Metastatic Colorectal Cancer : The role of Personalised Medicine, Biomarkers and Early tumour shrinkage. Dr Lee-Ann Jones

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1 Metastatic Colorectal Cancer : The role of Personalised Medicine, Biomarkers and Early tumour shrinkage Dr Lee-Ann Jones

2 Aim Metastatic Colorectal Cancer: Past: 5FU, oxaliplatin, irinotecan..blanket treatment for all. Present: Individualise therapy Biomarkers, doublets, triplets, targeted therapy Future: Fine tuning. Case presentations taking the theory into the clinic

3 Acknowledgements ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Annals of Oncology 23: , 2012 clinicaloptions.com/oncology Fighting a Smarter War on Colon Cancer: The Biomarker Divide

4 Statistics CRC = one of the most commonly diagnosed cancers worldwide Estimated 1.23 million cases in 2008 representing 9.7% of the total cancer burden. In Europe, in 2008 Estimated 3.2 million new cases of cancer 1.7 million deaths from cancer across 40 countries. The most common cancer was CRC with 436,000 cases (13.6% of the total). CRC was second in the league of cancer deaths with 212,000 deaths (12.3% of the total). > 70% of CRC deaths in the Western world occur in patients > 65 years of age.

5 Pattern of presentation Approximately 25% of CRC patients present with synchronous liver metastases Approximately 50% of CRC patients will develop metastatic disease, principally confined to the liver. For patients with hepatic colorectal metastases, hepatic resection (+/- resection of resectable extrahepatic disease [EHD]) provides the best chance of long-term survival and cure.

6 What are the Risk Factors for Colorectal Cancer? Polyps (a noncancerous or precancerous growth associated with aging); about 10% of polyps are flat and have high risk of becoming cancerous Age Inflammatory bowel disease (IBD) Diet high in saturated fats, such as red meat Personal or family history of cancer Obesity Smoking Race: Blacks have higher rates Other

7 Hereditary Colorectal Cancer Syndromes: HNPCC Hereditary non-polyposis colorectal cancer (HNPCC), sometimes called Lynch syndrome, accounts for approximately 5% to 10% of all colorectal cancer cases The risk of colorectal cancer in families with HNPCC is 70% to 90%, which is several times the risk of the general population People with HNPCC are diagnosed with colorectal cancer at an average age of 45 Genetic testing for the most common HNPCC genes is available; measures can be taken to prevent development of colorectal cancer

8 Hereditary Colorectal Cancer Syndromes: FAP Familial adenomatous polyposis (FAP) accounts for 1% of colorectal cancer cases People with FAP typically develop hundreds to thousands of colon polyps (small growths); the polyps are initially benign (noncancerous), but there is nearly a 100% chance that the polyps will develop into cancer if left untreated Colorectal cancer usually occurs by age 40 in people with FAP Mutations (changes) in the APC gene cause FAP; genetic testing is available Yearly screening for polyps is recommended Attenuated familial adenomatous polyposis (AFAP) is related to FAP; people have fewer polyps

9 Colorectal Cancer and Early Detection Colorectal cancer can be prevented through regular screening and the removal of polyps Early diagnosis means a better chance of successful treatment Screening should begin at age 50 for all average risk individuals (black people age 45) or sooner if you have a family history of colorectal cancer, symptoms, or a personal history of inflammatory bowel disease

10 Colorectal Cancer Staging Staging is a way of describing a cancer, such as the size of a tumor and if or where it has spread Staging is the most important tool doctors have to determine a patient s prognosis Staging is described by the TNM system: the size and location of the Tumor, whether cancer has spread to nearby lymph Nodes, and whether the cancer has Metastasized (spread to other areas of the body) Some stages are divided into smaller groups that help describe the tumor in even more detail Treatment depends on the stage of the cancer Recurrent cancer is cancer that comes back after treatment

Stage IV Colorectal Cancer The cancer has spread outside of the colon or rectum to other areas of the body Stage IV cancer is treated with chemotherapy.

11 Stage IV Colorectal Cancer The cancer has spread outside of the colon or rectum to other areas of the body Stage IV cancer is treated with chemotherapy. Surgery to remove the colon or rectal tumor may or may not be done Additional surgery to remove metastases may also be done in carefully selected patients

12 Case presentation: 1 Mr MW 44 year old male Diagnosis: Stage IV adenocarcinoma of the colon: 18th of September 2008 Sites of Disease: Liver mets with calcification, para-aortic lymph nodes Treatment: Left hemicolectomy (prior to staging) on the 18th of September T3 N2 grade II adenocarcinoma. (4/9 nodes positive.) K-ras wildtype Clinical Trial (Horizon III Folfox + Cediranib/ placebo) 1 cycle of treatment only as patient developed cardiac event with coronary artery spasm requiring stenting.

