Johanna Bendell Call-on Congress panel speaker
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  • Provided by Tona Gilmer– GSK212 inhibits both non-activated MEK1/2 (IC50 ~ 0.71 nM) and the activated-MEK1/2 (IC50 ~13 nM) (reference Gilmartin A et al.  Clin Cancer Res 2011 17:989-1000). Cell growth inhibition was determined after 3 days of compound treatment. pERK western blot was determined after 24 hours of compound treatment (cell growth inhibition should be referenced as Eastman S, unpublished and the Western blot should be referenced as Greger J, unpublished).Tona Gilmer: Constitutive activation of the RAS/RAF/MEK/ERK MAPK signaling pathway in melanoma can occur primarily through oncogenic mutations in BRAF or NRAS, or through autocrine growth factor stimulation. Activating mutations of BRAF at valine (V) 600 to glutamic acid (E) or lysine (K) occur in ~50% of melanoma cases, and promote downstream MEK–ERK signaling, resulting in cell proliferation, survival, invasion and metastasis. Both GSK2118436 and GSK1120212 are selective and potent kinase inhibitors. GSK436 targets RAF including the mutant forms of BRAF V600E (with IC50 value of 0.65 nM) and V600K with IC50 value of 0.5 nM. GSK212 inhibits both non-activated and the activated-MEK1/2 with IC50 values from 0.7-13 nM. Recent clinical trials with both (GSK2118436 and GSK1120212) as monotherapy have shown activity in melanoma patients with tumorsharboring BRAFV600E/K mutations. However, some tumors do not respond or develop resistance to these agents. Thus, an approach combining these two agents with different mechanisms of action to block the MAPK signaling pathway, may provide more effective treatment for this disease. In fact, GSK436 plus GSK212 has a synergistic effect on cell growth inhibition as exemplified in A375PF11 melanoma cells (shown at the right side of the slide), with combination index value ~ 0.65. The combination demonstrated more effective blockade of the MAPK signaling measured by a reduction in phospho ERK (western blot). *Cell growth inhibition was determined after 3 days of compound treatment. pERK western blot was determined after 24 hours of compound treatment.

Johanna Bendell Call-on Congress panel speaker Johanna Bendell Call-on Congress panel speaker Presentation Transcript

  • THERE ARE SO MANYPROMISING AGENTS COMING TO TREAT COLORECTAL CANCER Johanna Bendell, MD Director, GI Oncology Trials Sarah Cannon Research Institute Nashville, TN
  • What is on the horizon?• Biomarkers and molecular profiling to guide treatment selection• “Targeted therapies”• Combination therapies• Immunotherapy• New ways of delivering chemotherapy and targeted therapies
  • Why targeted therapy?• Going after what makes the cancer a cancer• Our drug development is catching up with the lab• Identification of certain pathways that are key in cancer development and survival• We are still learning – One set of targets does not fit all – All of the pathways talk to each other – Side effect profiles are different, but can be just as toxic to the patient – Chronic cancer treatment?
  • [TITLE]
  • Toward Personalized Care: MolecularProfiling Stricker et al. Semin Oncol. 2011
  • What biomarkers are wealready using in colorectalcancers? • Biomarkers can be prognostic or predictive • Microsatellite instability (MSI) • K-ras • B-raf • Rash • And more to come… • New drugs that are in early development are looking at companion diagnostics and specifying biomarker status early on
  • EGFR Pathway Signaling in CRC P P Ras KRAS mutation (40%–50%) EGFR Sos P P Grb2 Mutually exclusive Raf BRAF mutation (10%) MEK ERK Proliferation Metastasis Survival AngiogenesisMAPK: mitogen-activated protein kinase
  • KRAS as a Biomarker for Panitumumab Response in Metastatic CRC Patients With Wild-Type KRAS Patients With Mutant KRAS 1.0 Pmab + BSC Median Mean 1.0Proportion With PFS BSC alone Events/N (%) Pmab + BSC 0.9 in Wks in Wks Mean 0.9 BSC alone Median Proportion With PFS 0.8 12.3 19.0 Events/N (%) in Wks in Wks 115/124 (93) 0.8 0.7 114/119 (96) 7.3 9.3 9.9 0.7 76/84 (90) 7.4 0.6 95/100 (95) 7.3 10.2 HR: 0.45 (95% CI: 0.34–0.59) 0.6 0.5 Stratified log rank test: P < .0001 0.5 HR: 0.99 (95% CI: 0.73–1.36) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52 Weeks Weeks Amado et al., JCO 2008.
