# Presentation: 711904

## Current and Future Perspectives on Irinotecan Pharmacogenomics

**ACPS**
**Clinical Pharmacology Subcommittee**
**3 November 2004**
**Luis A. Parodi, PhD - Director and Site Head, Clinical Pharmacogenomics**
**Mark E. Morrison, MD, PhD - Medical Director, Team Leader, Camptosar**
**Akintunde Bello, PhD – Associate Director, Clinical Sciences**

## Presentation Overview

**Commitment to safety**
**Application of pharmacogenomics at Pfizer**
**Review & analysis of published data**
**Ongoing studies**
**Collaboration with FDA**

## Pharmacogenomics at Pfizer

- .

- DISEASE

- GENETICS

- TARGET

- VARIABILITY

- SELECTING

- RESPONDERS

- PHARMACO-
- GENOMICS

**Discovery**

**Development**

***Choosing the Best Targets***

***Better Understanding of Our Targets***

***Improving Early Decision Making***

***Predicting Efficacy and Safety***

## Chronology of Pharmacogenomics Activities Related to Irinotecan

*Ca. 1996-7* - Provided irinotecan clinical supplies to NCI in support of early irinotecan pharmacogenomics (PGx) research at University of Chicago
*2000 to present* - Supported and sponsored several irinotecan clinical trials with PGx
*2001 to present* - Provided grant support to NCCTG for PGx in N9741 Ph-3 mCRC trial
*2002* - Collaboration with Epidauros AG in PGx of drug transporters and metabolizing enzymes
*2004* - Initiating irinotecan neoadjuvant study with PGx component

## Irinotecan Disposition & Metabolism

**Biliary Excretion**

**GI Absorption**

**SN-38             SN-38G**

*********Glucuronidase***
***(Bacterial)***

**NPC & APC**

***CYP3A4/5***

***Carboxylesterases***
***(CE1 & CE2)***

***UGT1A1***

***MDR1 (PGP)?***
***MRP2?***
***C-MOAT?***

***Other UGT Isoforms?***

**Active Metabolite**** **

**Inactive **
**Metabolite**

**Inactive M****etabolites**** **

**Parent Drug**

- GI Lumen

***BCRP***

**Irinotecan**

**SN-38**

**SN-38G**

## Key Publications Correlating UGT1A1 7/7 Genotype and Safety

| Author*, Year | N | Tumor Type | Irinotecan Dose (mg/m2), Schedule, & Combo |
| --- | --- | --- | --- |
| Innocenti, 2004 | 66 | Lung 29%, GE 21%, 
CRC 15%, other 35% | 350 q-3-wk, single agent |
| Rouits, 2004 | 75 | CRC 100% | 85 wkly + FU/LV
180 biwkly + FU/LV     |
| Marcuello, 2004 | 95 | CRC 100% | 350 q-3-wk, single agent 350 q-3-wk + raltitrexed 
80 wkly + FU 
180 biwkly + FU/LV |
| Ando, 2000 | 118 | SCLC 18%, 
NSCLC 55%, 
CRC 18%, other 9% | Various  |
| Font, 2003 | 51 | NSCLC 100% | 70 wkly + docetaxel |

- *Full citations given in Background Document.

## Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 Genotypes Unadjusted Odds Ratio

| Author | n/N (%) |  | Est. Odds Ratio | 95% CI |
| --- | --- | --- | --- | --- |
|  | 7/7 | 6/6 + 6/7  |  |  |
| Innocenti | 3/6 (50%) | 3/53 (6%) | 16.7 | 2.3 - 120.6 |
| Rouits | 4/7 (57%) | 10/66 (15%) | 7.5 | 1.4 - 38.5 |
| Marcuelloa | 4/10 (40%) | 18/85 (21%) | 2.5 | 0.6 - 9.7 |
| Andob | 4/7 (57%) | 22/111 (20%) | 5.4 | 1.1 - 25.9 |
| aGr 3+ neutropenia.  
bGr 4 leukopenia and/or Gr 3+ diarrhea.  
 |  |  |  |  |

## Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 Genotypes Summary

**No adjustments for known risk factors **
- There seems to be a statistically significant association in 3 of 4 studies between 7/7 and severe neutropenia
** ****Potential causes for interstudy variation include****:**
** **Small sample sizes
-  Different schedules/dose intensity
-  Other known risk factors (bilirubin, age, performance status, pelvic radiation)
-  Difference in population and cancer types treated