13 FOLFOX and Avastin commenced off trial 3rd of November 2008 with 75% dose 5FU. Oct 2009: PD on PET/CT - Folfiri 02/02/2010: extensive PD liver - Irinotecan and Erbitux - good response

14 Chemo stopped in Sept due to side effects - treatment holiday Irinotecan and erbitux recommenced 15 Nov Patient consulted Dr C in JHB for hepatic embolisation and possible resection. Procedure failed to cause sufficient hypertrophy for surgery to be possible. Continue Erbitux and Irinotecan PD Oct 2011 treatment stopped Demised 26/3/2012 Survival 42 months

15 1/8/2011 4/1/2012

16 Case presentation: 2 Mrs BM: 41 year female presents 13/12/2011 with Hb 4 Fe deficiency aneamia, RUQ pain Diagnosis: ca ceacum with extensive liver metastases (> 50 metastases) Histology: moderatley diff adenocarcinoma k-ras wildtype Ca CEA raised 146 Treatment: Folfox and Avastin commenced 15/12/2011 Excellent response: Ca , CEA 4 10/7/2012: C8D1 - allergic reaction to oxaliplatin

17 24/1/2012 5/3/2012

18 23/7/ /10/2012

19 C8D15 ongoing - 5FU/LV and Avastin only (to continue until PD) Marker started increasing but scans remained stable 25/10/2012: PD in liver Plan: Folfiri and Cetuximab 2-weekly 27/12/2012: PD in liver after 2 month Folfiri/Cetux (8 week assessment) Severe RUQ pain due to subcapsular disease

20 27/12/2012

21 Plan: Capecitabine completed 1 cycle 23/1/2013: obstructive jaundice due to intrahepatic mets compressing port hepatis Stented no recovery of liver function Demised 10 Feb 2013 survival 14 months

GI Cancer Facts GI cancers represent the most common and fatal cancers in the world [1] 2012: 284,680 new diagnosis of GI cancers and 142,510 deaths in the US alone [2] Anal cancer Colorectal cancer

22 GI Cancer Facts GI cancers represent the most common and fatal cancers in the world [1] 2012: 284,680 new diagnosis of GI cancers and 142,510 deaths in the US alone [2] Anal cancer Colorectal cancer Esophageal cancer Gallbladder cancer Liver cancer Pancreatic cancer Small intestine cancer Stomach/gastric cancer No 2 cancers are alike and treatments must be selected based on an individual s tumor characteristics through personalized medicine 1. Jemal A, et al. CA Cancer J Clin. 2011;61: American Cancer Society. Cancer facts & figures 2012.

23 Clinical Trials: Phases Phase I trials determine the safety and dose of a new treatment in a small group of people Phase II trials provide more detail about the safety of the new treatment and determine how well it works for treating a specific type of cancer Phase III trials take a new treatment that has shown promising results when used to treat a small number of patients with cancer and compare it with the standard treatment for that disease; phase III trials involve a large number of patients

24 5-FU for 40 Yrs!! Heidelberger synthesises 5FU 5-FU bolus 5-FU infusion 24 hrs 48 hrs 46 hrs 120 hrs hrs LV + 5-FU 5-FU + LV 5-FU + Lev 5-FU + everything

25 Advances in the Treatment of Colorectal Cancer [1,2] FU Irinotecan Capecitabine Targeted therapies Oxaliplatin Cetuximab Bevacizumab Panitumumab KRAS 1. National Cancer Institute. Colon cancer treatment (PDQ) National Cancer Institute. Cancer drug information

26 Targeted therapies EGFR ab: Cetuximab and Panitumumab Biomarker: kras wildtype VEGF ab: Bevacizumab Monoclonal antibody to Vascular Endothelial Growth Factor (VEGF) Key role in cancer angiogenesis May improve delivery of chemotherapy by altering tumor vasculature and decreasing interstitial tumor pressure No known biomarker as yet.

