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Pharmacogenetics of Irinotecan Clinical perspectives: utility of genotyping

Pharmacogenetics of Irinotecan Clinical perspectives: utility of genotyping. Mark J. Ratain, MD University of Chicago 11/3/04. POSTER CHILD. FOR PHARMACOGENETICS. Relling & Dervieux, 2001. www.pharmgkb.org/ search/ pathway/ irinotecan/ liver.jsp.

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Pharmacogenetics of Irinotecan Clinical perspectives: utility of genotyping

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

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

  9. N9741: Overall Survival 100 90 IFL (med 15.0 mo) FOLFOX4 (med 19.5 mo) 80 IROX (med 17.4 mo) 70 60 % Alive 50 40 30 FOLFOX4 vs IFL (P=.0001; HR=0.66) 20 IROX vs IFL (P=.04) 10 0 0 1 2 Years Goldberg et al. J Clin Oncol. 2004;22:23.

  10. 100 80 60 Percent surviving 40 Treatment Group 20 IFL + placebo (n=411) IFL + bevacizumab (n=402) 0 0 Duration of survival (mo) 12 18 30 24 6 Survival • Mediansurvival: 15.6 vs 20.3 mo (HR=0.66, P<0.001) Hurwitz, NEJM, 2004 .

  11. Tournigand Trial: Schema No second-line or off study N=18 R A N D O M I Z A T I O N N=113 FOLFIRI FOLFOX Second-line N=81 FOLFOX FOLFIRI Second-line N=69 N=113 No second-line or off study N=31 Tournigand, J Clin Oncol, 2004

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

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

  14. 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

  15. UGT1A1 Testing for Gr 4 Neutropenia After CPT-11 (350 mg/m2 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

  16. UGT1A1 Testing for Gr 4 Neutropenia After CPT-11 (350 mg/m2 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

  17. UGT1A1 Testing for Gr 4 Neutropenia After CPT-11 (350 mg/m2 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

  18. 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

  19. 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)

  20. 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

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

  22. 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

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

  24. TS 5’UTR Allele (28 bp repeats) by Ethnic Groupadapted from Marsh, Human Mutation, 2000

  25. 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

  26. http://pharmacogenetics.org

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