Keynote Presentation I New Era of CRC Management: Impact of Tumor Sidedness and Molecular Subtypes of CRC

Transcription

1 Keynote Presentation I New Era of CRC Management: Impact of Tumor Sidedness and Molecular Subtypes of CRC Scott Kopetz, MD, PhD, FACP University of Texas MD Anderson Cancer Center Houston, Texas, United States

2 My Current View of mcrc Treatment in US RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS FOLFOXIRI + Bev Cetuximab + irinotecan + vemurafenib Salvage Oral Agents: MSI-High FOLFOX + Bev PD-1 inhibition Regorafenib RAS/BRAF wildtype Left sided FOLFOX + Cet/Pan (or Bev) FOLFIRI + Bev (or Cet/Pan) TAS-102 (Trifluridine /tipiracil) Right sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan Bev, bevacizumab; Cet/Pan, cetuximab/panitumumab; mcrc, metastatic colorectal cancer; MSI, microsatellite instable; MSS, microsatellite stable

3 My Current View of mcrc Treatment in US * RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS FOLFOXIRI + Bev Cetuximab + irinotecan + vemurafenib Salvage Oral agents: MSI-High FOLFOX + Bev PD-1 inhibition Regorafenib RAS/BRAF wildtype Left sided FOLFOX + Cet/Pan (or Bev ) FOLFIRI + Bev (or Cet/Pan) TAS-102 (Trifluridine /tipiracil) Right sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan

4 Prevalence of Extended RAS Mutations KRAS Exon 1 Exon 2 Exon 3 Exon WT 4% 5% NRAS Exon 1 Exon 2 Exon 3 Exon % 2% <1% 1 of 6 patients with codon 12/13 KRAS wildtype tumors harbor extended RAS mutations Atreya CE, Kopetz S. J Clin Oncol. 2015;33(7):

5 RAS Pathway Activity Atypical KRAS and NRAS: What To Do With the Rare Variant? KRAS KRAS Normalized (ERK2) Codon 12/13 Codon 59/61 Codon 146 Several notable atypical RAS mt with high activity included KRAS V14I, Q22K, D33E, N116S, and F156L (all >165% of WT activity) NRAS Normalized (ERK2) Conversely, within the typical mutations, KRAS G13C and K117R were not shown to increase activity above WT (However, these two mutations are very rare) 0.5 WT G12D G12S G12C G12V G12A G12R G12W G13D G13R G13V G13C I21V V29L T50I D57Y G60E Q61K Q61P Q61R Q61K Q61L Q61H A66T T74P K117N Q129H E132K A146T A146V A146P R164C R167Q P185A Mt, mutation(s); WT, wildtype NRAS Loree JM, et al. J Clin Oncol. 2017;35(Suppl 4):Abstract 3589.

6 My Current View of mcrc Treatment in US RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS FOLFOXIRI + Bev Cetuximab + irinotecan + vemurafenib Salvage Oral agents: MSI-High FOLFOX + Bev PD-1 inhibition Regorafenib RAS/BRAF wildtype TAS-102 (Trifluridine /tipiracil) Left sided FOLFOX + Cet/Pan (or Bev) FOLFIRI + Bev (or Cet/Pan) Right sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan

7 Increased incidence compared to BRAF wild type Increased Incidence Compared to BRAF Wildtype BRAF V600E Mutations Are Associated With Poor OS 1 Atypical Patterns of Metastases Overall Survival: CALGB/SWOG % P<0.05 P< % P< % P< % 50% 0% Innocenti F, et al. J Clin Oncol. 2017;35(Suppl 4): Abstract BRAF wild type CALGB/SWOG, The Cancer and Leukemia Group B/Southwest Oncology Group; L, left; OS, overall survival; R/T, right/transverse 1 Morris V, et al. Clin Colorectal Cancer. 2014;13(3):

8 BRAF Inhibition Leads to EGFR Feedback EGFR inhibitor alone is not active BRAF inhibition results in feedback activation of EGFR EGFR monoclonal antibody ligand P P Grb hsos KRAS NRAS HRAS BRAF mutation BRAF RAF V600E MAPKs Signaling Morkel M, et al. Oncotarget. 2015;6(25):

