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Novel Targets and Therapies for GI Malignancies: What does the future hold?

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  1. Novel Targets and Therapies for GI Malignancies: What does the future hold? David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY

  2. GI Cancers: US Incidence in 2013 • 292,200 new cases and 144,570 deaths (49%) • Case Fatality Rate: • Colorectal: 48% • Esophagogastric: 66% • Pancreatic: 85% • HCC: 70% • Male > Female • Ongoing rise in Esophageal and GEJ Adenocarcinoma, HCC Siegel et al, CA 63: 11-30; 2013

  3. Gene Amplification more Common in Esophagogastric Cancer • 296 Esophageal / Gastric Cancers, 190 CRC • Amplified genes in 37% Gas / Eso tumors • FGFR1-2 • HER2 • EGFR • MET • Targetable Receptors and Receptor Tyrosine Kinases • KRAS also amplified • Similar data for a Chinese series Dulak AM et al Can Res 72: 4383; 2012

  4. Molecular Targets: Esophageal and Gastric Cancer • KRAS mutation: <5% • BRAF mutation: <5% • EGFr mutation: <5% • HER2 over expression / amplification: 10% to 25% • Trastuzumab + chemo improves OS in HER2+ disease • CMET amplification: 10% • IHC over expression 40% Dulak AM, et al. Cancer Res. 2012;72(17):4383-4393. Dulak AM, et al. Nat Genet. 2013;45(5):478-486. Lordick F, et al. Lancet Oncol. 2013;14(6):490-499. Bang YJ, et al. Lancet. 2010;376(9742):687-697.

  5. ToGA Trial Design Phase III, randomized, open-label, international, multicenter study 5FU or capecitabine + cisplatin (n = 290) 3807 patients screened 810 HER2-positive (22.1%) HER2-positiveadvanced GC (n = 584) R 5FU or capecitabine + cisplatin + trastuzumab (n = 294) • Stratification factors • Advanced vs metastatic • GC vs GEJ • Measurable vs nonmeasurable • ECOG PS 0-1 vs 2 • Capecitabine vs 5-FU Bang Y, et al. Lancet. 2010;376(9742):687-697

  6. ToGA: Efficacy Outcome • Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC • Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-month increase in OS with trastuzumab • HR: 0.65 (95% CI: 0.51-0.83) ORR, overall response rate Bang Y, et al. Lancet. 2010;376(9742):687-697.

  7. Targeted Agents Phase III: HER2: Met Disease • LOGIC: Cape-Ox + / - Lapatinib (HER2+) • First line • Negative trial for OS • Benefit in Asian pts • TYTAN: Paclitaxel + / - Lapatinib (HER2+) • Second Line: Negative Trial • PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001 Bang et al GI Cancers Symposium 2013 Abstract 11

  8. CHEMORADIATION SURGERY RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) HER-2 (+) (FISH) TRASTUZUMAB + CHEMORADIATION SURGERY + TRASTUZUMAB (1 YR) HER-2 (-) (FISH) ALTERNATIVE STUDIES • Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy  Surgery • Maintenance trastuzumab post op • OS Primary Endpoint

  9. HER2-Directed Therapy Trials • Ongoing HER2 Trials • First-line • JACOB: Cape-Cis-Trastuzumab + / - Pertuzumab, 780 patients • HELOISE: Cape-Cis + 2 dose levels of Trastuzumab, 400 patients • Second-line: • GATSBY: Paclitaxel vs TDM-1

  10. Large molecule VEGF inhibitors PlGF VEGF-B VEGF-C, VEGF-D VEGF-A Y Bevacizumab Ramucirumab Y Aflibercept (VEGF Trap) VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangio- genesis Functions

  11. Targeted Agents Phase III: Negative Trials for VEGF, mTOR, and EGFr • AVAGAST: Cape-Cisplatin + / - Bevacizumab • Negative trial for OS • mTOR GRANITE: BSC vs Everolimus • Negative trial for OS • REAL 3: ECX + / - Panitumumab (U.K.) • Negative: Panitumumab had inferior outcomes • EXPAND: Cape-Cis + / Cetuximab (E.U.) • Negative: Cetuximab trended inferior • COG: BSC vs Gefitinib (U.K.): Negative Ohtsu A, et al. J Clin Oncol. 2011;29(30):3968-3976 Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943 Waddell T Lance Oncol 14: 481; 2013 Lordick F et al Lancet 14:490; 2013 Sutton JCO 30: 2012 (suppl 34 abstr 6)

