The treatment of metastatic colorectal cancer in 2007

Transcription

1 The treatment of metastatic colorectal cancer in 2007 Prof Eric Van Cutsem, MD, PhD Gastrointestinal Oncology Unit University Hospital Gasthuisberg Leuven - Belgium

2 CRC is a major health concern Life-time risk for CRC 4 6% 1 Worldwide Third most common cancer 2 > new cases 2 Second leading cause of cancer death (~ ) /year patients in Europe develop CRC 2 25% present with metastatic disease 40 50% eventually develop metastatic disease > deaths/year in Europe 2 1. Winawer S, Fletcher R, et al. Gastroenterol 2003: 124; GLOBOCAN

3 Maximising patient outcomes in CRC Maximising patient outcomes in CRC Diagnosis Thirdline Neoadjuvant/ Surgery Adjuvant First-line Secondline Colorectal cancer treatment in a context of Continuum of Care: Treatment Plan throughout the continuum of care, based on best available evidence More effective drugs now available and trend towards a targeted and possibly tailored therapy Multi-Disciplinary Approach: i.e. resection of liver metastases Goldberg R, Rothenberg M, Van Cutsem E et al. Oncologist 2007

4 Colorectal liver metastases Disease is limited to the liver: - Unresectable liver metastases Neoadjuvant or induction chemotherapy followed by resection if response Resectable liver metastases Neoadjuvant and/or adjuvant chemotherapy

5 The role of neo-adjuvant and adjuvant chemotherapy for livermetastases of colorectal cancer

6 Patterns of resectability in patients with CRC liver metastases Metastatic CRC 85% unresectable 15% resectable 10-20% potentially resectable 80-90% never resectable neoadjuvant chemotherapy to increase resectability? Class I Class II neoadj. and/or adjuv. CT to increase cure rate?

7 5-Yr Survival after resection of CR Livermetastases 22% 35% 25% 25% 33% 39% 25% 26% 32% 37% 38% 34% 58% 41% 58% 5% 0% 5% 3% -- 5% 4% 2% 0% 2.8% 0% 0.8% - 1% Foster Iwatsuki Nordlinger Adson Hughes Scheele Rosen AFC Gayowski Fong Minigawa Ercolani Choti Adam Abdalla Survival Op. Mort. Patients Year Authors

8 Nordlinger B et al, Proc ASCO 2007 EORTC 40983: Study design R a n d o m iz e FOLFOX4 6 cycles (3 months) Surgery Surgery FOLFOX4 6 cycles (3 months) N=364 patients with < 4 resectable livermetastases

9 Nordlinger B et al, Proc ASCO 2007 EORTC 40983: Results N pts CT N pts Surgery % absolute difference in 3-year PFS Hazard Ratio (Confidence Interval) P-value All patients % (28.1% to 35.4%) 0.79 ( ) P=0.058 All eligible Patients % (28.1% to 36.2%) 0.77 ( ) P=0.041 All resected Patients % (33.2% to 42.4%) 0.73 ( ) P=0.025

10 Progression-free survival in eligible patients 100 HR= 0.77; CI: , p= Periop CT +8.1% At 3 years Surgery only 36.2% 28.1% 0 O 0 N Number of patients at risk : (years) Nordlinger B et al, Proc ASCO 2007

11 Cytotoxic chemotherapy for metastatic CRC Survival Med (mo) 1 yr (%) 2 yr (%) Best Supp. Care 6 < 30 < 10 5-FU + FA Capecitabine Irinotecan Oxaliplatin

12 Van Cutsem E. Editorial J Clin Oncol The issues that face us to achieve a continuum of care 1st line chemo 2nd line chemo 3rd line chemo How to start? At progression change chemo, biologic or both? Independent sequences? 1st biologic 2nd biologic

13 Sistin Chape: Universal Judgement of Michelangelo The emerging Integrated Circuit of the Cell

14 J. FOLKMAN: 1971 The Angiogenic Switch and Antiangiogenic Therapy Somatic Mutation Small Avascular Tumor Tumor Secretion of Proangiogenic Factors Stimulates Angiogenesis Rapid Tumor Growth and Metastasis Angiogenic Inhibitors May Reverse this Process

15 Tumour vasculature resulting from VEGF-mediated angiogenesis is abnormal Normal blood vessels Tumour blood vessels Maturation/stabilisation factors present Less dependent on cell survival factors Basal integrin expression Less permeable Supporting cells present Growth and survival factors (e.g., VEGF) present Preferential expression of v 3, v 5, and 5 1 integrins Leaky Fewer supporting cells Jain., Semin Oncol 2002;29 (Suppl. 16):3 9; Carmeliet, Nat Med 2003;9:653 60; Lee et al., J Biol Chem 2003;278:

16 Normal and Tumor Vasculature Normal Blood Vessels Tumor Blood Vessels Maturation factors present Minimally dependent on cell survival factors Less permeable Supporting pericytes present Reduced integrin expression Growth and survival factors (eg, VEGF) present Leaky Fewer pericytes Preferential expression of α v β 3 α v β 5 & α 5 β 1 integrins Blau and Banfi. Nat Med. 2001;7:532. Jain. Nat Med. 2001;7:987.

