THE ROLE OF PREDICTIVE AND PROGNOSTIC MARKERS IN COLORECTAL CANCER

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1 THE ROLE OF PREDICTIVE AND PROGNOSTIC MARKERS IN COLORECTAL CANCER Cathy Eng, M.D., F.A.C.P. Associate Professor Associate Medical Director, Colorectal Center Dept of GI Medical Oncology November 5, 2010

2 Cancers of the Colon and Rectum International Statistics Colorectal cancer is the 3 rd most common cancer in men and the 2 nd most common in women. Incidence Worldwide 1.2 Million Mortality 609,000 per annum USA (2010) Incidence Mortality 142,540 51,370 Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010

3 Colorectal Cancer Trends in Males Center et al: CA Cancer J Clin 2009; 59:

4 Geographic Variation in Incidence of Colorectal CA in Men: 2008 Heterogeneity in South America Incidence/100,000 Bolivia (tan): 6.2 Columbia 10.6 Peru: 7.6 Brazil: 12 Argentina:25.3 vs in women Mortality: 15.2 vs. 9.4 in women

5 Background: Significance of Markers Definition Classic prognostic markers Chemotherapy options Chemotherapy alone Biologic Therapy : Kras WT: bevacizumab KRAS MT: limitations New predictive and prognostic markers

6 Pertinent Definitions: Prognostic marker: Determines prognosis regardless of type of treatment provided. Predictive marker: Presence or absence may impact the efficacy or toxicity of the treatment provided.

7 Advances in the Treatment of Colorectal Cancer FU Therapeutic concepts Palliative CT Adjuvant CT Neoadjuvant CT 5-FU = 5-fluorouracil; CT = chemotherapy. Cytotoxic therapies Irinotecan { Capecitabine Oxaliplatin K-ras Cetuximab Panitumumab Bevacizumab Targeted therapies {

8 Colorectal CA: Approximate 5-Year Survival by TNM Stage 140 % 5-Ye Year Survival IIIC (N 2 ) 27.3% IIIB 42% IIIA 59.8% 11% 0 Stage I Stage II (T 3-4 N 0 ) Stage III (LN+) Stage IV (Met)

9 Combination Chemotherapy Options: Pivotal Trials (No Biologic Therapy) Chemotherapy N RR (%) PFS (M) OS FOLFIRI TTP = 7 14M FOLFOX TTP = 7 15M XELOX (CapeOx) M FOLFOXIRI M Colucci et al. J Clin Oncol. 2005;23:4866; Cassidy et al: Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp ; Falcone, et al: J Clin Oncol May 1;25(13):1670-6

10 Classic predictive and prognostic markers of cytotoxic chemotherapy Agent 5-FU Irinotecan Oxaliplatin Marker Prognostic Efficacy TS + + Predictive Toxicity DPD + + TP + MSI + + (5-FU) + (5-FU) LOH 18q + UGT1A1 + ERCC1/2 + +

11 DPD, TS and TP Gene Expression vs Response to 5-FU/LV in Colorectal Cancer 1.2 Danenberg Tumo or Profile Scale DPD TS TP Response Non response m Patient ID Number Salonga, D. et al. Clin Cancer Res 2000;6:

12 Probability of survival in relation to the ERCC1 mrna expression level Low: 10.2 months (95% CI, 7.8 to 15.1 months) vs. High: 1.9 months (95% CI, 1.1 to 4.9 months) (P <.001; log-rank test) Shirota, Y. et al. J Clin Oncol; 19: Copyright American Society of Clinical Oncology

13 Significance of Microsatellite-Instability- High and 5-FU Resistance Genetic instability of the MMR proteins result in short, tandemly repeated nucleotide sequences due to frame shift or base pair substitutions known as microsatellites Sporadic: 15% sporadic colon cancers Hypermethylation 90% due to loss of MLH1 Germline: 5% of familial colorectal cancers Loss of MLH-2, MSH-6, or PMS-2 expression Presentation: Female, RT-sided, poorly differentiated, mucinous, signet ring tumors Several prior trials have correlated presence of MSI-H with 5-FU resistance

14 MSI-H as a Positive prognostic indicator independent of stage Gryfe; NEJM: Volume 342:69-77, 2000

15 2003 Analysis: Effect of MSI on Survival (No Chemotherapy) Percent Survival MSI-H MSS + MSI-L N= 42 N= 245 P-value = HR : 0.31 ( ) Years from Randomization Ribic, NEJM 2003