27 The Laws From Mount Sinai Agents that work in stage IV colon cancer will work in stages II and III Transitive math (A x B = B x A) Refractory stage IV = frontline stage IV FOLFOX = FOLFIRI Combining targeted agents would be our pathway to the promised land Dual antibody therapy EGFR expression is valuable We would keep finding blockbuster drugs/targets

28 Median OS (Mos) Survival and Percentage of Patients Receiving 3 Drugs in Phase III Trials drugs: 5-FU/LV, irinotecan, oxaliplatin Patients Receiving 3 Drugs (%) Grothey A, et al. J Clin Oncol. 2005;23:

29 Colon Cancer Is More Than 1 Disease 50% to 60% 40% to 50% [1] KRAS wild type Positive EGFR agents KRAS mutant Negative EGFR agents 15% to 20% [2,3] 80% to 85% [3] MSI-H MSS? No 5-FU Colon cancer also has many more than these 4 subgroups above that may change with time 1. Luo F, et al. Int J Exp Pathol. 2009;90: Sinicrope FA, et al. Am J Gastroenterol. 2006;101: Grady WM, et al. Gastroenterology 2008;135:

30 Genetic alterations in pathogenesis of CRC Modified Fearson and Vogelstein model: CRC progresses through activating mutations in oncogenes or deactivation of tumour supressor genes. Chromosomal instability (CIN) or Microsatellite instability (MSI) pathway.

31 CIN pathway: Chromosomal instability. Poorer prognosis MSI: 15% of CRC. Hereditary or sporadic. HNPCC (3% of all CRC) Predictor of response to 5FU:little benefit Require irinotecan based therapy Clinical relevance/ practice changing? KRAS: downstream mediator of EGFR signaling pathway. 40% of tumour are kras mutant Resistant to EGFR antibodies Poor prognostic marker in CRC

32 BRAF:10% CRCs. Mutations involve V600E amino acid substitution.? Targeted therapy: BRAF inhibitors. CIMP: 30% of CRCs. DNA methylation is the most common gene alteration in human tumours CIMP-H: associated with BRAF mutation if MSI positive better prognosis CIMP-L: associated with kras mutation Though to be a significant independent predictor of survival benefit from 5FU based chemotherapy.

33 Consider STEPs for a personalized treatment approach in mcrc Strategy (curative vs palliative) Tumor biology (aggressive vs indolent) EGFR dependency (wild-type vs mutant) Patient

34 Taking personalized treatment a step further: Predictive and prognostic markers in mcrc

35 Prognostic and predictive markers defined Prognostic Predictive Provide information on outcome independent of the therapy that is used Provide information on outcome with regard to a specific therapy Allows identification of patients who will benefit most with a specific treatment Aids selection of one particular treatment over another

Patient groups in mcrc GROUP 1: Potentially

metastases, high tumor burden, or tumor-related

initially asymptomatic, and less aggressive

PFS, OS maintain QoL Intensive therapy Less

36 Patient groups in mcrc GROUP 1: Potentially resectable metastases GROUP 2: Non-resectable metastases, high tumor burden, or tumor-related symptoms GROUP 3: Non-resectable metastases, initially asymptomatic, and less aggressive disease RR, resectablility RR, symptom control PFS, OS maintain QoL Intensive therapy Less intensive therapy Schmoll H-J & Sargent D. Lancet 2007;370:

37 ESMO guidelines

40 Prognostic clinical parameters in mcrc

41 Prediction model for OS in 5-FU treated mcrc Recursive partition and amalgamation method >10 9 /L n=146 WBC n=503 <10 9 /L >1 No. sites n=357 >1 1 ECOG PS n=2549 >300 U/L ALP n=935 No. sites n=2046 n=208 n=180 n=149 n=755 n=1111 0/1 <300 U/L >1 1 Median OS mo (95% CI) Learnin g set Validati on set HRG n=534; 20.9% IRG n=962; 37.7% LRG n=1111; 43.6% 6.1 ( ) 10.7 ( ) 15.0 ( ) 6.4 ( ) 10.9 ( ) 14.7 ( ) HRG, high-risk group; IRG, intermediate-risk group; LRG, low-risk group Köhne C-H, et al. Ann Oncol 2002;13:

42 Prediction model for OS in 5-FU treated mcrc Recursive partition and amalgamation method >10 9 /L n=146 WBC n=503 <10 9 /L >1 No. sites n=357 >1 1 ECOG PS n=2549 >300 U/L ALP n=935 No. sites n=2046 n=208 n=180 n=149 n=755 n=1111 0/1 <300 U/L >1 1 HRG n=534; 20.9% GROUP 2 IRG n=962; 37.7% LRG n=1111; 43.6% GROUP 1 GROUP 3 HRG, high-risk group; IRG, intermediate-risk group; LRG, low-risk group Köhne C-H, et al. Ann Oncol 2002;13:

43 Predictive and prognostic biomarkers : EGFR

44 Predictive and prognostic biomarkers in the EGFR signaling pathway Validated KRAS wt vs mt status Exploratory Specific KRAS mutations (p.g13d) BRAF Epiregulin Amphiregulin PTEN PI3K NRAS

45 Predictive and prognostic biomarkers in the EGFR signaling pathway Validated KRAS wt vs mt status Exploratory Specific KRAS mutations (p.g13d) BRAF Epiregulin Amphiregulin PTEN PI3K NRAS To date, KRAS status is the only validated biomarker predictive of efficacy for anti-egfr agents Further research on alternative biomarkers is needed

46 KRAS as a Biomarker for Pmab Response in mcrc Proportion Event Free (%) Proportion Event Free (%) Patients with mutant KRAS receiving panitumumab had 0% RR and SD similar to BSC alone (12% vs 8%) PFS log HR significantly different depending on KRAS status (P <.0001) Percentage decrease in target lesion greater in patients with wild-type KRAS receiving Pmab Patients With Wild-Type KRAS Treatment Group Pmab + BSC BSC alone Events HR: (95% CI: ; stratified log-rank P <.0001) Wks N % Median (Wks) Patients With Mutant KRAS Treatment Group Pmab + BSC BSC alone Events HR: 0.99 (95% CI: ) Wks N % Median (Wks) Amado RG, et al. J Clin Oncol. 2008;26:

47 EGFR signaling pathway: Targets for personalized therapy Ligand AREG/EREG Target for EGFR-Erbitux PTE N Proliferation/ maturation P PI3K py AKT py STAT Gene transcription P Cell cycle progression MYC JUN FOS MYC Chemotherapy/ radiotherapy resistance py Angiogenesis EGFR-TK GRB2 SOS Cyclin D1 Cyclin D1 Invasion and metastasis RA S MEK RAF MAPK Survival (anti-apoptosis) Meyerhardt JA & Mayer RJ. N Engl J Med 2005;352: ; Venook A. Oncologist 2005;10:

CRC: Biologic Subsets That Respond Differently to EGFR-Targeted Agents EREG or AREG Low expression of EGFR ligands decreased response to EGFR-targeted agents EGFR Mutant KRAS decreased response to

48 CRC: Biologic Subsets That Respond Differently to EGFR-Targeted Agents EREG or AREG Low expression of EGFR ligands decreased response to EGFR-targeted agents EGFR Mutant KRAS decreased response to EGFR-targeted agents PIP 1 KRAS PI3K PTEN BRAF Mutant BRAF decreased response to EGFR-targeted agents PIP 3 PTEN loss of expression decreased response to EGFR-targeted agents Signaling to the nucleus Siena S, et al. J Natl Cancer Inst. 2009;101: Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.

49 CRYSTAL Trial: Study Design and Treatment Arms Cetuximab + FOLFIRI EGFR-expressing mcrc R Cetuximab IV 400 mg/m 2 on Day 1, then 250 mg/m 2 wkly + irinotecan 180 mg/m FU 400 mg/m 2 bolus mg/m 2 as 46-hr CI + FA q2w Stratification factors Regions ECOG PS Populations Randomized patients: n = 1217 Safety population: n = 1202 ITT population: n = 1198 FOLFIRI Irinotecan 180 mg/m FU 400 mg/m 2 bolus mg/m 2 as 46-hr CI + FA q2w Van Cutsem E, et al. N Engl J Med. 2009;360:

50 Using biomarkers to optimize clinical outcome OS estimate Overall patient population CRYSTAL 1.0 Erbitux + FOLFIRI (n=599) FOLFIRI (n=599) HR=0.878 p= Time (months) Van Cutsem E, et al. J Clin Oncol 2011;29:

51 OS estimate Using biomarkers to optimize clinical outcome: KRAS test KRAS wt population CRYSTAL 1.0 Erbitux + FOLFIRI (n=316) FOLFIRI (n=350) HR=0.796 p= Time (months) Personalized treatment is a better approach than one treatment fits all Van Cutsem E, et al. J Clin Oncol 2011;29:

Is it possible to optimize clinical outcome further in KRAS wt patients? Relative decrease at week 8* 1.0 0.5 CRYSTAL (KRAS wt) FOLFIRI ERBITUX + FOLFIRI 0 0.

