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“Enfermedad limitada al hígado en cáncer colorrectal metastásico RAS WT: ¿qué aporta Panitumumab?”. Dr. Carles Pericay Pijaume Oncología Médica, Hospital.

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Presentation on theme: "“Enfermedad limitada al hígado en cáncer colorrectal metastásico RAS WT: ¿qué aporta Panitumumab?”. Dr. Carles Pericay Pijaume Oncología Médica, Hospital."— Presentation transcript:

1 “Enfermedad limitada al hígado en cáncer colorrectal metastásico RAS WT: ¿qué aporta Panitumumab?”. Dr. Carles Pericay Pijaume Oncología Médica, Hospital Universitari de Sabadell, Corporació Sanitària Parc Taulí (Sabadell) Madrid, 12 de Febrero de 2015

2 CRC liver metastases are common and predict a poor prognosis if untreated 1. Ferlay J et al. Eur J Cancer. 2013;49(6):1374–403; 2. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99. CRC, colorectal cancer. In 2012, CRC was the 2 nd most common cancer in Europe: 1 –447,000 new cases –215,000 deaths ~ 50% of CRC patients develop liver metastases 2 –Liver metastases responsible for 2/3 of CRC patient deaths 2 0-6% 5 year survival for untreated CRC liver metastases 3

3 Resection of liver metastases improves survival Simmonds PC et al. Br J Cancer. 2006;94(7):982–99 Error bars indicate range R0 resected (16 studies) Median 5-year survival, % Resected, R0/R1 unclear (19 studies) Non-radical resection (11 studies) Not resected (6 studies) 30% 32% 7% 0% Surgical series published after 1980

4 Current definition of liver metastases resectability 1. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 2. Spolverato G et al. World J Gastrointest Oncol. 2013;5(12):207–21; 3. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 4. Adams RB et al. HPB. 2013;15(2):91–103; 5. Adam R et al. Oncologist. 2012;17(10):1225–39; 6. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer [v ]. (accessed 20/02/2014). FLR, functional liver remnant; R0, resection with microscopically negative margins NCCN Guidelines criteria for resection suitability 6 “... the likelihood of achieving complete resection of all evident disease with negative surgical margins and maintaining adequate liver reserve” The criteria for liver metastasis resectability have not been standardized 1-3 Medical fitness for surgery Resectability 1-5 Oncological considerations Technical considerations e.g. Resectable extrahepatic disease Number of lesions ≥ 5 Tumour progression e.g. R0 with ≥ 25%–30% FLR Complex procedure

5 Yes ESMO 2012 Clinical Guidelines Stratification of mCRC patients for 1st-line treatment Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516 CT, chemotherapy; R0, resection with microscopically negative margins. Initially R0 resectable Potentially R0 resectable with CT & patient can tolerate CT and surgery Yes Group 0 Group 1 No Symptomatic or aggressive disease No Far advanced/bulky disease Group 2 Metastatic colorectal cancer Patient can tolerate CT Group 3 No Yes

6 mCRC patient distribution between ESMO guideline first-line treatment stratification groups Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45. *Some patients may become resectable following exceptional response to treatment. CT, chemotherapy; R0, resection with microscopically negative margins. Group 2*Group 1 Group 3 Group 0 Initially R0 resectable Metastatic colorectal cancer Non-resectable at clinical presentation ~15% 1,2 ~85% 1,2 Potentially resectable 10-30% % 2 Never resectable

7 mCRC patient distribution between ESMO guideline first-line treatment stratification groups Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45. *Some patients may become resectable following exceptional response to treatment. CT, chemotherapy; R0, resection with microscopically negative margins. Group 2*Group 1 Group 3 Group 0 Initially R0 resectable Metastatic colorectal cancer Non-resectable at clinical presentation ~15% 1,2 ~85% 1,2 Potentially resectable 10-30% % 2 Never resectable

8 What is conversion chemotherapy? 1. Adam R, et al. Oncologist 2012;17:1225–39; 2. Nordlinger B, Benoist S. J Clin Oncol 2006;24:4954–5; 3. Nordlinger B, et al. Clin Colorectal Cancer 2010;9:212–8; 4. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516. *Chemotherapy to convert unresectable liver metastases to resectable. Conversion chemotherapy* Resection mCRC with initially non-resectable liver metastases Tumour shrinkage

