1. Pharmacogenetics of Irinotecan Clinical perspectives: utility of genotyping Mark J. Ratain, MD University of Chicago 11/3/04

2. POSTER CHILD FOR PHARMACOGENETICS

3. Relling & Dervieux, 2001

4. www.pharmgkb.org/ search/ pathway/ irinotecan/ liver.jsp

5. Mass Balance Study of Irinotecan (Slatter, DMD, 2000)

6. Irinotecan Cytotoxic agent approved for metastatic colorectal cancer (CRC) –Usually administered in combination with 5-FU –Also active in many other malignant diseases Usage limited by toxicity –Life-threatening neutropenia (and associated infection) Primarily on q3 week schedule –Severe or life-threatening diarrhea (requiring parenteral fluids and/or hospitalization) Primarily on weekly (4 on, 2 off) schedule

7. Irinotecan is one of many FDA- approved choices for metastatic CRC 1 st line therapy –5-FU + leucovorin –Irinotecan –Oxaliplatin –Capecitabine –Bevacizumab 2 nd line therapy –Irinotecan –Oxaliplatin –5-FU + leucovorin –Cetuximab

8. How might clinicians choose among various choices? Personal experience Interpretation of phase III data Marketing influences Reimbursement Chemosensitivity testing Genotyping

9. 0 10 20 30 40 50 60 70 80 90 100 012 Years % Alive IFL (med 15.0 mo) FOLFOX4 (med 19.5 mo) IROX (med 17.4 mo) FOLFOX4 vs IFL (P=.0001; HR=0.66) IROX vs IFL (P=.04) N9741: Overall Survival Goldberg et al. J Clin Oncol. 2004;22:23.

10. Survival Median survival: 15.6 vs 20.3 mo ( HR=0.66, P<0.001). Percent surviving Duration of survival (mo) 20 0 121830 0 80 100 40 60 Treatment Group IFL + placebo (n=411) IFL + bevacizumab (n=402) 246 Hurwitz, NEJM, 2004

11. Tournigand Trial: Schema RANDOMIZATIONRANDOMIZATION FOLFIRI N=113 FOLFOX FOLFIRI N=69 N=81 Second-line No second-line or off study N=18 No second-line or off study N=31 Tournigand, J Clin Oncol, 2004

12. Tournigand Trial: Results Arm A Arm B FOLFIRI FOLFOX FOLFOX FOLFIRI Patients 109 81 111 69 Response 56% 15% 54% 4%

13. Tournigand, C. et al. J Clin Oncol; 22:229-237 2004 Fig 4. Overall survival curves

15. Neutropenia (q3 wk schedule) is Correlated with UGT1A1 Genotype (*28) (Innocenti et al, JCO, 2004) Bar represents median values. Nonparametric trend analysis among 6/6, 6/7, 7/7, p<0.01

16. UGT1A1 Testing for Gr 4 Neutropenia After CPT-11 (350 mg/m 2 q 3 wks) Sensitivity –50% of pts who have Gr 4 neutropenia are 7/7 Specificity –95% of pts who do not have Gr 4 neutropenia are not 7/7

17. UGT1A1 Testing for Gr 4 Neutropenia After CPT-11 (350 mg/m 2 q 3 wks) Positive predictive value –50% of pts who are 7/7 have Gr 4 neutropenia Negative predictive value –95% of pts who are not 7/7 do not have Gr 4 neutropenia

18. UGT1A1 Testing for Gr 4 Neutropenia After CPT-11 (350 mg/m 2 q 3 wks) Without testing, 100% of pts are treated and 10% have Gr 4 neutropenia With testing, 90% of pts are treated and 5% have Gr 4 neutropenia 5% absolute reduction –Test 20 to protect 1

19. Hypothesis Pharmacogenetic testing will improve outcomes in metastatic CRC –Will allow clinician to select drug regimen based on patient’s genetic (germline) characteristics Will lead to reduced toxicity Will lead to increased efficacy

20. UGT1A1 Testing Sufficient data exist to recommend that patients who are homozygous for *28 should not receive irinotecan at standard doses Alternative options –Accept greater toxicity –Reduce dose –Use alternative regimen (eg, oxaliplatin-based)

21. UGT1A1 Testing The optimal treatment of patients who are at reduced risk of irinotecan toxicity (eg, *1/*1) is unclear –Standard irinotecan-based regimens –High-dose irinotecan-based regimens May lead to increased efficacy –Oxaliplatin-based regimens

24. Most Common Mutation in DPD Exon 14-skipping mutation (Meinsma, DNA Cell Biol, 1995) –allelic frequency of approximately 0.01

25. DPD Testing (Exon 14-Skipping Mutation) for Gr 4 5-FU Toxicity Without test, all pts get treated and approximately 3% of pts will have toxicity With test, 98% of pts get treated and approximately 2% of pts will have toxicity 1% absolute reduction –Test 100 to protect 1

26. Different Lengths of a Polymorphic Repeat Sequence in the Thymidylate Synthase Gene Affect Translational Efficiency but Not Its Gene Expression Different Lengths of a Polymorphic Repeat Sequence in the Thymidylate Synthase Gene Affect Translational Efficiency but Not Its Gene Expression Kawakami, CCR, 2001

27. TS 5’UTR Allele (28 bp repeats) by Ethnic Group TS 5’UTR Allele (28 bp repeats) by Ethnic Group adapted from Marsh, Human Mutation, 2000

28. Parting Words Oncology is widely anticipated to be the best model for demonstrating the clinical importance of pharmacogenetics (germline polymorphisms) –Colorectal cancer is an important model because of the large number of active agents We have candidate genes, candidate polymorphisms, and abundant clinical data

29. http://pharmacogenetics.org