatellite instability Guinney J, et al. Nat Med. 2015;21(11):1350-1356.

FIRE-3: PFS and OS According to CMS in RAS Wildtype Accross All Treatment Groups PFS and OS according to CMS in RAS wild-type<br />across all treatment groups Probability of PFS P<.0001 Probability of Survival P<.0001 Months Since Randomization Months Since Randomization Stintzing S, et al. J Clin Oncol. 2017;35(Suppl 4): Abstract 3510.

Immunotherapy in mcrc Checkmate-142: Nivolumab + Ipilimumab in MSI-H PFS, % OS, % Andre T, et al. J Clin Oncol. 2018;36(suppl 4S): Abstract 553.

Is There Role for Immunotherapy in 95% of CRC Tumors That Are MSS? Can we convert noninflamed tumors to become inflamed? Inflamed Immune Excluded Immune Desert MSI-H (3% to 5%) CD8+ T cells infiltrated, but nonfunctional MSS (>95% of mcrc) CD8+ T cells accumulated, but not efficiently infiltrated CD8+ T cells absent from tumor and periphery Accelerate or remove brakes on T cell response Bring T cells in contact with cancer cells Increase number of antigen-specific T cells or increase antigen presentation MSS, microsatellite stable Kim JM, et al. Ann Oncol. 2016;27(8):1492-1504. Hegde PS, et al. Clin Cancer Res. 2016;22(8):1865-1874.

Combination Approaches for MSS CRC: PD-L1 + MEK Inhibitor PFS OS Patients Median (95% CI) 6-Month Median (95% CI) 6-Month 12-Month All (n = 84) 1.9 months (1.8, 2.3) 18% 9.8 months (6.2, 14.1) 65% 43% MSS (n = 42) a 2.5 months (1.8, 3.7) 27% 13.0 months (6.0, 25.8) 71% 51% KRAS mutant (n = 57) b 2.0 months (1.8, 2.3) 22% 9.5 months (6.0, 17.6) 67% 44% KRAS wildtype (n = 25) b 1.8 months (1.8, 2.6) 9% 10.0 months (4.9, 17.1) 65% 43% Data cutoff: September 4, 2017. a Of the remaining 42 non-mss patients, 32 patients had unknown MSI status, 9 patients were MSI-low and 1 patient was MSI-high. b 2 patients had unknown KRAS mutation status. Bendell J, et al. J Clin Oncol. 2018;36(suppl 4S): Abstract 560.

Phase III Trial of Cobimetinib and Atezolizumab in Chemotherapy-Refractory mcrc (COTEZO/IMblaze370) Patients with unresectable locally advanced or metastatic CRC (received at least 2 chemotherapy regimens)* N = 360 R 2:1:1 Atezolizumab + cobimetinib Atezolizumab Regorafenib Primary endpoint: OS Secondary endpoints: PFS, CR, PR, DOR, HRQoL (EORTC QLQ-C30) Stratified by tumor extended RAS status and time since diagnosis of first metastasis MSI-H capped at approximately 5%; 95% MSS At least 180 patients with extended RAS-mutant tumors to be enrolled PD PD PD *Experienced disease progression or was intolerant to at least two systemic chemotherapy regimens including fluroropyrimidines, irinotecan, or oxaliplatin DOR, duration of response; HRQoL, health-related quality of life; OS, overall survival National Institutes of Health. http://clinicaltrials.gov/ct2/show/nct02788279. Accessed 8 February 2018. Accrual completed

Take-Home Messages - RAS, BRAF, and MSI are crucial to make clinical decisions in mcrc - Novel molecular targets are being evaluated with promising results (HER2) - Exciting results are emerging for BRAF mutant tumors - Novel therapeutic strategies should take into consideration heterogeneity and clonal dynamics - Novel therapeutic strategies should integrate immune and stromal factors - Immunotherapy is an excellent option for patients with MSI-H tumors - For MSS CRC tumors, novel strategies are promising

Thanks cmontagut@hospitaldelmar.cat