  12. EGFr: Definitive Cetuximab + Chemo RT • SCOPE-1 • Cape-Cis  Cape-Cis-RT + / - RT • 258 pts (65 AC,188 SCC) • RTOG 0436 • Pac-Cis-RT + / - Cetuximab • 328 pts (203 AC,125 SCC) Crosby Lancet 14: 627; 2013 Suntha JCO 32: 2014 (suppl 3; abstr LBA6

  13. VEGF Revisited? • Apatinib • Small-molecule multitargeted TKI with activity against VEGFR • China • 144 patients, placebo vs 850 mg/d or 425 mg BID • OS 2.5 months  4.0 months, 4.5 months • RR 10% • Phase III Trial Planned • Ramucirumab: Humanized moAb Targeting VEGr2 receptor TKI, tyrosine kinase inhibitor; VEGFR, VEGF receptor Li J, et al. J Clin Oncol. 2013;31(26):3219-3225. Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

  14. VEGFr: Ramucirumab in Gastric Cancer: REGARD Trial Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo RANDOMIZATION, 355 patients BSC + Ramucirumab 8 mg/kg q 2 weeks BSC + Placebo Fuchs CS, et al. Lancet. 2014;383(9911):31-39

  15. VEGF Revisited? Ramucirumab: REGARD Trial • PFS improved 2.1 months  3.8 months (HR 0.483, P<.0001) • OS improved 3.8 months  5.2 months (HR 0.776, P = .047) • Disease control improved from 23% to 49% (P<.0001) • Essentially no toxicity (rare grade ≥3 hypertension 8%) Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

  16. REGARD Trial: Results 100 Ramucirumab (n = 238) Placebo (n = 117) Censored OS, % 80 60 HR (95% CI) = 0.776 (0.603-0.998) Log-rank P value (stratified) =.047 OS PFS 40 20 Ramucirumab (n = 238) Placebo (n = 117) Censored 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28 Number at risk Ramucirumab Placebo 238 117 154 66 92 34 49 20 17 7 7 4 3 2 0 1 0 0 100 PFS, % 80 60 HR (95% CI) = 0.483 (0.376-0.620) Log-rank P value (stratified) <.0001 40 20 Time Since Randomization, Months Time Since Randomization, Months 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Number at risk Ramucirumab Placebo 238 117 213 92 113 27 65 11 61 7 45 4 30 2 18 2 18 2 11 2 5 2 4 1 2 1 1 0 1 0 1 0 1 0 0 0 Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

  17. VEGFr: RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2day 1,8 &15 of a 28-day cycle N = 330 R A N D O M I Z E Treat until disease progression or intolerable toxicity Survival and safety follow-up S C R E EN Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 • Important inclusion criteria: • - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma • - Progression after 1st line platinum/fluoropyrimidine based chemotherapy • Stratification factors: • - Geographic region, • - Measurable vs non-measurable disease, • - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) Wilke GI Symposium 2014 LBA 7

  18. RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer • 665 pts with POD on fluorinated pyrimidine + platinum • Weekly paclitaxel 80 mg/m2 + /- Ram 8 mg/kg • PFS improved 2.9 months  4.4 months (HR 0.635, P<.0001) • OS improved 7.4 months  9.6 months (HR 0.807, P = .0169) • RR improved from 16% to 28% (p = 0.0010 (P<.0001) • Increased toxicity neutropenia and hypertension Wilke GI Symposium 2014 LBA 7

  19. Ramucirumab • First-line: FOLFOX + / - Ramucirumab • Randomized phase II • Other VEGF agents • FOLFOX + / - Pazopanib (TKI)

  20. VEGF Adjuvant Trials Gastric Cancer • MAGIC 2 Trial: EOX + / - Bevacizumab • Amended for HER2 + patients • Randomized to + / - Lapatinib (HER1-2 TKI)

  21. CMET Pathway Goyal L, et al. Clin Cancer Res. 2013;19(9):2310-2318.

  22. CMET: Rilotumumab: Gastric Cancer First Line Phase II ARM A Rilotumumab (15 mg/kg) + ECX Q3W (n = 40) RANDOMIZE ARM B Rilotumumab (7.5 mg/kg) + ECX Q3W (n = 40) ARM C Placebo + ECX Q3W (n = 40) Stratification factors: ECOG PS 0 vs 1 LA vs Metastatic E: Epirubicin: 50 mg/m2 IV, day 1 C: Cisplatin: 60 mg/m2 IV, day 1 X: Capecitabine: 625 mg/m2 BID orally, days 1-2 Rilotumumab: IV over 60 ± 10 minutes prior to chemotherapy ClinicalTrials.gov identifier: NCT00719550Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