9 Conversion CT + surgery for treatment of mCRC with unresectable liver metastases Adam R, et al. J Clin Oncol 2009; 27: *Last preoperative regimen, FL (18%), FOLFOX (62%), FOLFIRI (6%), FOLFOXIRI (9%), Other (5%) Minimum follow-up 5 years Response evaluated every 2 months mCRC with unresectable liver metastases (n = 184) Conversion chemotherapy* Surgery Study objectives: evaluation of possibility of cure, determination of predictive factors of disease cure F O L L O W - U P Single centre study of consecutive patients

10 An oncosurgical approach offers the chance of cure to a subgroup of initially non-resectable patients Adam R, et al. J Clin Oncol 2009; 27: Cure = disease-free ≥ 5 years after last hepatectomy / last resection of extrahepatic metastases; CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival Time (years) 796 Survival probability % 19% 27% 15% OS(n = 184) DFS(n = 184) 1 10-year survival5-year survival Cure was achieved in 16% of CRC patients with liver metastases who became eligible for surgery after response to conversion chemotherapy

11 Response to CT correlates with liver resectability Folprecht G, et al. Ann Oncol 2005;16:1311–9. CT, chemotherapy Rate of liver resection following CT Selected patients, r = 0.96 P = Non-selected patients, r = 0.74 P < Phase III trial data, r = 0.67 P = Patient selection and efficacy of pre-operative CT were strong predictors for resectability of liver metastases Resection rate 0.9 Response rate

12 NO16966: BEV + CT significantly improves PFS but not RR or OS in combination with XELOX/FOLFOX4 (ITT) Response rate (%) Placebo + FOLFOX4/XELOX BEV + FOLFOX4/XELOX 38 p=0.99 Months RR Response rate (%) Placebo + IFL BEV + IFL p=0.004 RR AVF2107g: Bevacizumab significantly improves RR, PFS and OS in combination with IFL (ITT)

13 CRYSTAL: Cetuximab + FOLFIRI significantly improves RR, PFS and OS vs FOLFIRI (KRAS wt) Response rate (%) FOLFIRI Cetuximab + FOLFIRI p<0.001 RR OPUS: Cetuximab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt) Response rate (%) FOLFOX4 Cetuximab + FOLFOX p= RR

14 PRIME: Panitumumab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt) Response rate (%) FOLFOX Pani + FOLFOX p=0.018 RR

15 CRYSTAL y OPUS (KRAS WT) nRR (%)R0 resections (%) CRYSTAL FOLFIRI + ERBITUX FOLFIRI p< p=0.03 OPUS FOLFOX + ERBITUX FOLFOX p< p=0.22 FOLFIRI + ERBITUX FOLFIRI p= p=0.15 FOLFOX + ERBITUX FOLFOX p= p=0.35 All patients Liver limited Van Cutsem ASCO-GI 2011

16 PRIME: Increased R0 resection rate in LLD Patients (%) KRAS wtKRAS wt: LLD Patients (%) Douillard J-Y, et al. J Clin Oncol 2010;28:4697–4705; Petrelli F, et al. Int J Colorectal Dis 2012;27:997–1004

17 Conceptualizing the relevance of DpR for survival Lethal tumor load Baseline tumor load Time under treatment Tumor shrinkage No tumor shrinkage PFS  PFS  OS Mansmann UR, et al. ASCO GI 2013 (Abstract no. 427)

18 CRYSTAL and OPUS: More patients demonstrate ETS when treated with cetuximab 38%62% 31%69% ≥20%* (n=54) <20%* (n=24) <20%* (n=115) ≥20%* (n=184) Cetuximab + FOLFOX4 Cetuximab + FOLFIRI CRYSTAL OPUS Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3) *Radiologic evaluation reported by the investigator and reviewed by an IRC n=299 n=78 mOS 30.0 mo mOS 18.6 mo mOS 26.0 mo mOS 15.7 mo HR 0.53 p<0.001 HR 0.43 p=0.006 Probability of OS Cetuximab + FOLFIRI Cetuximab + FOLFOX4 ≥20%* (n=54) <20%* (n=24) <20%* (n=115) ≥20%* (n=184) (months) (months)

19 PRIME: More patients had RECIST response or ETS at week 8 with panitumumab + CT than with CT alone Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P) Patients with RECIST response Patients with ETS Patients (%) FOLFOX (n = 298) Pani + FOLFOX (n=286) FOLFOX (n = 298) Pani + FOLFOX (n=284)