16 Percent Survival 2003 Analysis: Effect of chemotherapy in MSI-H patients Control Treatment N= 42 N= Ribic, NEJM 2003 Years from Randomization P-value = HR : 2.17 ( )

17 5-yr Overall Survival by Treatment Stage II dmmr patients % Alive P-value = for treatment by MMR (dmmr vs. pmmr) N = 55 Untreated N = 47 stage II patients fared better for OS Untreated 93% Treated 75% HR: 3.15 ( ) p= Years Sargent et al: ASCO 2008

18 Significance of MSI Predictive for lack of efficacy for 5-FU monotherapy only. Confirmed by Accent database (Sargent et al, JCO, 2010) Not informative re: FOLFOX Most informative in the stage II setting for monotherapy only.

19 MSI and Adjuvant Irinotecan? CALGB 89803: Tissue from n=723/1264 MSI status and DFS: HR 0.51, p=0.117 Adjuvant irinotecan: 5-year DFS for MSI-H = HR of 0.76 (95% CI, 0.64 to 0.88) vs 0.59 (95% CI, 0.53 to 0.64), (P =.03). Bertagnolli et al, JCO, 2009

20 ECOG 5202 Therapy Based on Genetics Stratify: Stage IIA or IIB MSS or MSI 18qLOH Low-Risk: MSS or MSI-L with retention of 18q alleles; MSI-H High-Risk: MSS/18qLOH or MSI/18qLOH Observation only Randomize to: FOLFOX6 FOLFOX6+BEV Primary endpoint: 3-year DFS Secondary endpoints: OS, toxicity, correlation between tumor biology and survival 20

21 Pivotal Trials in Metastatic Colorectal Cancer

22 Phase III Trial of IFL ± Bevacizumab in First-Line MCRC: Previously untreated MCRC ECOG PS 0-1 N=923 Primary end point: OS R A N D O M I Z A T I O N n=411 n=402 n=110 Secondary end points: PFS, ORR, and DOR IFL + placebo IFL + bevacizumab 5 mg/kg q2w 5-FU/LV + bevacizumab* 5 mg/kg q2w PD PD +Bev PD *Third arm discontinued after predetermined interim analysis demonstrated the safety of IFL + bevacizumab; Patients could continue bevacizumab therapy in combination with secondline therapy following progression. Avastin (bevacizumab) PI; Hurwitz et al. N Engl J Med. 2004;350:2335.

23 There Are NO Known Predictive Biomarkers for Anti-VEGF Therapy IFL +/- Bev Trial Proposed Biomarker Plasma VEGF Primary Tissue VEGF (ISH, IHC) Upstream Mediators of VEGF (ras, raf, P53) Other Angiogenic Mediators (TSP-2) Outcome Not Predictive Not Predictive Not Predictive Not Predictive Jubb et al. J Clin Oncol 24: , 2006 Ince et al. J Natl Cancer Inst. 97(13):981-9, 2005 Holden et al. ASCO. Abstract: 3555, 2005

24 Genetic Model of Colorectal Cancer Courtesy of Gail Wilkes, RN, Courtesy of Gail Wilkes, RN, Bergers & Benjamin, 2003; Kerbel & Folkman, 2002; Margolin, Gordon, Holmgren, et al., 2001; Kurahashi, Kaneko, and Makino, et al., 2002; Mendelsohn, Howley, Israel, et al., 2001, pp ; Smith, Carey, Beattie et al., 2002

25 Significance of Personalized Targeted Therapy

26 The EGFR signal transduction pathway EG FR EGFR ligand Target for anti-egfr Target for TKI 26 RAS PI3K PTEN BRAF MEK MAPK Signaling to the nucleus AKT/PKB mtor Proliferation/ maturation Chemotherapy radiotherapy resistance Angiogenesis Invasion and metastasis Survival (antiapoptosis)

27 QOL Limiting Factor with EGFR Targeted Therapy-associated Dermatologic Toxicity Acneform rash on chest Acneform rash on face Paronychial inflammation Segaert S, Van Cutsem E. Ann Oncol. 2005;16:

28 Cetuximab and K-ras in the epidermal growth factor receptor (EGFR) pathway Khambata-Ford, S. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