17 Tumor Vasculature is Abnormal Normal colon Nearby colorectal cancer Tumor vasculature is dilated, highly chaotic, and tortuous, with a lack of hierarchical vessel arrangement Carmeliet P, et al. Nature 2000;407: Konerding et al; Microenvironment of Human Tumors 2002

18 Anti-VEGF antibody normalises the tumour vasculature Anti-VEGF Reduces interstitial fluid pressure vessel density Increases drug delivery Jain R. Nature Med 2001;7:987 9; Willett CG, et al. Nat Med 2004;10:145 7; Tong R, et al, Cancer Res 2004;64:3731 6

19 Agents targeting the VEGF pathway Antibodies inhibiting VEGF receptors Antibodies inhibiting VEGF (e.g. bevacizumab) Permeability Soluble VEGF receptors (VEGF-TRAP) VEGF VEGF receptor-2 Cation channel P P P P Small-molecules inhibiting VEGF receptors (TKIs) (e.g. PTK-787) P P P P P P P P Ribozymes (Angiozyme) Migration, permeability, DNA synthesis, survival Angiogenesis Lymphangiogenesis

20 Clinical Results in Metastatic Colorectal Cancer Bevacizumab in combination with chemotherapy in metastastic CRC pivotal trial: IFL: increased activity in first line 5-FU/FA monotherapy: increased activity in first line FOLFOX: increased activity in second line Oxaliplatin based: increased activity in first line Cetuximab +/- irinotecan: high activity in irinotecan refractory CRC Bolus 5-FU/FA plus bevacizumab: not active in irinotecan and oxaliplatin refractory CRC

21 Superior PFS + OS with 1 st line IFL + bevacizumab vs IFL Probability of being progression free Median progression-free survival 6.2 vs 10.6 months HR=0.54 p< IFL + bevacizumab IFL + placebo 6.2m 10.6m Probability of survival Median survival 15.6 vs 20.3 months HR=0.66 p< m 20.3m IFL + bevacizumab IFL + placebo Time (months) Time (months) Hurwitz H, et al. N Engl J Med 2004;350:

22 Bevacizumab: Safety Overview Bevacizumab does not increase chemotherapy related toxicities. Bevacizumab has specific side effects: Hypertension Proteinuria Thromboembolic events: arterial Bleeding: minor mucosal (epistaxis) and major hemorrhage (non small cell lung cancer) Gastrointestinal perforation Wound healing/postoperative bleeding Kabbinavar F et al. J Clin Oncol 2003;21:60 5 Hurwitz H et al. NEJM 2004;350: Giantonio BJ, et al. Presented at: 2005 Gastrointestinal Cancers Symposium; January 2005; Hollywood, FL, USA. Abstract 169a

23 Arterial thromboembolic events* Arterial TE events Chemotherapy alone 2.0% (15/741) bevacizumab plus chemotherapy 4.5% (45/1004) Mortality 0.4% (3/741) 0.8% (8/1004) Risk factors for arterial thromboembolic events included history of prior arterial thromboembolic events such as stroke or heart attack age of 65 years or older Arterial events included in analysis CVA (stroke), transient ischemic attack, subarachnoid hemorrhage myocardial infarction, angina (unstable angina), arterial thrombosis and other arterial thromboembolic events *Pooled analysis of five randomised trials

24 EGFR pathway inhibition SKIN TUMOR pegfr pegfr 1 2 pmapk K Shc PI3K K Grb2 Sos Shc Grb2 Sos Ras pmapk PTEN Akt Raf pakt Ki67 mtor p27 FKHR GSK-3 Bad MEK1/2 MAPK Ki67 p27 D1 Cyclin Cell cycle progression Survival Proliferation p27 Tabernero J et al 2003

25 Anti-EGF Receptor Therapies Monoclonal antibodies (cetuximab, panitumumab, matuzumab,...) R R Ligand CELL MEMBRANE Tyrosine kinase inhibitors (gefitinib, erlotinib,ci-1033, EKB-569, ) K K Signal Transduction

26 Cetuximab +/- irinotecan in irinotecan refractory CRC: Response Ratio Percentage cetuximab + irinotecan (n=218) 23 [18-29] * 11 [6-18] cetuximab (n=111) 56 [49-62] ** 32 [24-42] 0 Response Rate * p=0.0074; ** p<0.001; [] = 95% CI Disease Control (CR+PR+SD) Cunningham D Van Cutsem E. N Engl J Med 2004

27 Panitumumab in mcrc: : phase 3 trial R A N D O M I Z E 1:1 Panitumumab PD Follow-up 6.0 mg/kg Q2W + BSC Optional BSC PD Panitumumab Follow-up Crossover Study Key inclusion: Disease progression on CT scan after fluoropyrimidine, irinotecan and oxaliplatin EGFr membrane staining on 1% tumor cells Stratification: ECOG score: vs. 2 Geographic region Van Cutsem E et al. J Clin Oncol 2007