20 OS was significantly longer in patients achieving RECIST response or ETS in both arms ●Patients demonstrating ETS who received pantitumumab plus FOLFOX showed a greater OS benefit compared with those receiving FOLFOX alone (30.0 vs 25.1 months) FOLFOXFOLFOX + pani ETS <20% (n=130) ≥20% (n=158) <20% (n=87) ≥20% (n=197) Median OS, months (95% CI) 16.6 (12.4–18.8) 25.1 (22.1–32.8) 10.7 (9.4–16.1) 30.0 (27.2–33.1) HR, p-valueHR=0.52, p<0.0001HR=0.43, p< Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P) FOLFOXFOLFOX + pani RECIST response <30% (n=130) ≥30% (n=112) <30% (n=141) ≥30% (n=145) Median OS, months (95% CI) 17.6 (15.4–20.2) 29.5 (22.5–34.5) 18.0 (14.0–21.7) 30.3 (26.6–36.8) HR, p-valueHR=0.54, p<0.0001HR=0.53, p<0.0001

21 Downsizing initially unresectable metastases offers similar 5-year survival as initially resectable patients 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Kanas GP, et al. Clin Epidemiol 2012;4:283–301; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99. *median; CRC, colorectal cancer; CT, chemotherapy. Initially non-resectable Resection 37% (8-79%) 2 0% (0-6%) 3 Initially resectable Resection 38% (30-68%) 2 Conversion CT Untreated CRC liver metastases 5-year survival* (range)

22 A meta analysis of resectability and outcomes with anti-EGFR mAb therapy (KRAS exon 2 WT, LLD) Petrelli F, Barni S. Int J Colorectal Dis 2012;27: CT, chemotherapy; mCRC, metastatic colorectal cancer; LLD, liver limited disease; mAb, monoclonal antibody; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Comparison of first-line CT + / - cetuximab or panitumumab –KRAS WT initially unresectable liver-limited mCRC Meta analysis of RCTs: –Primary outcome: rate of R0 resection –Secondary outcomes: PFS, OS and ORR Four RCTs involving 484 KRAS WT patients were included: –PRIME, Douillard 2010 –COIN, Maughan 2011 –CRYSTAL, Van Cutsem 2011 –OPUS, Van Cutsem 2011

23 Impact of anti-EGFR mAb therapy on outcomes (KRAS exon 2 WT, LLD) Petrelli F, Barni S. Int J Colorectal Dis 2012;27: CT, chemotherapy; mAb, monoclonal antibody; R0, resection with microscopically negative margins. Meta-analysis indicates EGFR inhibitors increase R0 resection rate by 60% in mCRC patients with unresectable liver-limited disease Response rate CT alone P = CT+ EGFR mAb R0 resection rate CT alone P = 0.04 CT + EGFR mAb

24 Trial FOLFIRI + panitumumab in 1st-line mCRC protocol ID: ; ClinicalTrials.gov ID: NCT Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138: DoR, duration of response; PFS, progression-free survival; TTP, time to progression; DoSD, duration of stable disease; TTF, time to treatment failure; ORR, overall response rate. mCRC (n = 150) FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W on day 1 of each cycle) E N D O F T R E A T M E N T S T U D Y E N D O F F O L L O W - U P S A F E T Y 8 weeks after end of treatment Disease assessment every 8 weeks until week 48, then every 3 months until disease progression Study endpoints: ORR (1°), PFS, disease control rate, DoR, TTP, DoSD, TTF, safety -The incidence of R0 resection was also reported

25 KRAS WT tumours were more likely to respond to treatment with panitumumab plus FOLFIRI Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138: CT, chemotherapy; R0, resection with microscopically negative margins. A higher proportion of patients with KRAS WT than with KRAS MT had an objective response and R0 resection Objective response rate KRAS MTKRAS WT R0 resection rate, patients with LLD KRAS MTKRAS WT

26 PRIME study FOLFOX4 ± panitumumab in 1 st -line treatment of metastatic CRC ID: ; ClinicalTrials.gov ID: NCT ; 1. Douillard JY, et al. J Clin Oncol 2010; 28: ; 2. Douillard JY, et al. N Engl J Med 2013; 369: *KRAS status was prospectively analysed; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; DoR, duration of response; ORR, objective response rate; OS, overall survival; TTR, time to response; Q2W, every 2 weeks. mCRC KRAS* WT (n = 1183) Disease assessment every 8 weeks FOLFOX4 (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFOX4 (Q2W) R 1:1 E N D O F T R E A T M E N T F O L L O W - U P L O N G T E R M Study endpoints: PFS (1°), OS, ORR, TTR, DoR, safety and tolerability -Primary Analysis: pre-specified; after >50% of KRAS exon 2 WT patients had died 1,2 -Updated OS Analysis: exploratory; after >80% of KRAS exon 2 WT & MT patients died 2