9 Mean Tumor tumor volume(mm3) Volume 3 ) Percentage Change in Tumor Size From Baseline BRAF Inhibition + Inhibition of EGFR Feedback Provides High Response Rates * Feedback Through EGFR Is Blocked With Dual BRAF+EGFR Feng Tian, Van Morris With EGFR + Irinotecan = 35% Hong DS, et al. Cancer Discov. 2016;6(12): NTC:Vehicle, control chow Control BRAF PLX4720 inhibition chow EGFR inhibition Combined BRAF+EGFR CETUXIMAB: IP 40mg/kg twice a week PLX4720 chow+cetuximab IP VIC regimen: Vemurafenib, irinotecan, cetuximab Days Post-Cell post cell implant Implant RR, relative risk * Hypothesis-generating studies. Results need investigation in randomised, Phase III studies. Combinations are not currently licensed

10 Dual BRAF + EGFR Inhibition: SWOG 1406 Eligibility: 1) BRAF V600 mutation 2) Prior treatment for metastatic disease 3) No more than 2 prior progression on chemotherapy 4) No prior cetuximab Stratified: 1) Prior treatment with irinotecan R Arm A Cetuximab + Irinotecan Arm B Vemurafenib + Cetuximab + Irinotecan Cetuximab + Irinotecan + Vemurafenib Optional cross-over PFS PFS, progression-free survival Kopetz S, et al. J Clin Oncol. 2017;35(suppl 4S): Abstract 520.

11 Efficacy of VIC Regimen Progression-Free Survival Response Rate HR 0.48 (95% CI ) P =.001 Kopetz S, et al. J Clin Oncol. 2017;35(suppl 4S): Abstract 520.

12 Addressing BRAF/EGFR Resistance Can response rate and PFS of BRAFi/EGFRi be augmented by MEKi? 1,2 Patient population BRAF V600E mutant 1 to 2 prior regimens in metastatic setting Randomization Arm A - Triplet Therapy Binimetinib* + Encorafenib + Cetuximab n = 205 Arm B - Doublet Therapy Encorafenib + Cetuximab n = 205 Arm C - Control Arm FOLFIRI + Cetuximab or irinotecan + Cetuximab n = % response rate PFS 8 months Ongoing Phase III BEACON Study Huijberts S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 517P. Now available for enrollment in Japan (Dr Yoshino): NCT Hong DS, et al. Cancer Discov. 2016;6(12): Ahronian LG, et al. Cancer Discov. 2015;5(4):

13 My Current View of mcrc Treatment in US RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS FOLFOXIRI + Bev Cetuximab + irinotecan + vemurafenib Salvage Oral agents: MSI-High FOLFOX + Bev PD-1 inhibition Regorafenib RAS/BRAF wildtype Left sided FOLFOX + Cet/Pan (or Bev) FOLFIRI + Bev (or Cet/Pan) TAS-102 (Trifluridine /tipiracil) Right sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan

14 Microsatellite Instability High (MSI-H) Is Associated With High Mutation Rates and Immune Activation MSI-H Tumor: Anti-CD3 Ab HLA, human leukocyte antigen Vogelstein B, et al. Science. 2103;339(6127):

15 Good Durability of Nivo and Nivo+Ipi Nivolumab + Ipilimumab a,b OS (%) Nivolumab 1,e,f 9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5] 12-mo rate (95% CI], % 71 (61.4, 78.7) 50 [38.1, 61.4] Nivolumab + Ipilimumab a,d Nivolumab 1,e,f 9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7] 12-mo rate (95% CI), % 85 (77.0, 90.2) 73 [61.5, 82.1] No. at Risk PFS (%) Nivolumab + ipilimumab ~50% Nivolumab Months Nivolumab + ipilimumab Nivolumab Combination therapy provided improved long-term clinical benefit relative to monotherapy during a similar follow-up period Nivolumab + ipilimumab Nivolumab Months ~60% Ipi, ipilimumab; Nivo, nivolumab Andre T, et al. J Clin Oncol. 2018;36(suppl 6S): Abstract 553. Dr. Muro will provide more details during Keynote II 15

16 My Current View of mcrc Treatment in US RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS FOLFOXIRI + Bev Cetuximab + irinotecan + vemurafenib Salvage Oral agents: MSI-High FOLFOX + Bev PD-1 inhibition Regorafenib RAS/BRAF wildtype Left sided FOLFOX + Cet/Pan (or Bev) FOLFIRI + Bev (or Cet/Pan) TAS-102 (Trifluridine /tipiracil) Right sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan

17 Anatomic Definitions of Right and Left Right Hemicolectomy Superior Mesenteric Artery Left Hemicolectomy Inferior Mesenteric Artery DeVita Jr VT, et al. Cancer: Principles & Practice of Oncology, 6th Edition. Philadelphia: Lippincott Williams & Wilkins; 2001.