  23. PFS and OS in c-MetHigh Patients Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

  24. Ongoing Trials: Met Inhibitors • Targeting CMET, + IHC • RILOMET-1 • ECX + / - Rilotumumab (targeting ligand HGF) • MetGastric • FOLFOX + / - MetMab (targeting receptor) • Tyrosine Kinase Inhibitors • Promising phase I activity in CMET amplified

  25. Fibroblast growth factor receptor • Ligand activated trans membrane growth factor receptor • Signals via RAS  Map kinase and PI3K-AKT but also via Hedgehog and Notch pathways, and WNT • Phase II Trials • Dovitinib (TKI) in FGFR gene amplified gastric cancer • Dovitinib + Docetaxel in gastric cancer

  26. PARP Inhibitors: Olaparib in Gastric Cancer Gastric/GEJ Cancer with POD on FP RANDOMIZATION: Paclitaxel + Olaparinib Paclitaxel Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

  27. PARP Inhibition in Gastric Cancer: Olaparib • Patients randomized to Paclitaxel + / Olaparib • Tissue testing for ATM protein • Negative in13% = In vitro sensitivity to olaparib • 124 patients randomized, ATM + / - • OS benefit in ATM + / -, Greater in ATM – • Phase III Trial planned Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

  28. Trials of Targeted Agents

  29. Esophagogastric Cancer: Immunotherapies • Agents that deregulate immune suppression • Anti PD-1 phase I: • PD-1: T cell programmed cell death receptor, blockade may enhance immune responses • Active in NSCLC, RCC • 7 gastric cancers, no activity • Anti PDL-1 phase I • MPDL3280A: Blocks ligand • PR in 1/1 Gastric Cancer, 26/29 responses ongoing • Enhanced activity in PDL-1 + patients • Ipilimumab • Anti CTLA-4 antibody • Phase II • FOLFOX  capecitabine maintenance vs ipilumimab Ribas A, et al. N Eng J Med. 2012;366:2443 Herbst R et al. JCO 31 (supp): Abstract 3000

  30. HCC: Sorafenib is the Standard for Advanced Disease SHARP TRIAL ASIA PACIFIC TRIAL OS 7.9  10.7 months, HR 0.69 OS 4.5  6.2 months, HR 0.68 Llovet NEJM 359: 378; 2008 Chang Lancet Oncol 10:25; 2009

  31. Sorafenib in HCC Modest single agent activity in Child’s A pts with HCC Toxicity monitoring and dose reduction are key Outcomes vary depending on geographic region, etiology and severity of cirrhosis No biomarker has been identified

  32. Failed Phase III Trials Sorafenib OS consistently 8.5-10 months

  33. Ongoing Single Agent Studies • Angiogenesis: • Ramucirumab, TSU-68, Cedirinab, Pazopanib, lenvatinib, Axitinib • CMET: • Tivantinib, cabozantinib, foretinib, METmab, IMC-280, LY2875358 • EGFR: • Lapatinib, cetuximab • mTOR: • Everolimus, temsirolimus, sirolimus, CC-23

  34. Ongoing Single Agent Studies • MEK • Selumetinib, rafametinib • HDAC • Belinostat, resminostat • HSP-90 • Genetespib • Oncolytic viruses • JX-594 • Immunotherapy • Tremelimumab, PD-1, PD-L1

  35. CMET Targeted Therapy in HCC OS CMET High • Tivantinib vs Placebo in HCC • CMET TKI • 107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib • 160 mg tivantinib vs placebo • Cross over permitted at POD • TTP HR 0.64, p = 0.04 • OS not different, given cross over (6.2-6.6 months) • CMET IHC low, better prognosis, no benefit from tivantinib • CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib • Phase III Trial planned in CMET high pts Santoro Lancet Oncol 14: 55; 2013

  36. CMET Targeted Therapy in HCC • Cabozantinib vs Placebo in HCC (4007) • CMET and VEGR2 TKI, most patients failed sorafenib • 107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib • 100 mg cabozantinib, stable disease randomized to placebo or continuation • Cross over permitted at POD • 41 treated • PFS 4.4 mos, OS 15 mos in all pts • RR 5%, Stable disease 78% • Larger phase II trial planned Verslype et alJ Clin Oncol 30: 2012 (suppl Abst 4007)