  • Amphiregulin/Epiregulin• EGFR ligands: – 1 in C. Elegans – 4 in Drosophila – 7 in mammals: EGF, TGF-α, HB- EGF, amphiregulin (AREG), betacellulin, epiregulin (EREG) and epigen1 – EREG and AREG bind more weakly to EGFR than EGF but much more potently and prolonged – EREG preferentially activates heterodimers2• High gene expression levels of EREG and AREG predict response to cetuximab3 – High levels define tumors that are EGFR-dependent? 1. Singh AB, et al. Cell Signal. 2005;17(10):1183-1193. 2. Shelly M, et al. J Biol Chem. 1998;273(17):10496-10505. 3. Khambata-Ford S, et al. J Clin Oncol. 2007;25(22):3230-3237,
  • EREG as a Predictive Marker for Cetuximab Efficacy • Combimarker: KRAS wildtype and high EREG – The right predictive test – High EREG predicts cetuximab benefit for OS High EREG by minimum-P threshold Low EREG by minimum-P threshold 100 100 Cetuximab + BSC Cetuximab + BSC 80 80Proportion Alive Proportion Alive 60 60 40 40 BSC alone BSC alone 20 20 HR 0.46 [0.32-0.65], P<.0001 HR 0.93 [0.51-1.71], P = .81 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 84 80 76 66 43 28 18 8 30 25 16 13 8 5 85 73 54 26 19 14 10 5 26 18 15 10 5 3 Time From Randomization, months Time From Randomization, months Jonker D, et al. J Clin Oncol. 2009;27(15S): Abstract 4016.
  • Combimarker: KRAS WildtypePLUS EREG High –All comers n = 394 (100%) HR: 0.7 –KRAS wildtype n = 230 (58%) HR: 0.55 –Combimarker n = 169 (44%) HR: 0.46Could use of the combimarker effectively “stack thedeck” to choose patients who would benefit fromcetuximab use in earlier lines of therapy?Jonker D, et al. J Clin Oncol. 2009;27(15S): Abstract 4016.
  • BRAF Mutations in CRC • BRAF is primary effector of EGF KRAS signaling Tumor Cell • BRAF mutations: – Occur most frequently in exon 15 (V600E) P P Ras – Found in 4% to 14% of patients with CRC P P Raf – Mutually exclusive with KRAS mutations MEK Tumor cell proliferation Erk and survivalYarden Y, et al. Nat Rev Mol Cell Biol. 2001; 2(2):127-137. Di Nicolantonio F, et al. J Clin Oncol. 2008; 26(35):5705-5712.Artale S, et al. J Clin Oncol. 2008;26(25):4217-4219..
  • CRYSTAL plus OPUS: Pooled analysis of OS in patients with KRAS wt/BRAF mt tumors 1.0 KRAS wt/BRAF wt HR [95% CI]: 0.840 [0.710–0.993] 0.9 p=0.041 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months 0.8 FOLFIRI / FOLFOX4: (n=381) median 21.1 months Probability of overall survival KRAS wt/BRAF mt 0.7 HR [95% CI]: 0.633 [0.378–1.060] p=0.079 0.6 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 14.1 months FOLFIRI / FOLFOX4: (n=38) median 9.9 months 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60Number of patients Time (months)CT + cetuximab 349 317 268 225 163 120 80 63 19 4 0CT 381 350 283 212 149 107 63 46 17 2 0CT + cetuximabCT 32 25 16 12 8 5 2 2 2 0 0 38 24 14 6 6 3 3 1 0 0 0Van Cutsem E, et al. N Engl J Med 2009;360:1408-17; Bokemeyer C, et al. J Clin Oncol 2009;27:663-71 HR, hazard ratio
  • Vemurafenib in V600E+ mCRC 100 75 1 PR and 4 MRs (≥10% shrinkage)%Change From Baseline 50 (Sum of Lesion Size) 25 0 -25 (RECIST cutoff for PR, 30%) -50 -75 -100 n=19 Evaluable Patients Interim - 12/31/09
  • Rationale for Combination BRAF/MEK RAS BRAF RR ~60 % GSK2118436 Key toxicity: SCC MEK GSK1120212 RR ~40 % Key toxicity: rash 1. Synergy in combination 2. Overcome/prevent potential BRAF resistance via activation of MAPK pathway pERK 3. Potentially decrease incidence of BRAFi-induced hyperproliferative skin lesionsProliferation, survival, Invasion, metastasisInfante ASCO 2011
  • BRAF plus MEK inhibitorsCorcoran ASCO 2012
  • EGFRi+BRAFi has in vivo activity on BRAFV600E mutant CRC xenograftsCorcoran RB et al, Cancer Discov 2012;2:227-35Prahallad A et al, Nature 2012;483:100-3
  • Met Pathway and Targeted AgentsAppleman (2011) JCO ePub 18
  • Activity of Tivantinib (ARQ197) + cetuximab/irinotecan Median # prior therapies: 2 (range 1-4) 19Eng et al. ASCOGI 2011
  • GI155 - ACCOMPLISH Schema &Regimen Schema Regimen Drug Induction Regimen Maintenance Regimen MetMAb (or 10 mg/kg IV Day 1 10 mg/kg IV Day 1 placebo) Bevacizumab 5 mg/kg IV Day 1 5 mg/kg IV Day 1 Oxaliplatin 85 mg/m2 IV Day 1 Discontinued Leucovorin 400 mg/m2 IV Day 1 400 mg/m2 IV Day 1 400 mg/m2 IV bolus 400 mg/m2 IV bolus then 5-FU then 2400 mg/m2 over 2400 mg/m2 over 46 hours 46 hours starting Day 1 starting Day 1 a Objective response or stable SD after 4 cycles – mFOLFOX-6 continued for a further 4 cycles; b Patients with measurable disease in lesions between cycles 4 and 8 may elect to continue treatment for a maximum of 12 cycles prior to commencing maintenance treatment if in the best interests of the patient and after consultation with the Study Chair; c Objective response or SD at cycle 8 – commence maintenance treatment.