27 PRIME study RAS analysis Post-hoc analysis objective Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster). RAS WT, KRAS & NRAS exons 2/3/4; LLD, liver-limited disease Post-hoc analysis to evaluate tumour shrinkage, resection rates and PFS and OS outcomes for patients with RAS WT and LLD treated in the 1 st -line PRIME study

28 PRIME study RAS analysis Patient population and objective (RAS WT LLD patients, updated analysis) Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster). CLM, colorectal liver metastases; LLD, liver-limited disease; RAS, KRAS & NRAS exons 2/3/4. LLD (n = 41) LLD (n = 48) Other only mets (n = 39) Other only mets (n = 36) Liver plus other mets (n = 172) FOLFOX4 (n = 252) First-line mCRC RAS WT (n = 505) FOLFOX4 + Panitumumab (n = 253) Liver plus other mets (n = 169)

29 PRIME study RAS analysis Objective response and tumour shrinkage (RAS WT LLD patients, updated analysis) Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster). # Patients assessed at baseline and week 8; § Patients assessed at baseline and at least one other time point; LLD, liver-limited disease; RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive. Objective response Tumour shrinkage ≥ 30% at wk 8 # Maximum tumour shrinkage § FOLFOX4 Panitumumab + FOLFOX4 P = 0.231P = 0.015P = n = 41n = 48n = 35n = 43n = 39n = 46

30 PRIME study RAS analysis Metastasectomy and complete resection rates (RAS WT, LLD patients, updated analysis) Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster). *Subgroup of patients with metastasectomy; LLD, liver-limited disease; RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive. Metastasectomy (all resections) Complete resection* P = 0.349P = FOLFOX4 (n= 41) Panitumumab + FOLFOX4 (n= 48) FOLFOX4 (n= 41) Panitumumab + FOLFOX4 (n= 48)

31 PRIME study RAS analysis PFS, OS (RAS WT, LLD patients, updated analysis) Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster). LLD, liver-limited disease; PFS progression-free survival; OS, overall survival; RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive. PFS Events n (%) Median OS months Panitumumab + FOLFOX4 (n = 48) 38 (79)11.3 FOLFOX4 (n = 41) 37 (90)9.9 OS Months Kaplan-Meier estimate HR (95% CI) = 0.75 (0.48, 1.19) P = Kaplan-Meier estimate Months HR (95% CI) = 0.71 (0.43, 1.16) P = Events n (%) Median OS months Panitumumab + FOLFOX4 (n = 48) 32 (67)40.7 FOLFOX4 (n = 41) 31 (76)33.4

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33 1- Hurwitz 2004, 2- Saltz 2008, 3- Okines 2009, 4- Masi 2010, 5- Falcone 2012, 6- Wong 2011, 7- Gruenberger 2008, 8- Gruenberger 2013 StudyTreatmentSelected patients nTR (%)R0 (%) AVF B-IFL IFL No40245< 2 NO B-FOLFOX B-XELOX No First-BEAT 3 B-CT (oxali/CPT)No (12/7) GONO 4 B-FOLFOXIRINo (LLD)57 (30) 77 (80)(26) TRIBE 5 b-FOLFOXIRI FOLFIRI No (LLD) (32) 12 (28) LLD CRC patients Gruenberger 7 B-XELOXResectable BOXER 6 B- XELOXnon-resectable and borderline OLIVIA 8 B-FOLFOXIRI B-FOLFOX6 non- resectable disease % 23% NEOADJUVANT BEVACIZUMAB IN LIVER METASTASES

34 CELIM: Tasas de Respuesta y Resección R0 All patients Cetuximab + FOLFOX6 Cetuximab + FOLFIRI KRAS wtKRAS mt n=106n=53 n=67n=27 CR/PR62%68%57%70%41% 95% CI52–72%54–80%42–70%58–81%22–61% R0 resections34%38%30%33% 95% CI25–44%25–52%18–44%22–45%14–50% Folprecht G, et al. Lancet Oncol 2010; 11: 38–47 Folprecht G, et al. EMCC 2011 (Abstract-Poster No. 6009)

