Colorectal Cancer in 2017: From Biology to the Clinics. Rodrigo Dienstmann

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1 Colorectal Cancer in 2017: From Biology to the Clinics Rodrigo Dienstmann

2 MOLECULAR CLASSIFICATION Tumor cell Immune cell Tumor microenvironment Stromal cell

3 MOLECULAR CLASSIFICATION Biomarker Tumor cell Genomics Epigenomics Transcriptomics Proteomics Biomarker Immune cell Transcriptomics Proteomics Tumor microenvironment Biomarker Stromal cell Transcriptomics Proteomics

4 MOLECULAR CLASSIFICATION BRAF mutation HER2 amplification Microsatellite instability (MSI) Tumor cell Genomics Immunoscore Immune cell Proteomics Tumor microenvironment TGFβ signature Stromal cell Transcriptomics

5 BIOMARKER RESEARCH Predictive Prognostic Biology understanding

6 PRECISION MEDICINE PARADIGMS IN CRC PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi molecular multi marker adaptive (immune) multi drug Dienstmann et al, Nat Rev Cancer 2017

7 PRECISION MEDICINE PARADIGMS IN CRC PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi molecular multi marker adaptive (immune) multi drug Genomics and transcriptomics Targeted and Immuno-oncology drug development Dienstmann et al, Nat Rev Cancer 2017

8 Single gene single marker single drug Matched Targeted Agent KRAS mutation BRAF mutation PIK3CA mutation MET overexpression MEK inhibitor BRAF inhibitor PI3K inhibitor MET inhibitor Dienstmann et al, J Clin Oncol 2013

9 Single gene single marker single drug Matched Targeted Agent Response rate KRAS mutation BRAF mutation PIK3CA mutation MET overexpression MEK inhibitor BRAF inhibitor PI3K inhibitor MET inhibitor <5% Dienstmann et al, J Clin Oncol 2013

10 Single gene single marker single drug VHIO experience Dienstmann et al, Mol Cancer Ther 2012

11 HOW TO IMPROVE CLINICAL BENEFIT FURTHER? Deeper biological understanding of the disease - Genomic - Transcriptomic - Stromal-immune

12 TCGA, Nature 2012 CO-OCCURRING ALTERATIONS

13 DYNAMICS OF TARGET INHIBITION

14 CLONAL SELECTION TEMPORAL HETEROGENEITY Misale et al, Cancer Discov 2014

15 Dienstmann et al, Nat Rev Cancer 2017

16 PRECISION MEDICINE PARADIGMS IN CRC PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi molecular multi marker adaptive (immune) multi drug Dienstmann et al, Nat Rev Cancer 2017

17 Multi gene multi marker multi drug *ctdna Dienstmann et al, J Clin Oncol 2013

18 Multi gene multi marker multi drug Matched Targeted Agent KRAS, NRAS, BRAF, PIK3CA wild-type BRAF mutation ERBB2 amplification, KRAS wild-type EGFR mutation, RAS/BRAF wild-type Anti-EGFR mab BRAF inh + anti-egfr mab + MEK inh Anti-HER2 mab + pan-her inh Second generation anti-egfr mab

19 Multi gene multi marker multi drug Matched Targeted Agent BRAF mutation BRAF inhibitor + anti-egfr mab + MEK inhibitor Van Cutsem et al, ESMO-WGIC 2015

20 Multi gene multi marker multi drug Matched Targeted Agent ERBB2 amplification KRAS wild-type Anti-HER2 mab + pan-her inhibitor Siena et al, ASCO 2015

21 Multi gene multi marker multi drug Matched Targeted Agent EGFR mutation KRAS wild-type NRAS wild-type BRAF wild-type Second generation anti-egfr mab SYM004 * ** ** * * * * * * RAS/BRAF mutation * EGFR mutation Dienstmann et al, Cancer Discov 2015

22 Multi gene multi marker multi drug Matched Targeted Agent KRAS, NRAS, BRAF, PIK3CA wild-type Anti-EGFR mab Response rate BRAF mutation ERBB2 amplification, KRAS wild-type EGFR mutation, RAS/BRAF wild-type BRAF inh + anti-egfr mab + MEK inh Anti-HER2 mab + pan-her inh Second generation anti-egfr mab ~30%

23 HOW TO IMPROVE CLINICAL BENEFIT FURTHER? Deeper biological understanding of the disease - Genomic - Transcriptomic - Stromal-immune