18 Detriment In Overall Survival (Months) 2001: Prognosis In the 5-FU Era E2290 Trial PS2 (vs PS0) Symptomatic Right sided (vs Left) PS1 (vs PS0) Poorly diff (vs. Moderate) Lymph node metastases Liver metastases 5-FU, 5-fluorouracil; PS, performance status O Dwyer PJ, et al. J Clin Oncol. 2001;19(9):

19 2009: Sidedness and Single-Agent Cetuximab: CO-17 OS: Left Colon: 10.1 vs 4.8 months Right Colon: 6.2 vs 3.5 months PFS: Left Colon: 5.4 vs 1.8 months Right Colon: 1.9 vs 1.9 months DISCLAIMER: Anti-EGFR therapy should only be initiated in patients with confirmed RAS WT status Brule SY, et al. Eur J Canc. 2015;51(11):

20 Classic Mechanisms of Oncogenesis in Colorectal Cancer

21 Percentage of the Lesions (%) Histology of Premalignant Lesions: SSA Sessile serrated adenomas (SSA) are more prevalent in right colon Conventional tubular and tubulovillous adenomas: Uniformly distributed, but adenomas are more likely to have high grade dysplasia or associated adenocarcinoma at smaller sizes in the right colon than in the left colon Is there a granular figure in the literature? Anatomic Locations of the Colon Yang JF, et al. Arch Pathol Lab Med. 2015;139(3):

22 Embryologic Definitions Processes of cell migration and differentiation required during normal embryologic development require distinct gene expression patterns within the midgut and hindgut Differential gradients of various homeobox (HOX) genes establishes craniocaudal polarization The transverse colon represents a major break in HOX gene patterns Carlson B. Human Embryology and Developmental Biology, 4 th Edition. Philadelphia: Mosby, Inc., an affiliate of Elsevier Inc

23 Microbiome: Biofilms Prominent in R Side Dejea CM, et al. Proc Natl Acad Sci U S A. 2015;111(51):

24 Bile Acid Bile acids are putatively carcinogenic. Normally synthesized and conjugated in the liver and secreted in bile, they are conjugated by microbiome Primary bile acid conjugated cholic acid is 10-fold higher in the R colon than the L colon, and converting enzyme activity is likewise higher in R and L colon Nistal E, et al. Front Oncol. 2015;5:220.

25 % methylated % Methylated Methylation: Inherent and Age-Associated Normal mucosa has substantially different epigenetic signatures, resulting in altered gene regulation Aging is associated with acquisition of methylation of normal tissue predominantly in R colon Methylation Varies in R and L Normal Colon Right Left Kaz AM, et al. Epigenetics. 2015;9(4): Meigatti M, et al. Oncogene. 2009;28(6):

26 Specific Impact of Location on Prognosis Loree JM, et al. Clin Cancer Res. 2018;24(5):

27 Mutation Prevalence Varies by Tumor Location Loree JM, et al. Clin Cancer Res. 2018;24(5):

28 Right-Sided Primaries Are More Likely To Have Concomitant Genetic Features Associated With Poor Outcomes Right-side Circle sizes reflect relative prevalence Left-side Left Right BRAF mutant CIMP High MSI-High None of the above Lee MS, et al. J Clin Oncol. 2016;34(suppl): Abstract 3560.

