Colon Cancer: State of the Art

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1 Colon Cancer: State of the Art Heinz-Josef Lenz Professor of Medicine and Preventive Medicine Associate Director, Clinical Research J Terrence Lanni Chair in Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery USC/Norris Comprehensive Cancer Center Los Angeles, California

2 HEINZ-JOSEF LENZ COLORECTAL CANCER: STATE OF THE ART ADVISORY BOARDS: BAYER, BOEHRINGER-INGELHEIM, MERCKSERONO, ROCHE, GENENTECH, BMS CLINICAL TRIAL SUPPORT: ROCHE, BAYER, TAIHO, DAICHI, INCYTE, BOEHRINGER-INGELHEIM, BMS, PFIZER, MERCK, MERCKSERONO, SWOG, NCI, NIH THE SPEAKER WILL DIRECTLY DISCLOSURE THE USE OF PRODUCTS FOR WHICH ARE NOT LABELED (E.G., OFF LABEL USE) OR IF THE PRODUCT IS STILL INVESTIGATIONAL. 14th Annual California Cancer Conference Consortium August 10-12, 2018

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4 The Colorectal Cancer Subtyping Consortium (CRCSC) identifies a network of molecular subtypes Subtype 2.2 TA C5 D Subtype 1.3 B C1 C4 Subtype 1.1 CCS3 E Stem-like B_score CCS1 Group A Group B C_score Enterocyte CMS2 Group C CMS4 Group D C2 C Inflammatory CCS2 A_score Subtype 2.1 C3 Goblet-like Group E Group F Subtype 1.2 CMS1 A CMS3 Dienstmann R, et al. ASCO 2014 (Abstract No. 3511)

5 Proportion Without Event OS All Patients by CMS Subtype CMS Events/Total Median (95% CI) CMS1 85/ ( ) CMS2 173/ ( ) CMS3 58/ ( ) CMS4 127/ ( ) Logrank P-value: < Months From Randomization Presented by: Heinz Josef Lenz

6 Proportion Without Event OS CMS1 Patients by Arm Arm Events/Total Median (95% CI) Bevacizumab 36/ ( ) Cetuximab 49/ ( ) Logrank P-value: Months From Randomization Presented by: Heinz Josef Lenz

7 Proportion Without Event OS CMS2 Patients by Arm Arm Events/Total Median (95% CI) Bevacizumab 94/ ( ) Cetuximab 79/ ( ) Logrank P-value: Months From Randomization Presented by: Heinz Josef Lenz

8 Heterogeneity also exists within individual tumors Ding et al., Nature 2010 Mutations present in 5 90% of sequencing reads from one tumor Navin et al., Nature 2011 Independent subclones coexisting in a single anatomic site in breast Gerlinger et al., NEJM 2012 Two-thirds of mutations in single biopsies were not uniformly detectable throughout all sampled regions Both sensitive and resistant RNA expression patterns

9 Intra-tumor copy number heterogeneity in CRC at the single gland level C. Curtis & colleagues

10 Liquid Biopsies Tumor specific change (e.g. Mutation) Tumor Tumor cell release DNA and RNA Circulating Tumor Cells (CTC) CTC Circulating tumor DNA Normal DNA Blood Vessel Circulating tumor RNA

11 MGH GI Cancer Center Liquid Biopsy Program HER2 amp CRC (n=2) MET amp 5% gastric (n=2) 5% FGFR2 gastric (n=1) 2% FGFR2 biliary (n=8) 21% BRAF mcrc (n=5) 13% RAS WT CRC (n=21) 54% single mechanism identifed (n=17) 43% no mechanism identified (n=8) 21% multiple mechansims identified (n=14) 36% N=39 Routine liquid biopsy assessment can effectively identify mechanisms of resistance across different tumor types and treatments Mechanism of resistance identified in 80% 36% with multiple resistance mechanisms (range 2-12; median 3) In patients with matched tumor biopsies, ctdna identified additional resistance mechanisms in 64%

12 EGFR antibodies in RAS-WT CRC Anti-EGFR antibodies RTK EGFR 10 distinct resistance alterations identified across 21 patients KRAS mutations RAS KRAS NRAS HRAS KRAS amplification EGFR ECD mutations MET amplification CRAF ARAF BRAF ERBB2 amplification Novel MEK1 mutation MEK Some patients with 5 or more alterations present in ctdna ERK PROLIFERATION AND SURVIVAL

13 Therapeutic intervention in preclinical trials to overcomeresistance to anti-egfr antibody blockade. A Bertotti et al. Nature 000, 1-5 (2015) doi: /nature14969