52 Is it possible to optimize clinical outcome further in KRAS wt patients? Relative decrease at week 8* CRYSTAL (KRAS wt) FOLFIRI ERBITUX + FOLFIRI deeper response 20% more responders 1.0 *Radiological evaluation of changes in tumor size by investigator and reviewed by an IRC Piessevaux H, et al. ESMO 2010 (Abstract No. 596P)

53 Is it possible to optimize clinical outcome further in KRAS wt patients? Early tumour shrinkage (ETS)

54 Inducing tumor shrinkage is essential Tumor shrinkage Increases the chance of resecting metastases Promotes symptom relief Improves long-term outcomes

55 CRYSTAL and OPUS: Cetuximab increases early tumor shrinkage (week 8) Erbitux + FOLFIRI CRYSTAL FOLFIRI 38% 62% 20%* (n=184) 51% 49% <20%* (n=115) 20%* (n=163) <20%* (n=169) n=299 Erbitux + FOLFOX4 OPUS n=332 FOLFOX4 31% 69% 20%* (n=54) <20%* (n=24) 54% 46% 20%* (n=41) <20%* (n=49) n=78 n=90 *Radiologic evaluation reported by the investigator and reviewed by an IRC Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

56 Probability of PFS Probability of PFS Probability of PFS Probability of PFS Early tumor shrinkage with Cetuximab correlates with prolonged PFS Erbitux + FOLFIRI Erbitux + FOLFOX mpfs 7.3 mo mpfs 5.7 mo %* (n=184) <20%* (n=115) mpfs 14.1 mo 20%* (n=54) <20%* (n=24) mpfs 11.9 mo *Radiologic evaluation reported by the investigator and reviewed by an IRC HR 0.32 p< (months) HR 0.22 p< (months) FOLFIRI FOLFOX mpfs 7.4 mo 0 mpfs 7.2 mo %* (n=163) <20%* (n=169) mpfs 9.7 mo 10 20%* (n=41) <20%* (n=49) mpfs 7.2 mo HR 0.58 p< (months) HR 0.89 p=ns 20 Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3) CRYSTAL OPUS (months)

57 Probability of OS Probability of OS Early tumor shrinkage with Cetuximab correlates with prolonged OS Probability of OS Probability of OS Erbitux + FOLFIRI mos 18.6 mo 10 Erbitux + FOLFOX4 20 mos 15.7 mo 20%* (n=184) <20%* (n=115) mos 30.0 mo %* (n=54) <20%* (n=24) 50 mos 26.0 mo HR 0.53 p< (months) HR 0.43 p=0.006 FOLFIRI FOLFOX mos 18.6 mo mos 17.8 mo 20%* (n=163) <20%* (n=169) mos 24.1 mo %* (n=41) <20%* (n=49) 50 mos 21.6 mo HR 0.71 p= HR 0.89 p=ns CRYSTAL OPUS (months) (months) (months) *Radiologic evaluation reported by the investigator and reviewed by an IRC Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

58 Probability of OS Probability of OS Early tumor shrinkage with Cetuximab correlates with prolonged OS Probability of OS Probability of OS Erbitux + FOLFIRI mos 15.7 mo mos 30.0 mo mos 26.0 mo mos 17.8 mo mos 24.1 mo 0.4 HR 0.71 mos 18.6 mo HR p=0.006 mos 18.6 mo In patients treated 1st line with Cetuximab + p< standard chemotherapy, (months) early 0 tumor shrinkage is FOLFOX4 associated with improved overall survival Erbitux + FOLFOX %* (n=184) <20%* (n=115) 20%* (n=54) <20%* (n=24) *Radiologic evaluation reported by the investigator and reviewed by an IRC HR 0.43 p= (months) FOLFIRI %* (n=163) <20%* (n=169) 20%* (n=41) <20%* (n=49) 20 mos 21.6 mo 30 HR 0.89 p=ns 40 Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3) CRYSTAL OPUS (months) (months)

59 Early tumor shrinkage and survival in CRYSTAL and OPUS In patients with KRAS wt tumors treated with chemotherapy +cetuximab Early tumor shrinkage ( 20% at week 8) was experienced by: 64% of patients in CRYSTAL and 69% of patients in OPUS Early tumor shrinkage translated into a long-term clinical benefit of: 12 mo median PFS and 28 mo median OS in CRYSTAL 12 mo median PFS and 26 mo median OS in OPUS Piessevaux H, et al. ESMO 2010; Abstract No. 596P Piessevaux H, et al. ASCO GI 2011; Abstract No. 398

60 ??? What happens if your patient does not demonstrate ETS at 8 weeks, or shrinkage is <20%? Do we have enough evidence to use molecular/ets data to make clinical decisions? What is the impact of pre-treatment markers vs. on-treatment markers on clinical practice? Are there other biomarkers apart from KRAS that should be considered?