29 Consensus Molecular Subtypes (CMS) Joint Analysis of ~4000 Cases With RNA Expression Guinney J, et al. Nat Med. 2015;21(11):

30 Loree JM, et al. Clin Cancer Res. 2018;24(5): CMS Varies By Sidedness

31 My Current View of mcrc Treatment in US * RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS MSI-High FOLFOXIRI + Bev FOLFOX + Bev Cetuximab + irinotecan + vemurafenib PD-1 inhibition Salvage Oral agents: Regorafenib RAS/BRAF wildtype Left sided FOLFOX + Cet/Pan (or Bev ) FOLFIRI + Bev (or Cet/Pan) TAS-102 (Trifluridine /tipiracil) Right sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan

32 My Current View of mcrc Treatment in US * RAS mutated FOLFOX + Bev FOLFIRI + Bev BRAF mutated, MSS MSI-High FOLFOXIRI + Bev FOLFOX + Bev Cetuximab + irinotecan + vemurafenib PD-1 inhibition Salvage Oral agents: Regorafenib RAS/BRAF wildtype Left sided Right sided FOLFOX + Cet/Pan (or Bev ) FOLFIRI + Bev (or Cet/Pan) Clinical data will be presented in detail in later sessions by Drs Yeh and Yoshino FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cet/Pan TAS-102 (Trifluridine /tipiracil)

33 But Still Much We Don t Understand Loree JM, et al. Clin Cancer Res. 2018;24(5):

34 Liquid Biopsies Growth of PubMed Citations 3000% 2500% 2000% CTC ctdna 1500% 1000% 500% 0% CTC, circulating tumor cells; ctdna, circulating tumor DNA Diaz LA Jr, et al. J Clin Oncol. 2014;32(6):

35 Characteristics and Terminology for ctdna Normal cells/tissue 167 bp fragments of DNA, a nucleosome Circulating cell-free DNA cfdna, ccfdna ctdna Tumor The linker DNA between nucleosomes is cleaved leaving 167 bp cell-free DNA fragments (145 bp plus a ~20 bp segment wrapping histone H1). Originally described by Wyllie in Chandrananda D, et al. BMC Med Genomics. 2015;8:29. Wyllie AH. Nature. 1980;284(5756): Slide courtesy of Rick Lanman.

36 Variables Impacting Quantification of ctdna Tumor Volume Copy number alterations, tumor heterogeneity Clearance, degradation, lymphatic drainage, renal function Rate of release: apoptotic, necrotic, macrophage mediated Tumor histology, Ki67/grade, metastatic site, vascularity Inflammation, immune response, trauma, surgery ctdna quantification

37 Concordance of Tissue and ctdna in mcrc: 93% Accuracy Prospective AGEO Study: NGS: A subset of patients did not have detectable ctdna: Metachronous disease, peritoneal only, low tumor markers AGEO, Association des Gastro-Entérologues Oncologues; NGS, next generation sequencing Bachet J-B, et al. J Clin Oncol. 2017;35(Suppl 4): Abstract

38 Detection Rates Are Higher in Patients With Untreated mcrc or With Disease Progression All patients (N = 416) Lymph Node Involvement Liver Involvement Newly Diagnosed or Recently Progressing 84% 95% 96% 98% Lima, et al. Unpublished data

39 # Patients Timely Tissue Availability: mcrc In the US, initial diagnosis is commonly performed in a different system than treatment 70% of patients in US have chemotherapy administered in a different system/location than surgery Most patients do not have tissue available for testing at first visit Treatment decisions await molecular testing Overman MJ, et al. Annals Oncol. 2016;27(6): Median Time for Return of Tissue Based Testing: 6 days 23 days Days 27 days Time from order to tissue received

40 Days Prospective Study Comparing ctdna and Tissue Decision Impact of ctdna Testing Physicians felt plasma testing improved the quality of provided care Patients felt plasma testing improved satisfaction Plasma testing results available before tissue testing results Results (per case) 87% 97% 89% vs 26 days ctdna FFPE Allan Pereira 107 consecutive patients with mcrc Low quartile Median High quartile Pereira A, et al. PLoS One. 2017;12(7):e

41 Interrogation of Resistance Mechanisms Multiple resistance mutations detected in each patient Strickler JH, et al. Cancer Discov. 2018;8(2):

42 Conclusions: Current Biomarkers Extended RAS testing BRAF mutation Microsatellite instability testing Tumor Location: Sidedness Circulating tumor DNA for profiling HER2 amplification Fusions Consensus molecular subtypes Circulating tumor DNA for minimal residual disease

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