14 Interesting Findings 1. In a small series of 10 patients who all had mt ras in tissue and liquid biopsy treated with bev based chemotherapy. 5/10 changed to wt Ras under chemotherapy ) Gazzaniga et al Annals of Oncology (2017) 28 (suppl_5): v573-v594) 2. Case report in JCO Precision Oncology from same group reported PR in one of this patient treated with cetuximab 14

15 ESMO, 2016 ASCO, ESMO, JUNE, SEP, ST LINE MET / ADVANCED COLORECTAL KRAS wt All RAS wt Codons 12 & 13 CALGB/SWOG FOLFIRI or FOLFOX MD choice N N = = * N = 526 Chemo + Cetuximab Chemo Cetuximab OS = mos mos PFS PFS = = mos OS = 32.5 mos : NO DIFFERENCE Chemo + Bevacizumab Chemo OS + = Bevacizumab OS = mos PFS PFS = = mos OS = 31.2 mos * Right or left-sided primary Included in sidedness analysis

16 80405: Overall Survival by Sidedness (all RAS wt) Side N (Events) Median (95% CI) HR (95% CI) p Left Right 325 (238) 149 (114) 35.2 ( ) ( ) ( ) 0.009

17 80405: OS by Sidedness (Bevacizumab) Side N (Events) Median (95% CI) HR (95% CI) Adjusted p Left Right 152 (119) 78 (58) 32.6 ( ) ( ) ( ).50

18 80405: OS by Sidedness (Cetuximab) Side N (Events) Median (95% CI) HR (95% CI) Adjuste d P Left Right 173 (119) 71 (56) 39.3 ( ) ( ) ( ) 0.001

19 80405: Sidedness Predictive for Biologics Biologic by 1 Side Interaction BIOLOGIC SIDE OF PRIMARY HAZARD RATIO 95% CI P (adjusted*) Any biologic OS Cetux v Bev; left Cetux v Bev; right 1.81 (1.15, 2.84) P int = PFS 1.94 (1.28, 2.95) P int = Cetux v Bev OS Left 0.77 (0.59, 0.99) 0.04 PFS 0.84 (0.66, 1.06) 0.15 Cetux v Bev OS Right 1.36 (0.93, 1.99) 0.10 PFS 1.64 (1.15, 2.36) *Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases

20 Probability of PFS Probability of OS FIRE-3: Right-sided tumors Progression-free survival Overall survival 1.0 Right-sided mcrc Cetuximab + FOLFIRI (n=38) Bevacizumab + FOLFIRI (n=50) 1.0 Right-sided mcrc Cetuximab + FOLFIRI (n=38) Bevacizumab + FOLFIRI (n=50) HR = 1.44 (95% CI: ) p = HR = 1.31 (95% CI: ) p = Cetuximab + FOLFIRI Bevacizumab + FOLFIRI Months Numbers at Risk Cetuximab + FOLFIRI Bevacizumab + FOLFIRI Months Numbers at Risk

21 Probability of PFS Probability of OS FIRE-3: Left-sided tumors Progression-free survival Overall survival A 1.0 Left-sided mcrc Cetuximab + FOLFIRI (n=157) Bevacizumab + FOLFIRI (n=149) B 1.0 Left-sided mcrc Cetuximab + FOLFIRI (n=157) Bevacizumab + FOLFIRI (n=149) HR = 0.90 (95% CI: ) p= HR = 0.63 (95% CI: ) p = Months Months Cetuximab + FOLFIRI Bevacizumab + FOLFIRI Numbers at Risk Cetuximab + FOLFIRI Bevacizumab + FOLFIRI Numbers at Risk

22 Distinct Biology of R v. L CRC Analysis of PETACC-3 samples (n=2849) BRAF mut MSI KRAS PIK3CA Mucinous differentiation Right EREG expression 18q loss 20q Gain EGFR gain HER2 gain High mutation Frequency Poor Prognosis Missiaglia, ASCO 2013 Left Sensitive to Cetuximab Good Prognosis

23 LEFTy Organization

24 LEFTy Organization

25 HR for OS According to Primary Tumor Location Loree JM,... Kopetz S; Clin Cancer Res 2018

26 Treatment options based on Location: My Take RAS wt Right-sided Left-sided T + EGFR-i D/T + Bev D + EGFR-i D + Bev if ORR is a primary goal if OS is a primary goal if OS is a primary goal if EGFR-i are not accepted/tolerated D: chemo doublet T: chemo triplet default recommendation default recommendation

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28 Microsatellite Instability

