I Progressi dell’Oncologia Medica Le terapie a bersaglio molecolare Colon Carlo Garufi Direttore UOC Oncologia Medica ASL Pescara Napoli, 20 maggio2016

Welch HG, Robertson DJ. N Engl J Med 2016;374: Colorectal-Cancer Mortality (Top) and Stage-Specific Incidence (Bottom) among People 50 Years of Age or Older in the United States, 1975–2012.

Clin Colorectal Cancer 2015 Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer

The New Agents Agents Aflibercept Regorafenib Ramucirumab TAS102 Trastuzumab Setting II line ≥ III line Not yet available Activity demnstrated No new agents in first line therapy since 2010

Overall Survival in mCRC - Phase III Studies Kopetzt al, J Clin Oncol 2009 (modified) Irinotecan Oxaliplatin Bevacizumab Cetuximab Panitumumab 5FU/AF5FU bolus >30 FIRE CAIRO C CRYSTAL 28,4 TRIBE 31.0 CALGB 32.0 >30 FIRE CAIRO C CRYSTAL 28,4 TRIBE 31.0 CALGB Terapia personalizzata

Le Terapie a bersaglio Molecolare: Colon Cosa abbiamo imparato? Cosa non ha funzionato? Vi sono nuovi e validi bersagli? La terapia immunologica è una “terapia target”?

Saltz L. et al NEJM, 2000 De Gramont A. et al JCO 2000 Giacchetti S. et al, JCO 2000 Douillard JY. et al The Lancet 2000 Trials di polichemioterapia vs monochemioterapia: Sopravvivenza 12.6 vs 14.8 m 14.1 vs 17.4 m

ADJUVANT: OXA-based vs IRI-based MOSAIC FOLFOX NSABP C-07 FLOX NO16968 XELOX CALGB IFL ACCORD 02 FOLFIRI PETACC-3 FOLFIRI 3 0

ADJUVANT THEREPY: THE RESULTS OF BIOLOGICS BEVACIZUMAB - C-08 Negative - AVANT Negative - Quasar 2 Closed CETUXIMAB - NO 147 Negative - PETACC 8 Negative

Ciardiello et al., ASCO 2014 Popolazione RAS wtCRYSTAL Δ = + 8,2 mesi Mesi FOLFIRI + Cetuximab (n=130) FOLFIRI (n=154) Probability of OS RAS: selezione del paziente HR=0.69 p=0.0024

CALGB / SWOG 80405

Dominik P. Modest et al. JCO 2015;33: Impatto delle II linee nel FIRE-3

BEV + FOLFIRI (n=110) Randomise 1:1 Irinotecan/ CETUXIMAB FOLFOX PD COMETS study design Study conducted in 11 centres in Italy Primary endpointProgression-free survival (PFS) Secondary endpointsOverall survival (OS) from randomisation; PFS 2° and 3°line; Overall response rate Safety FOLFOX Irinotecan/ CETUXIMAB Clinicaltrials.gov: NCT Research Funding Source: AIFA (Agenzia Italiana del Farmaco) Code FARM 6XB38F 101 events were required to achieve a power of 80% of detecting a HR of 0.57 in favour of one of the two sequences, translating in an increase of median overall PFS from 4 to 7 months, with a type I error of 5%, two- sided, using the Mantel-Cox version of the log-rank test. 110 assessable patients were needed to reach the target number of events. PFS

Months Progression of Survival ARM A ARM B Patients at Risk Events ARM A ARM B Totals 52 X 2 (log-rank)= (p=0-585)  Cascinu S. et al ASCO 2015 COMETS study: PFS

Studio SPIRITT Phase II, multicenter, open-label, randomized, 2-arm study designed to estimate the treatment effect of panitumumab* + FOLFIRI vs bevacizumab* + FOLFIRI in wild type KRAS mCRC pts whose disease progressed during a first-line bevacizumab* + oxaliplatin-based chemotherapy. No major differences between the panitumumab* and bevacizumab* arms in terms of OS and PFS Clinical Colorectal Cancer, Vol. 14, No. 2,

Studies of interest in relation to potential utility of 1 st -line panitumumab + FOLFIRI in mCRC Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7; Douillard J-Y, et al. N Engl J Med 2013;369:1023−34; Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P); Karthaus M et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P); Peeters M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster); Price TJ, et al. Lancet Oncol 2014;15:569−79; Van Cutsem E, et al. J Clin Oncol 2015;33:692−700. PRIME 1 st -line: FOLFOX + Pmab vs FOLFOX (Phase 3) n = 1183 PEAK 1 st -line: FOLFOX + Pmab or Bev (Phase 2) n = 285 PLANET 1 st -line: FOLFIRI + Pmab vs FOLFOX + Pmab (Phase 2 LLD) n = 77 Study st -line: FOLFIRI + Pmab (Phase 2, single arm) n = 154 Study nd -line: FOLFIRI + Pmab vs FOLFIRI (Phase 3) n = 1186 ASPECCT 3 rd -line: Cmab vs Pmab (Phase 3) n = 999 CRYSTAL 1 st -line: FOLFIRI + Cmab vs FOLFIRI (Phase 3) n = st -line panitumumab + FOLFIRI in mCRC Safety/efficacy of FOLFOX combination Safety/efficacy with FOLFOX & FOLFIRI Safety/efficacy of 1 st -line FOLFIRI combination Safety/efficacy of 2 nd -line FOLFIRI combination Biological plausibility FF0030