35 POCHER: Alta tasa de respuestas y resecciones Response rateR0 resection rate Patients (%) 79% 60% Patients (%) 2-year OS rate 68% Patients (%) Garufi C, Br J Cancer, 2010

36 Phase II trial of panitumumab plus FOLFOX4 or FOLFIRI in subjects with KRAS wild-type colorectal cancer and liver-limited disease: The PLANET study A. Abad 1 *, B. Massuti 2, C. Grávalos 3, P. Escudero 4, C. Guillén-Ponce 5, J.L. Manzano 1, A. Gomez 6, Mª J. Safont 7, J. Gallego 8, J. Sastre 9, C. Pericay 10, R. Dueñas 11, C. López- López 12, F. Losa 13, M. Valladares 14, E. González 15, A. Yuste 2, A. Carrato 5, Enrique Aranda 6 On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) 1.Germans Trias i Pujol Hospital –ICO, Badalona, Spain; 2. General Hospital, Alicante, Spain; 3. Doce de Octubre Hospital, Madrid, Spain; 4. Clínico Lozano Blesa Hospital, Zaragoza, Spain; 5. Universitario Ramón y Cajal Hospital, Madrid, Spain; 6. Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba. Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Spain; 7. General Hospital, Valencia, Spain; 8. General Universitario de Elche Hospital, Alicante, Spain; 9. Hospital Clínico San Carlos, Madrid; Center affiliated to the Red Temática de Investigación Cooperativa, RD06/0020/0021, Spain, Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid; 10. Sabadell Hospital, Corporación Sanitaria Parc Taulí, Barcelona, Spain; 11. Complejo Hospitalario de Jaén Hospital, Jaén, Spain; 12. Marqués de Valdecilla Hospital, Santander, Spain; 13. General de L´Hospitalet Hospital, Barcelona, Spain; 14. Complejo Hospitalario Universitario Hospital, La Coruña, Spain; 15. Virgen de las Nieves Hospital, Granada, Spain; *actual address: Oncology Unit, Campus CIMA, Barcelona, Spain ▼Panitumumab in 1 st -line mCRC ▼ This medicinal product is subject to additional monitoring. All suspected adverse reactions should be reported

37 PLANET study Objectives To evaluate the efficacy and safety of the addition of Pmab to standard CT regimens, either FOLFIRI or FOLFOX4, as first-line treatment in WT KRAS CCR patients with liver-only metastases. To explore possible differences in outcomes according to other RAS mutations.

38 ClinicalTrials.gov identifier: NCT R 1:1 Sponsor: Spanish Cooperative Group for Digestive Tumour Therapy (TTD) Principal investigators: Dr. Albert Abad & Dr. Alfredo Carrato FOLFOX4 (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W)) Response Rate, Resectability Rate, Safety, PFS,OS WT KRAS liver- only mCRC not suitable for initial surgery N=80 PLANET study Study design

39 PLANET study Endpoints Primary Endpoint: Objective response rate (ORR) over the entire Pmab+CT treatment period Secondary Endpoints: Resection rate (R0+R1) of liver metastases Time to resection Progression-free survival (PFS) Overall survival (OS) Adverse Events (AEs) and peri-operative safety Exploratory Endpoints: Response according to molecular biomarkers (RAS status)

40 PLANET study Key eligibility criteria Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster). EGFR, epidermal growth factor receptor >18 years of age WT KRAS CRC Synchronous or metachronous liver-only metastases deemed resectable or unresectable, meeting one of the following criteria –≥4 liver metastases –≥1 metastasis >10 cm in diameter –Liver metastases not resectable No prior anti-EGFR therapy Karnofsky performance status ≥70% Adequate haematologic, renal and metabolic function

41 PLANET study Patient disposition and characteristics Pmab- FOLFOX4 (N = 38) Pmab- FOLFIRI (N = 39) TOTAL (N = 77) Male, n (%)31 (81.6)28 (71.8)59 (76.6) Median age, years (min, max)65 (32, 79)63 (37, 83)64 (32, 83) Mean body mass index, kg/m 2 (SD)27.4 (4.4)25.9 (3.6)26.7 (4.0) Median time since CCR diagnosis, months (Q1, Q3) 3.4 (1.3, 22.7) 1.6 (0.6, 11,5) 1.9 (0.6, 22.2) Technically resectable liver metastases, n (%)12 (31.6)12 (30.8)24 (31.2) Prior surgery for primary tumor, n (%)26 (68.4)22 (56.4)48 (62.3) Prior adjuvant/neoadjuvant CT and/or radiotherapy, n (%) 6 (15.8)4 (10.3)10 (13.0) Prior FOLFOX, n (%)3 (7.9)3 (7.7)6 (7.8) 77 patients were analyzed – 38 received Pmab-FOLFOX4 – 39 received Pmab-FOLFIRI Abad et al. Presented at the 16th World Congress on Gastrointestinal Cancer, June 25-28, 2014, Barcelona (Spain); Abstract nº PD-0006