24 Guinney, Dienstmann et al, Nat Med 2015

25 Guinney, Dienstmann et al, Nat Med 2015

26 Guinney, Dienstmann et al, Nat Med 2015

27 Supervised immune and stromal infiltration analysis CMS1 CMS2 CMS3 CMS4 Becht et al, Clin Cancer Res 2016

28 Supervised immune infiltration analysis T cell chemokine T cell inhibition Myeloid cell chemokine Angiogenesis Immunosuppression Complement CMS1 CMS2 CMS3 CMS4 Becht et al, Clin Car Res 2016

29 Dienstmann et al, Nat Rev Cancer 2017

30 Overall survival Relapse-free survival Guinney, Dienstmann et al, Nat Med 2015

31 PRECISION MEDICINE PARADIGMS IN CRC PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi molecular multi marker adaptive (immune) multi drug Dienstmann et al, Nat Rev Cancer 2017

32 Multi molecular multi marker adaptive (immune) multi drug Unpublished

33 Multi molecular multi marker adaptive (immune) multi drug

34 Lenz et al. ASCO 2017, abstr 3511

35 RIGHT vs. LEFT colon Lee et al, ASCO 2016 CMS1 enrichment < EGFR overexpression < EGFR ligand overexpression > BRAF mut > NF1/MEK1/PIK3CA/PTEN mut > MSI and CIMP high CMS2 enrichment > EGFR overexpression > EGFR ligand overexpression > IRS2 amplification < BRAF mut Guinney, Dienstmann et al, Nat Med 2015

36 Multi molecular multi marker adaptive (immune) multi drug In vitro CRC cell line drug screen HERACLES trial in HER2+ CRC HER2 GCN> 9.6 HER2 GCN< 9.6 Ragnhild A. Lothe Lab, Dept. Mol Oncol Unpublished

37 Multi molecular multi marker adaptive (immune) multi drug Predictive value hypothesis targeted therapies RAS/BRAF wt Epithelial Canonical CMS2 Strategy: anti-egfr therapy + pan-her inhibitors?

38 MSI tumors and response to PD-1 blockade PEMBROLIZUMAB NIVOLUMAB Le DT, et al. N Engl J Med 2015 Overman MJ, et al. ASCO 2016

39 Multi molecular multi marker adaptive (immune) multi drug Predictive value hypotheses immune therapies Hypermutated CRC MSI Strategy: PD1 blockade + OX40 agonist?

40 Multi molecular multi marker adaptive (immune) multi drug Predictive value hypotheses immune therapies Inflamed CRC Mesenchymal TGFβ activated CMS4 Strategy: PD1 blockade + TGFBR inh or angiogenic multi-tki MSS

41 Multi molecular multi marker adaptive (immune) multi drug Predictive value hypotheses immune therapies Immune desert CRC Strategy: PD1 blockade + MEK inh or epigenetic therapy or T cell bispecific mab (CEA-CD3)? Epithelial CMS2 MSS Metabolic CMS3

42 Atezolizumab (PDL1 block) + cobimetinib (MEK inh) in mcrc Bendell et al, ASCO 2016

43 Predictive value hypotheses immune therapies Becht et al. Advances Immunol 2016

44 MoTriColor project H2020 FFPE gene expr. classifier

45 How to translate this hypotheses to clinical practice? CMS classifier CINICAL LAB : NanoString, IHC panels RESEARCH LAB: Almac, many others - NOW: Retrospective analysis of clinical trials with standard regimens - NEXT: Stratification in ongoing trials with immuno-oncology drugs - FUTURE: Drug repurposing and novel-novel combinations = targeting pathway dependencies

46 How to translate this hypotheses to clinical practice? - Retrospective analysis of clinical trials with standard regimens ASCO 2018 Tuesday 9:45 am Clinical Science Symposium oral session Clinical utility of colon cancer molecular subtypes: Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 trial. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mcrc): Analysis of CALGB/SWOG (Alliance).

47 How to translate this hypotheses to clinical practice? - NEXT: Stratification in ongoing trials with immuno-oncology drugs - FUTURE: Drug repurposing and novel-novel combinations = targeting pathway dependencies

48 TAKE HOME MESSAGES Dienstmann et al, Nat Rev Cancer 2017

49 TAKE HOME MESSAGES Dienstmann et al, Nat Rev Cancer 2017

50 PREDICTIVE Still unknown what combination of molecular markers (mutation + MSI + gene/protein expression) will provide the best prediction of drug response.

51 Gastrointestinal Tumors Group Molecular Prescreening Program Molecular Therapeutics Unit ODysSey Group Ragnhild A. Lothe Scott Kopetz Justin Guinney Josep Tabernero

52 Marisa et al. ASCO 2017, abstr 3509

53 Stintzing et al. ASCO 2017, abstr 3510