29 Phase III: Panitumumab vs. BSC: Impact of KRas on PFS (WT vs. Mutant) Proportion with PFS Pmab + BSC (WT) BSC Alone (WT) Events/N (%) Median In Weeks Mean In Weeks 115/124 (93) Pmab + BSC (MT) 76/84 (90) /119 (96) WT: HR = 0.45 (95% CI: ) Stratified log-rank test, p < Weeks Amado et al. JCO; Apr 1;26(10): , 2008

30 Background of KRAS: The presence of the KRAS mutation is the first globally utilized predictive marker for the treatment of MCRC. Implications: Reduction in unnecessary exposure Reduction in financial burden Reduction in unnecessary toxicities 30%-50% of all patients Result: Limited treatment options for 2 nd line and beyond

31 The CRYSTAL Trial FOLFIRI +/- Cetuximab Study Design EGFR-expressing Metastatic CRC R Weekly Cetuximab + FOLFIRI Primary Endpoint: PFS Populations Randomized patients: n=1217 Safety population: n=1202 ITT population: n=1198 FOLFIRI Van Cutsem E, et al. J Clin Oncol. 2007;25 (suppl). Abstr

32 CRYSTAL Efficacy (initial results) Primary endpoint : PFS ITT population independent review PFS subgroup: liver mets only PFS Estimate Cetuximab + FOLFIRI (n = 599) FOLFIRI (n = 599) 8.0 mo HR = 0.851; 95% CI, Stratified log-rank P = mo 1-year PFS rate 23% vs 34% PFS (mo) PFS Estimate Cetuximab + FOLFIRI (n = 122) FOLFIRI (n = 134) 9.2 mo HR = 0.637; 95% CI, Stratified log-rank P = mo PFS (mo) Van Cutsem E, et al. J Clin Oncol ;25 (suppl). Abstr

33 CRYSTAL Study - Update in PFS and OS by KRAS Cetuximab + FOLFIRI HR=0.63; p=0.007 mpfs WT (n=172): 9.9 months mpfs M T (n=105): 7.6 months FOLFIRI HR=0.97; p=0.87 mpfs WT (n=176): 8.7 months mpfs MT (n=87): 8.1 months estimate Progression-free survival Cetuximab + FOLFIRI mutant Cetuximab + FOLFIRI WT Median OS in patients 0.6 with KRAS WT tumors was 23.5 M in the cetuximab arm compared 0.5 with 20M in the chemotherapy-alone arm, for 0.4 FOLFIRI mutant a 20% reduction in risk (P =.0094) FOLFIRI WT Months Months Van Cutsem et al: ASCO 2008

34 Novel Predictive and Prognostic Markers

35 The EGFR signal transduction pathway EG FR EGFR ligand Target for anti-egfr Target for TKI 35 RAS PI3K PTEN BRAF MEK MAPK Signaling to the nucleus AKT/PKB mtor Proliferation/ maturation Chemotherapy radiotherapy resistance Angiogenesis Invasion and metastasis Survival (antiapoptosis)

36 Fig 3. (A and B) In wild-type KRAS patients, those carrying a BRAF-mutated tumor had Retrospective a shorter progression-free Analysis survival of the (PFS) Impact and overall of survival BRAF (OS) than wild-type BRAF patients (log-rank test, P =.0010 and P <.0001, respectively) on response to anti-egfr therapy Kras WT All patients Di Nicolantonio, F. et al. J Clin Oncol; 26: Copyright American Society of Clinical Oncology

37 Updated CRYSTAL Data: KRAS/BRAF 540/1198 subjects (45% of ITT) 1 : KRAS evaluable population 1063 (89%) subjects: updated KRAS evaluable population 666 (63%) KRAS wild-type 625 (59%) KRAS wild-type/braf evaluable KRAS wild-type/braf wild-type 566/625 (91%) KRAS wild-type/braf mutant 59/625 (9%) Sample numbers for KRAS and BRAF mutation status were increased using DNA extracted from tumor from paraffin blocks or formalin fixed paraffin embedded slide mounted sections prepared to evaluate tumor EGFR expression KRAS (codons 12/13) and BRAF (V600E) mutations were detected using a PCR clamping and melting curve technique BRAF mutations were detected in a total of 60/1000 (6%) evaluable samples,1 patient was also KRAS mutant 1 Van Cutsem E, et al. N Engl J Med 2009;360:

38 CRYSTAL: Clinical efficacy in KRAS wild-type tumors by BRAF mutation status Median OS mo [95% CI] KRAS wt/braf WT (n=566) FOLFIRI (n= 289) 21.6 [ ] Cetuximab +FOLFIRI (n= 277) 25.1 [ ] KRAS wt/braf MT (n=59) FOLFIRI (n=33) 10.3 [ ] Cetuximab +FOLFIRI (n=26) 14.1 [ ] HR [95% CI] [ ] [ ] p-value a Median PFS mo [95% CI] HR [95% CI] [ ] p-value a OR rate (%) [95% CI] Prognostic 8.8 but NOT 10.9 powered 5.6 for [ ] [ ] [ ] prediction of efficacy of therapy 42.6 [ ] 61.0 [ ] 8.0 [ ] [ ] [ ] p-value b < [ ] a Stratified log-rank test; b Cochran-Mantel-Haenszel test CI, confidence interval; OR, best overall response; OS, overall survival; PFS, progression-free survival; mo, months; mt, mutant; wt, wild-type

39 EGFR Ligand Expression: Amphi- and Epiregulin AREG and EREG are endogenous ligands for EGFR Ligand binding to the EGFR initiates a signaling cascade Activates tyrosine kinase (TK) activity, which modulate cellular proliferation, differentiation, and survival In malignant cells, EGFR TK is inappropriately activated EGFR overexpression and increased production of receptor ligands may cause excessive signaling in tumor cells Arteaga CL. J Clin Oncol. 2001;19(suppl 18):32s-40s; Herbst RS, Shin DM. Cancer. 2002;94: ; Ritter CA and Arteaga CL. Semin Oncol. 2003;(suppl 1):311.

40 mrna levels of epidermal growth factor receptor ligands epiregulin and amphiregulin (EREG: P = AREG: P = Khambata-Ford, S. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

41 Patients Free of Tumor Progression (%) Epiregulin/Amphiregulin Levels Correlate With PFS in mcrc EREG p = EREG expression cutoff 500 High Low Patients Free of Tumor Progression (%) AREG p = AREG expression cutoff 100 High Low v 57 days v 57 days Time (days) Hazard ratio = % CI = to Time (days) Hazard ratio = % CI = to Khambata-Ford S, et al. J Clin Oncol. 2007;25:

42 The EGFR signal transduction pathway EG FR EGFR ligand Target for anti-egfr Target for TKI 42 RAS PI3K PTEN BRAF MEK MAPK Signaling to the nucleus AKT/PKB mtor Proliferation/ maturation Chemotherapy radiotherapy resistance Angiogenesis Invasion and metastasis Survival (antiapoptosis)

43 The EGFR signal transduction pathway EG FR EGFR ligand Target for anti-egfr Target for TKI 43 RAS PI3K PTEN BRAF MEK MAPK Signaling to the nucleus AKT/PKB mtor Proliferation/ maturation Chemotherapy radiotherapy resistance Angiogenesis Invasion and metastasis Survival (antiapoptosis)

44 Dutch TME Trial: Impact of PI3K on Prognosis in Rectal Cancer 5-yr: 27.8% vs. 9.4% He et al: Clin Cancer Res Nov 15;15(22): Epub 2009 Nov 10.

45 Challenges in The Treatment for the KRAS MT Patient

46 Treatment Options for the KRAS MT First line: MCRC patient Chemo + bevacizumab or no biologic agent 2 nd line: Chemo + continuation of bev or no biologic (BRiTE trial) Clinical trial > 3 rd line: Clinical trial

47 Alternate Pathways for KRAS MT Tumors Prenen et al: Clin Cancer Res Jun 1;16(11): Epub 2010 May 11. Review.

48 Concordance of Primary vs. Met? N=107 Santini et al: The Oncologist, Vol. 13, No. 12, , December 2008;

49 Concordance demonstrated in small studies No verification from larger phase III trials of site of KRAS testing Anecdotal experience T.H.: Discordance of local recurrence R.S. Discordance of primary vs. met

50 Variability in Mutation Status

51 De Roock et al: JAMA, October 27, 2010 Vol 304, No. 16

52 OS by mutation status in Cetuximab treated patients. De Roock et al: JAMA, October 27, 2010 Vol 304, No. 16

53 Conclusions: Rather than pursuing standard cytotoxic chemotherapy we are pursuing select approaches Goal: reduce unnecessary toxicities and exposure of the patient. Be cautious of pursuing a select prospective predictive marker w/o validation of large studies May be unnecessarily excluding patients