29 % C h a n g e fro m B a s e lin e S L D % C h a n g e fro m B a s e lin e S L D M M R -p ro fic ie n t C R C M M R -d e fic ie n t C R C Pembrolizumab M M R -p ro fic ie n t C R C M M R -d e fic ie n t C R C MMR-deficient CRC, N=28 MMR-proficient CRC, N=25 Response Rate 57% 0% Disease Control Rate 89% 16% Le DT, et al. NEJM 2015 and ASCO 2016

30 a C h a n g e i n S u m o f T a r g e t L e s i o n s S i z e ( % ) Overman et al. Lancet Oncology 2017 MSI-high CRC: Nivolumab Monotherapy RR 31% SD 39% PD 24% Disease Control 12weeks in 69% On treatment Off treatment CR or PR First occurrence of new lesion O n T r e a t m e n t O f f T r e a t m e n t C o m p l e t e o r P a r t i a l R e s o p o n s e F i r s t O c c u r r e n c e o f N e w L e s i o n C h a n g e T r u n c a t e d t o % W e e k s

31 Investigator-Assessed Best Change in Target Lesion Size (%) Investigator-Assessed Best Change in Target Lesion Size (%) Investigator-Assessed Best Change in Target Lesion Size (%) Reduction in Target Lesions Regardless of PD-L1 Expression, BRAF or Lynch History 100 BRAF Mutation Status Tumor PD-L1 Expression 50 Mutant Wild type + Confirmed CR/PR % < 1% + Confirmed CR/PR Clinical History of Lynch Syndrome Yes No + Confirmed CR/PR Overman et al. Lancet Oncology

32 IMblaze370: randomised, Phase III, multicentre, open-label study in mcrc Loss of clinical benefit Unresectable locally advanced or metastatic CRC Received 2 prior regimens of cytotoxic chemotherapy for metastatic disease ECOG PS 0-1 MSI-H capped at 5% R 2:1:1 N=363 Atezolizumab 840 mg IV q2w + cobimetinib 60 mg oral 21/7 days Atezolizumab 1200 mg IV q3w Regorafenib 160 mg oral 21/7 days Stratification Extended RAS mutation status ( 50% patients in each arm) Time since diagnosis of first metastasis (< 18 months vs 18 months) Primary endpoint OS a Atezo + cobi vs rego Atezo vs rego Data cutoff date: March 9, 2018 INV-assessed key secondary endpoints PFS ORR DOR Atezo, atezolizumab; cobi, cobimetinib; INV, investigator; rego, regorafenib. a Two-sided type I error rate of 0.05 was controlled by hierarchical testing (testing atezo vs rego only if atezo + cobi vs rego was positive). NCT World Congress On Gastrointestinal Cancer, 2018 Bendell J, et al. IMblaze370 32

33 Overall survival Median OS, mo (95% CI) HR vs rego (95% CI) Atezo + cobi (n = 183) 8.9 (7.00, 10.61) 1.00 (0.73, 1.38) Atezo (n = 90) 7.1 (6.05, 10.05) Rego (n = 90) 8.5 (6.41, 10.71) 1.19 (0.83, 1.71) N/A P value a N/A 12-mo OS, % 38.5% 27.2% 36.6% N/A, not applicable. HRs are from stratified log-rank tests. Data cutoff: March 9, a For descriptive purposes only. World Congress On Gastrointestinal Cancer, 2018 Bendell J, et al. IMblaze370 33

34 HER2 Overexpression HER2/neu 3+ (2+)

35 HERACLES Trial Trastuzumab + Lapatinib in HER2+ / KRAS-wt pts refractory to ani-egfr AK 849 patients screened, 46 patients (5.4%) HER2+ (2+/3+); 23 patients evaluable for response ORR 35%, DCR 78% Siena, et al. ASCO 2015

36 Optimal treatment of mcrc in the presence of braf

37 Clinical Efforts in BRAF mut BRAFi+ EGFRi Roche/Genentech BRAFi+ EGFRi + PI3Ki Novartis BRAFi+ EGFRi + chemo US Cooperative Groups BRAFi+ EGFRi + MEKi GSK 37

38 Study Design R E G I S T R A T I O N Local BRAF testing No local BRAF testing BRAF V600E Mutation Central Testing Performed R A N D O M I Z A T I O N ARM 1: Cetuximab + Irinotecan ARM 2: Vemurafenib + Cetuximab + Irinotecan Progression Progression Off Study STEP 3: Crossover to add Vemurafenib Off Study Wild-type (off study) Vemurafenib 960mg PO bid continuous Cetuximab 500mg/m2 IV q2weeks Irinotecan 180mg/m2 IV q2weeks Presented by: Scott Kopetz, MD, PhD