42 PLANET study Response rate and resectability – presented a ESMO

43 Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster). WT RAS, WT KRAS & NRAS exons 2/3/4; NA, not achieved PLANET study OS P log rank = P Wilcoxon = P log-rank = P Wilcoxon = Proportion event-free (%) Median, months (95% CI) Panitumumab + FOLFOX (20.6–NA) Panitumumab + FOLFIRI 42.4 (17.8–51.5) WT KRAS exon Months WT RAS Median, months (95% CI) Panitumumab + FOLFOX (26.4–NA) Panitumumab + FOLFIRI 45.8 (32.8–51.5) 4050

44 Metastases are: –Limited to liver and / or lung –Clearly R0-resectable, even without preoperative chemotherapy Treatment aim is curative and to decrease risk of relapse ESMO Clinical Groups for 1 st -line treatment Definition of Group 0 (initially resectable) patients Schmoll HJ, et al. Ann Oncol 2012; 23: R0, resection with microscopically negative margins. Group 2Group 1 Group 3 Group 0 Non-resectable at clinical presentation Initially R0 resectable

45 EORTC intergroup study [EPOC] Surgery ± FOLFOX4 for resectable liver metastases from colorectal cancer ClinicalTrials.gov identifier: NCT Nordlinger B, et al. Lancet 2008; 371: ; Nordlinger B, et al. Lancet 2013; 14: mCRC metastatic colorectal cancer; LLD, liver limited disease; OS, overall survival; PFS, progression free survival. R 1:1 mCRC with initially resectable LLD (n = 364) FOLFOX4 6 cycles None FOLFOX4 6 cycles None Study endpoints: PFS (1°), OS, resectability, tumour response, safety Open label, phase 3 study S U R G E R Y

46 EORTC intergroup study [EPOC] Progression free survival Nordlinger B, et al. Lancet 2008; 371: PFS, progression free survival. Proportion event-free (%) Years All eligible patients All resected patients HR (96% CI) = 0.77 (0.60, 1.00) P = HR (96% CI) = 0.73 (0.55, 0.97) P = year PFS, % Surgery + FOLFOX4 (n = 171) 36.2 Surgery (n = 171) year PFS, % Surgery + FOLFOX4 (n = 151) 42.4 Surgery (n = 152) 33.2 Perioperative FOLFOX4 reduced the risk of PFS events by ~25%

47 EORTC BOS-2 study Patients with resectable liver metastases ClinicalTrials.gov identifier: NCT BOS, biologics, oxaliplatin and surgery, OS, overall survival. R KRAS WT mCRC with resectable LLD (n = 360) 6 cycles mFOLFOX6 mFOLFOX6 + bevacizumab mFOLFOX6 + panitumumab 6 cycles mFOLFOX6 mFOLFOX6 + bevacizumab mFOLFOX6 + panitumumab Open label, phase 2 study Study endpoints: PFS (1°), pathological response rate, resection rate, OS, safety S U R G E R Y F O L L O W - U P

48 Conclusiones El CCRm tiene mal pronóstico si no se trata. La cirugía hepática ofrece posibilidad de curación (15%) Hasta un 30% de los tumnores inicialmente irresecables se convierten en resecables tras QT de conversión Las combinaciones de quimioterapia con tratamientos biológicos ofrecen tasas de respuestas superiores a 50% en pacientes no seleccionados, y superiores a 70% en pacientes con enfermedad limitada al hígado. Los datos de los estudios fase III (PRIME), y los estudios de los estudios fase II con pacientes seleccionados (PLANET), permiten emular los resultados de otras combinaciones

49 Conclusiones Cuando hablemos del tratamiento de conversión en pacientes afectos de CCRm potencialmente resecables, las combinaciones con panitumumab han demostrado ser igualmente eficaces que otras combinaciones de tratamiento estudiadas con anterioridad.


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