28 Progression-Free Survival Event-free Probability Panitumumab BSC Hazard ratio=0.54 (95% CI: 0.44, 0.66) Stratified log-rank test p < Patients at risk: Panitumumab BSC Weeks from Randomization Primary Analysis, All Randomized Analysis Set, Central Radiology Van Cutsem E et al. J Clin Oncol 2007

29 Kaplan- Meier Progression-Free Survival Rates at Prespecified Time Points % Progression Free (95 % CI) 60% 50% 40% 30% 20% 10% 0% Patients at risk: Panitumumab BSC 49% 30% Primary Analysis, All Randomized Analysis Set, Central Radiology 35% 14% 26% 9% 18% 5% 10% 4% Panitumumab (N=231) BSC (N=232) 4% 1% 1% 1% Wk 8 Wk 12 Wk 16 Wk 24 Wk 32 Wk 40 Wk Van Cutsem E et al. J Clin Oncol 2007

30 EGFR-inhibitor induced skin reactions Acne-like rash Post inflammatory effects dry skin fissura paronychia pruritus Description of severe cases THERAPY SUGGESTIONS Topical anti-acne creams (drying effect) +/- tetracyclines +/- antihistamines Pulse dye laser Emollients Hydrocolloid dressing or Propylene glycol+/- acetylsalicyl Anti-septic soaks Silver nitrate (pyogenic granuloma) S Segaert & E Van Cutsem, Ann Oncology 2005

31 1. Saltz et al. Proc ASCO Saltz et al. J Clin Oncol Cunningham D Van Cutsem E. N Engl J Med Van Cutsem et al. EORTC/NCI Geneva Xiong H et al. J Clin Oncol Kies et al. Proc ASCO Correlation of rash and survival after treatment with cetuximab Survival (months) CRC CRC CRC CRC Pancreatic SCCHN Study: BOND Saltz (2001) 1 Saltz (2004) 2 Cunningham Van Cutsem Xiong (2004) 5 Kies (2002) 6 (2004) 3 (2004) 4 No reaction Grade 1 Grade 2 Grade 3

32 CRYSTAL trial: Study design Cetuximab + FOLFIRI EGFR-expressing metastatic CRC R Cetuximab IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly + irinotecan (180mg/m 2 ) + 5-FU (400 mg/m 2 bolus mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks Stratification factors: Regions ECOG PS Populations Randomized patients n=1217 Safety population n=1202 ITT population: n=1198 FOLFIRI irinotecan (180 mg/m 2 ) + 5-FU 400 mg/m 2 bolus mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks Van Cutsem E et al, Proc ASCO 2007

33 PFS estimate CRYSTAL trial: Primary endpoint PFS met ITT population independent review 8.0 mo 8.9 mo Cetuximab + FOLFIRI, n=599 FOLFIRI, n=599 HR = 0.851; 95% CI = [ ] Stratified log-rank p-value = year PFS rate 23% vs 34% Subjects at risk Progression-free survival time (months) FOLFIRI alone Cetuximab FOLFIRI Van Cutsem E et al, Proc ASCO 2007

34 CRYSTAL trial: Surgery with curative intent FOLFIRI alone Cetuximab + FOLFIRI Percentage (%) ,5 6 Surgery with curative intent ITT population (pre-planned) p=0.0034* odds ratio 3.0 [95% CI: ] 1,5 4,3 No residual tumor after resection Percentage (%) Liver metastases only population (exploratory) No residual tumor in patients with liver metastases n=599 / group n=599 / group n=134 / n=122 *CMH test Van Cutsem E et al, Proc ASCO 2007

35 Challenges with EGFR inhibitors in CRC: determining the best treatment strategies Clinical setting Chemorefractory patients First-line treatment mcrc: liver metastases Adjuvant treatment Combination with radiotherapy in rectal cancer Status Proven activity Promising activity in phase 2 studies Phase 2 studies show high resection rate of initially unresectable metastases Studies ongoing / planned Phase 1 2 studies ongoing / planned

36 Tailored Treatment

37 Can we find parameters to predict response to EGFR inhibitors? PTEN Bcl-2 BclXl Ki67 p27 Angiogenesis IL-8 VEGF

38 Treatment Algorithm for Metastatic CRC No prior adjuvant therapy FOLFOX /Xelox + bevacizumab¹ FOLFIRI + bevacizumab¹ FOLFIRI FOLFOX / Xelox Irinotecan+ cetuximab Irinotecan+ cetuximab Capecitabine (5-FU/FA) ± bevacizumab¹ FOLFOX / Xelox FOLFIRI ¹ if no cardiovascular contraindications

39 Individualisation of treatment in metastatic CRC with increasing number of active agents TS TP Novel targets: EGFR, VEGF, Cox-2, IGF P53 Tumor Patient.. MSI Topo I Individual personal treatment Pharmacogenetic : cytotoxic metabolism

40 Is progress made in chemotherapy and other treatments options of colon cancer? Yes The dream. The reality...

41