39 Primary Endpoint: Progression-free survival 100% 80% N Events Median 95% Conf Int Cetuximab + Irinotecan ( ) Vemurafenib + Cetuximab ( ) + Irinotecan 60% 40% HR = 0.48 (95% CI ) P= % 0% Months after randomization April data cutoff Presented by: Scott Kopetz, MD, PhD

40 Response Rate 100% Cetuximab + Irinotecan Cetuxim ab + Irinotec an (n=45) a Vemurafe nib + Cetuxima b + Irinotecan (n=43) a P-value c 20% 0% -30% -100% Partial response 4% 16% 100% Vemurafenib + Cetuximab + Irinotecan Stable disease 18% 48% Progression b 56% 12% P= % 0% -30% Disease Control 22% 67% Rate a 93 patients had measurable disease; b Including symptomatic deterioration; c Chi-squared -100% Presented by: Scott Kopetz, MD, PhD April data cutoff

41 BEACON CRC Phase 3 Study Design 1 Safety Lead-in Completed Phase 3 Currently Enrolling ENCO 300 mg QD + BINI 45 mg BID + CETUX 400 mg/m 2 (initial), then 250 mg/m 2 QW R 1:1:1 Triplet therapy ENCO + BINI + CETUX n=205 Doublet Therapy ENCO + CETUX n=205 Control Arm FOLFIRI + CETUX, or IRI + CETUX n=205 Disease progression Disease progression Disease progression Continued follow-up for evaluation of OS N=30 1. Clinicaltrials.gov/ct2/show/NCT ; (February 2018). Van Cutsem et al., ESMO GI 2018

42 Best % Change from Baseline Best Percentage Change in Tumor Measurements from Baseline Cetuximab + Irinotecan from SWOG S P a rtia l R e s p o n s e (n = 1 1 ) C o m p le te R e s p o n s e (n = 3 ) * * * Patients *Patients with lymph node disease with decreases in short axis dimensions consistent with RECIST 1.1 defined Complete Response. One patient had no baseline sum of longest diameters and is not presented. 1. Kopetz S, et al. J Clin Oncol. 2017;35:Abstr 3505, with permission. Van Cutsem et al., ESMO GI 2018

43 Overall survival (%) BEACON SLI: Overall Survival year OS rate: 62% Survival Rate 1 Prior Regimen 2 Prior Regimens 6 mo 88% 85% 12 mo 63% 62% Median OS: Not reached Data fully mature through 12.6 months 10 0 Patients at risk Patients with BRAF V600 mutation (N=29) Censored patients Time (mo) Van Cutsem et al., ESMO GI 2018

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45 RSK Ras and effector dependencies KRAS subtype lines: depend on the canonical RAS-RAF MAPK pathway upregulate genes involved in the maintenance of the epithelial phenotype RSK subtype lines: depend on the RSK-MTOR/PI3K axis to drive aerobic metabolism to supplement glycolysis express mesenchymal markers ZEB1, TGFB, TWIST KRAS Tina Yuan, Rachel Bagni, Cyril Benes, Arnaud Amzallag, Bob Stephens, Ming Yi, FNLCR Cell Feb 2018

46 KRAS suptype: RAF/MEK/ERK dependencies 1. Inhibition of this signaling with MEK inhibitors such as trametinib, selumetinib alone or in combination 2. Inhibition of ERK with inhibitors such as MK- 8353, BVD Combination of MEK and ERK inhibition to overcome resistance 4. Pan raf inhibitors LY RAF/MEK inhibitor RO Combination of AKT/MEK PI3K/MEK inhibitors 7. Cdk4/6 and MEK inhibitors

47 MLH1 rs Outcome Data from KRAS mut mcrc patients in TRIBE FOLFIRI/bevacizumab arm HR 3.14 (95%CI ) Median OS 25.8 vs 18.4 months

48 CCL2 rs4586 Outcome Data from KRAS mut mcrc patients in TRIBE FOLFIRI/bev Arm HR 0.51 (95%CI ) Median PFS 25.8 vs 18.4 months

49 Current View of mcrc Treatment RAS mutated FOLFOX + Bev FOLFIRI + Bev FOLFOX + cetux BRAF mutated, MSS MSI-High FOLFOXIRI + Bev FOLFOX + Bev Vemurafenib/ Cetuximab/Irinotecan or Clinical Trial PD-1 inhibition Salvage Oral agents: RAS/BRAF wild type Left Sided FOLFOX + Cet/Pan (or Bev) FOLFIRI + Bev (or Cet/Pan) Rego TAS-102 Right Sided FOLFOX + Bev FOLFIRI + Bev Irinotecan + Cetuximab/Pantimumab

50 The one who knows more, may decide better

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