  37. Promising Signals • Ramucirumab • Anti VEGFr2 • RR 10%, PFS 4 months, OS 12 months • Lenvatinib • VEGFr1-3, FGFr1-4, RET, KIT, PDGFrβ TKI • 37% modified RECIST response rate • TTP 12.8 months, OS 18.7 months • Immunotherapy • Anti CTLA-4 • RR 17%, PFS 6 months

  38. Ongoing Trials • First Line • Sorafenib vs Sorafenib + Doxorubicin (CALGB 80802) • Lenvantinib vs Sorafenib • Sorafenib + Local Regional Therapy • Sorafenib + / - SBRT (RTOG 1112) • Sorafenib + / - TACE (ECOG) • Sorafenib vs Y90 • Second Line • Ramucirumab vs BSC • ADI-PEG 20 vs BSC • Tivantinib and Cabozantinib vs BSC • Regorafenib vs BSC

  39. Pancreatic Cancer • Improvements in Chemotherapy • Gemcitabine  G + Nab-Paclitaxel  FOLFIRINOX • OS 6 months  8.5 months  11.1 months • Response: 6%  23%  32% • Targeted Agents • Only approved agent is EGFr TKI Erlotinib

  40. Gemcitabine + Erlotinib R A N D O M I Z E Gemcitabine + Placebo NCI PA.3 Phase III TrialUntreated Advanced Pancreas Ca Stratify N= 569 • LA vs M1 • Center • PS 0-1 vs 2 Primary Enpoint OS 80% power, 33% increase Moore, et al. J Clin Oncol, 2007

  41. 1.00 0.75 Survival Distribution Function 0.50 0.25 0 0 6 12 18 24 Months PA.3 Overall Survival HR= 0.82 (0.69-0.99) p= 0.038 *Adjusted for PS and extent of disease at baseline † From Cox regression model ‡ From 2-sided log-rank test Moore, et al. J Clin Oncol, 2007

  42. Molecular CorrelatesGemcitabine +/- Erlotinib PA.3 • N= 569 pts – 117 samples (21%) • EGFR (+) or (–) no correlation with outcome • Post-hoc K-ras mutational status analysisTrend to OS benefit in the pts with wild-type K-ras Moore, et al. ASCO, 2007 (Abst #4521)

  43. Genetic Alterations in Pancreatic Ca Other Genetic Changes Gene Mutation/ Deletion • p16 80% • K-ras (B-raf) 90%+ • p53 70% • SMAD4/ TGFβR1+2 55% • BRCA 1, 2, PALB2 5-8% • Mismatch repair genes 4% • STK11 (Peutz-Jeghers) 5% • MKK4 5-13% • FANCC/ FANCG 5% Amplification/ Overexpression • PI3K/ Akt, c-myc, Shh/ Gli, Notch, etc (10-30%) • Telomere shortening • Widespread allelic loss Infiltrating pancreatic ca Courtesy, M. Goggins (JHCC)

  44. NegativePhase III Anti-Vascular Trials in PC Kindler, HJ. J Clin Oncol, 2010. Van Cutsem, E. J Clin Oncol, 2009. Kindler, HJ. Lancet Oncology, 2011. Rougier, P. ESMO, GI, 2010

  45. New Targets, New Drugs

  46. Phase II: GVAX + / - CRS-207 • GVAX: Irradiated, GM-CSF secreting allogeneic pancreatic cancer cell lines given intradermally, preceded by Cytoxan to reduce T regs • CRS-207: Live-attenuated Listeria monocytogenes which expresses mesothelin  immune stimulant • 90 pts previous treated randomized 2: 1 to C/GVAX + CRS-207 or C/GVAX alone • OS 6.1 vs 3.9 months (HR 0.54, p = 0.011) • More CA 19-9 stabilization with combination Le J Clin Oncol 32: 2014 (suppl 3; abstr 177)

  47. Recent Negative Phase II-III Targeted Therapy

  48. Novel Targets • Stroma and Microenvironment • PEGPH20: degrades hyaluronic acic, may increase drug delivery • Onoing phase II: • Nab-P + / - PEGPH20 • FOLFIRINOX + / - PEGPH20 • BRCA mutant pancreatic cancers (5%) • Deficient homologous DS DNA repair • Results in genomic instability, chromosomal deletion and exchange • PARP inhibition • Cis-Gem + / Veliparib, randomized phase II