  • Immune-Modulating Therapies• Immune system contains receptor-ligand pairs that inhibit or stimulate immune response• Balance necessary to fight infections but not develop autoimmunity Infection-fighting Autoimmunity
  • PD-1 and PD-1-Like Inhibitors Tumor cell T cell B7H1/B7DC PD1 3. 4. 2. B7-CD28 family B7-1/B7-2 CTLA-4 1. B7H3 ? 5. TNFR/ligand family CD27L CD27 6.1. FDA-approved Ipilimumab2. Monoclonal antibody that targets PD1 (receptor)3. Recombinant fusion protein of B7DC (PD-L2 ligand), targets PD14. Monoclonal antibody that targets B7H1 (PD-L1 ligand)5. Monoclonal antibody that targets B7H3 ligand6. Agonist anti-CD27 monoclonal antibody
  • Immunotherapy: PD-1 Inhibitor Suppressive/dysfunctional T cells are Tumor present in tumors CD8+PD-1+ PD-1 inhibitor CD8+PD-1- 1. Functional anti-tumor response with CD8+PD-1- T cells infiltrate and kill tumor cells. 2. T cell memory is established What about combinations? Bevacizumab?
  • Genomic Landscape of CRC… 2006 PIK3CA FBXW7 TP53 Facts: 11 colorectal tumors First Generation Sequencing KRAS 13,023 genes APC 21 Mb target sequence 135,483 primer pairs ~90 mutated genes/tumor 11 recurrent mutations/tumor The List of Candidate Genes: Total 142 Usual suspects APC, KRAS, PIK3CA, PTEN, SMAD4, TGFBR2, TP53…Wood L et al, Science (2007); Sjoblom T et al, Science (2006)
  • Genomic Landscape of CRC… 2012 16% 84% Facts: 224 T/N pairs Next-Generation Sequencing – Whole Exome Seq >20X coverage 32 somatic recurrent mutations per tumorCancer Genome Atlas Network, Nature (2012)
  • Molecular Classification of CRC… 2012 Right-sided, MSI-H, Hypermethylated, BRAF mut, Chromosomal stability Left-sided, Rectal, MSS, KRAS mut, CIN +veCancer Genome Atlas Network, Nature (2012)
  • CRC subtypes – dMMR/EMT… 2013 A-type B-type C-type 22% 62% 17% BRAFmt 39% BRAFmt 2% BRAFmt 13% MSI 49% MSS 87% MSI 13% dMMR 68% dMMR 1% dMMR 36% Adj Rx + Adj Rx + Adj Rx -
  • Molecular Profiling and Matched Targeted Agents in Colorectal Cancer Patients enrolled in Phase I trials BRAF inh BRAF mut mTOR inh + anti-IGFR1 mAb PTEN low 3 5 anti-HGF mAb pMET high 10 42 PI3K pathway inh Second-generation 11 PIK3CA mut or PTEN low anti-EGFR mAb KRAS wt refractory to cetuximab/panitumumab 11Dienstmann et al. Mol Cancer Ther. 2012;11:2062-71.
  • There is so much more tocome…• We are learning at an exponential rate• We finally have drugs to hit the right targets• And the targets may change over time• We are learning more about specific colorectal tumors – Are there people more at risk? – Location of the tumor, etc• Clinical trials are essential to ending this disease