61 Personalized care with Cetuximab Predictive markers of Cetuximab efficacy: KRAS status: cetuximab is recommended for treatment of patients with KRAS wt mcrc Early tumor shrinkage ( 20% at week 8): Predictive of increased survival in patients treated with Cetuximab + CT The identification of patients who are most likely to obtain a clinical benefit allows for important improvements in the efficiency of resources allocated to the treatment of mcrc Tumor shrinkage Enables R0 resection of liver metastases Promotes symptom relief Van Cutsem E, et al. J Clin Oncol 2011;29: ; Piessevaux H, et al. ESMO 2010 (Abstract No. 596P); Piessevaux H, et al. ASCO GI 2011 (Abstract No. 398); Belda-Iniesta C, et al. ASCO 2012 (Abstract No. 3601)

62 VEGF inhibition

63 Phase III Trial of IFL ± Bevacizumab in mcrc: PFS PFS (%) HR: 0.54 (P <.00001) Median PFS: 6.2 vs 10.6 mos 20 IFL + placebo IFL + bevacizumab Mos Hurwitz H, et al. N Engl J Med. 2004;350:

64 First-line Bevacizumab in Metastatic Colorectal Cancer: OS OS (Mos) AVF2107g [1] NO16966 [2] BICC-C [3] TREE-2 [4] * *P <.001; P = Hurwitz H, et al. N Engl J Med. 2004;350: Saltz LB, et al. J Clin Oncol. 2008;26: Fuchs C, et al. ASCO Abstract Hochster, et al. ASCO Abstract 3510.

65 Dual blockade? More is not always better!

66 CAIRO2 Trial: Randomized Study Design (Arms A and B) Randomization Arm A Capecitabine Oxaliplatin Bevacizumab Arm B Capecitabine Oxaliplatin Bevacizumab Cetuximab Tol J, et al. N Engl J Med. 2009;360:

67 PFS Probability CAIRO2 Trial: Progression-Free Survival Arm A (without cetuximab) median PFS:10.7 mos ( ) Arm B (with cetuximab) median PFS: 9.4 mos ( ) HR for progression = 1.22 P = Mos From Randomization Tol J, et al. N Engl J Med. 2009;360:

68 CAIRO2: KRAS Genotyping (N = 501) Wild Type and Mutation Wild Type (n = 305; 61%) Mutation (n = 196; 39%) Arm A, n (%) 156 (50%) 108 (52%) Arm B, n (%) 158 (50%) 98 (48%) Median PFS, mos P Value Arm A Arm B P value Tol J, et al. N Engl J Med. 2009;360:

69 New Laws in Colon Cancer: Where Do We Go From Here? Most KRAS-mutated tumors do not respond to EGFR therapy Many KRAS wild-type tumors do not respond to EGFR therapy No biomarker for VEGF-targeted therapy yet Next horizons? BRAF MSI

70 Future drugs Aflibercept: Recent data with aflibercept showed significantly increased response rates, PFS and OS in combination with FOLFIRI in second line. (now available on named patient basis under section 21 application) Regorafenib is a dual targeted VEGFR2-TIE2 tyrosine kinase inhibitor, which has shown significant improvement of PFS and OS in third/last line as single agent compared with placebo. BIBF 1120 is a pan VEGFR, PDGF and FGF tyrosine kinase inhibitor, which has shown comparative efficacy and toxicity in combination with FOLFOX versus FOLFOX bevacizumab in first-line treatment

71 Cediranib is a pan VEGFR TK inhibitor, which showed in a large phase III trial with FOLFOX in first-line comparable efficacy versus FOLFOX/bevacizumab; however, quality of life measurements favoured bevacizumab. (Case 1) and just when you think you know it all..

72 Proposal for sequence of salvage-chemotherapy:

73 Q & A

Κίκα Πλοιαρχοπούλου. Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών

Κίκα Πλοιαρχοπούλου. Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών Κίκα Πλοιαρχοπούλου Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών Time (months) Survival outcomes in mcrc have progressively improved over the past two decades Treatment options for many patients Multidisciplinary