## Severe (Gr 3+) Diarrhea Risk: 7/7 vs 6/6 + 6/7 Genotypes Unadjusted Odds Ratio

**Association between 7/7 and severe diarrhea**
-  2 of 5 studies show statistical significance

|  | n/N (%) |  | Est. Odds Ratio | 95% CI |
| --- | --- | --- | --- | --- |
|  | 7/7 | 6/6 + 6/7  |  |  |
| Innocenti | 1/6 (17%) | 2/53 (4%) | 5.1 | 0.4 - 66.6 |
| Rouits | 2/7 (29%) | 11/66 (17%) | 8.4 | 0.3 - 11.7 |
| Marcuelloa | 7/10 (70%) | 22/85 (26%) | 6.7 | 1.6 - 28.1 |
| Andob | 4/7 (57%) | 22/111 (20%) | 5.4 | 1.1 - 25.9 |
| Font | 1/7 (14%) | 11/40 (27%) | 0.4 | 0.05 - 4.1 |
| aGr 3+ diarrhea;  bGr 4 leukopenia and/or Gr 3+ diarrhea. |  |  |  |  |

## Summary of published data

**Comprehensive review of published literature **
**Evaluate the frequencies of severe neutropenia & diarrhea and genotypes **
**Conclusion:****  **
- Significant association of the UGT1A1 7/7 genotype and the risk of developing Grade 4 neutropenia
- The association with severe diarrhea not as consistent between studies
**Translation of association data to a predictive performance requires assessing multiple parameters**
- Sensitivity, specificity, and positive & negative predictive values.

## Severe Neutropenia:Translating Associations into a Predictive Test

|  | Clinical Sensitivity | Clinical Specificity | PPV* | NPV* |
| --- | --- | --- | --- | --- |
| Innocenti | 0.5 | 0.94 | 0.5 | 0.94 |
| Rouits | 0.29 | 0.95 | 0.57 | 0.85 |
| Marcuello | 0.18 | 0.92 | 0.4 | 0.79 |
| Ando | 0.15 | 0.97 | 0.57 | 0.8 |
| Overall | 0.22 | 0.95 | 0.5 | 0.83 |
| * PPV, positive predictive value; NPV, negative predictive value. |  |  |  |  |

- _Assumption_: 	Genotyping assay is 100% accurate for detection of 		UGT1A1*28 allele

**Balancing neutropenia and efficacy in 7/7 positive patients:**
- Neutropenia is generally manageable
- Dose reduction may be unnecessary for 50%, with unknown consequences

## Ongoing Activities

**Ongoing Pfizer sponsored and supported trials aim to:**
- Better quantify the association between the UGT1A1*28 variant (as well as other genetic factors) and severe neutropenia & diarrhea
**Discussions are in progress with FDA on revising the Camptosar label to include pharmacogenomics information**

## Pfizer-Supported and -Sponsored Trials with a Pharmacogenomic Component* (Nov 2004)

| Protocol | Study Pop’n | Regimens | n***/N |
| --- | --- | --- | --- |
| NCCTG N9741 | 1st-line CRC | IFL, FOLFOX, IROX | 520/795 |
| SWOG 0124 | Extensive SCLC | cis + irino,
cis + etop | n/620 |
| NCCTG N0147 | Stage 3 Adj CRC | FOLFOX  cetux, 
FOLFIRI  cetux,
FOLFOX   FOLFIRI  cetux | n/4800 |
| PFE BICC-C†** | 1st-line CRC | FOLFIRI + bev  celecox,
IFL + bev  celecox,
(irino + cape  celecox) | >250/1200 |
| PETACC-3† | Stg 2-3 Adj CRC | FU/LV, FU/LV/irino | >700/3278 |
| * Multiple genes tested.  ** BICC-C amended to add bev and close irino + cape + celecox arm.  *** Number of patients on whom genomic analyses were/will be performed.   
† Pfizer-sponsored trial. |  |  |  |

## What do we hope to learn from these studies?

**Better define magnitude and strength of the association between UGT1A1*28 and safety**
**Identify other potential covariates of severe neutropenia & diarrhea**
**Provide information & guidance to health care practitioners to aid in their treatment decisions**