EGFR activation may involve downstream signalling pathways that include RAS proteins Berg M, Soreide K. Discov Med 2012;14:207−14; Di Fiore F, et al. Br J Cancer 2010;103:1765−72; Han W, Lo HW. Cancer Lett 2012;318:124−34; Herbst RS, Shin DM. Cancer 2002;94:1593−611. EGFR homodimer RAS GTP RAS GDP RAF MEK ERK Elk Myc JNK Jun JNKK PAK Nck Rac PLCγ PKC PTEN PI3K S6K AKT mTOR ProliferationAnti-apoptosisSurvivalAngiogenesisMetastasis Fos EGF TGF-α EGFR EGFR EGF FF0004

Ahn DH & Goldberg RM, Future Oncology 2016

Vauthey JN et al. Ann Surg 2013

Garufi C et al. Br J Cancer 2010 Tumor shrinkage

68.6 % 15.4 % 42.9 % 80.8 % p=0.001 chir No chir 88.5 % 71.4 % POCHER Study - Update analysis 3-yrs OS Garufi C. 2012

Relevant Resection Trials in CRC PhaseRegimenEnd-Point BOS2resectableR-ph II n= 300FOLFOX vs FOLFOX + BEVA FOLFOX + Pmab peri PFS NSABP C-11resectableR-ph III n= 670FOLFOX/FOLFIRI Post vs peri RFS PANTERresectableR-ph III n= 430FOLFOX + Cmab Post vs peri DFS EXPERTresctableR-ph III n= 500FOLFOX + Cmab Peri vs FOLFOX post PFS ATOMunresectableR-ph II n= 180FOLFOX + Cmab vs FOLFOX + Beva PFS OLIVIAunresectableR-ph II n= 80FOLFOX + BEVA vs FOLFOX IRI+ Beva Resection Rate CELIM-2unresectableR-ph II n= 232FOLFIRI + Cmab vs FOLFOXIRI + Cmab Resection Rate POCHER-2unresectableR-ph II n= 300FOLFOX+ Cmab vs FOLFOXIRI + Cmab Resection Rate

Falcone A et al. JCO 2007;25: Cremolini et al, ASCO GI ‘15 FOLFIRI + bev: N = 256 / Died = 200 FOLFOXIRI + bev: N = 252 / Died = 174 FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 29.8 mos HR: 0.80 [ ] p=0.030

Clarcke JM, Expert Opin. Biol.Ther Critical mediators of angiogenesis

La Risposta Patologica Completa: 4%-10%

IFN Infart-Like Necrosis Li Chang HH et al. Am J Surg Pathol 36: , 2012; B ibeau F. et al BJC 109: , 2013

Overall survival curves by the degree of pathological response. Blazer D G et al. JCO 2008;26: ©2008 by American Society of Clinical Oncology

LB, n : k colon con metastasi epatiche sincrone; kras mutato Valutazione prima del trattamento con FOLFIRI + Bevacizumab

LB, n : k colon con metastasi epatiche sincrone; kras mutato Valutazione dopo tre mesi di trattamento con FOLFIRI + Bevacizumab

Cortesia della dr.ssa Maria Grazia Diodoro, Anat. Patologica IRE

Le Terapie a bersaglio Molecolare: Colon Cosa abbiamo imparato? Cosa non ha funzionato? Vi sono nuovi e validi bersagli? La terapia immunologica è una “terapia target”?

Guinney J et al, Nature Medicine 2015

Boland CR and Goel A, Gastroenterology 2010

The two molecular pathways involved in the development of CRC with MSI Boland CR and Goel A, Gastroenterology 2010

MSI testing algorithm proposed in 2012 by the Association for Molecular Pathology. Jonathan C. Dudley et al. Clin Cancer Res 2016;22: ©2016 by American Association for Cancer Research

Lawrence et al, Nature 2013 Somatic variations in 3083 tumor pairs

a mutation rate >12 per 10 6 (median number of total mutations, 728) mutation rate <8.24 per 10 6 (median number of non-silent mutations, 58) Hypermutated tumorsNon - Hypermutated tumors CANCER GENOME ATLAS NETWORK Nature 2012 Overall, 32 recurrent somatic mutated genes were identified 15 hypermutated CRC 17 non-hypermutated CRC

Immunity.Immunity Mar 15;44(3): doi: /j.immuni Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability.

Conclusioni Non diamo mai nulla per scontato: I vs II linea, adiuvante vs avanzato, etc Il primo trattamento è quello che conta, l’impatto delle seconde linee è meno rilevante di quello che sembra (scegliamo la prima linea e non abbandoniamola finché non siamo sicuri di una franca, chiara, documentata progressione) La nuova classificazione molecolare del cancro del colon forse ci permetterà di colpire meglio nuovi e vecchi target I pazienti MSI-instabili sono il nuovo target per l’immunoterapia

Tha Cancer Moonshot ”we can do this for the loved ones we've lost -- and the families we can still save.” B. Obama Jan 1, 2016