Oncology Yaning Wang, Ph.D. Associate Director for Science - - PowerPoint PPT Presentation

Exposure-Response in Oncology

Yaning Wang, Ph.D. Associate Director for Science Division of Pharmacometrics Office of Clinical Pharmacology OTS/CDER/FDA

Disclaimer: My remarks today do not necessarily reflect the official views of the FDA

2

Outline

• Motivation
• Case study
• Summary

3

Declining Success Rate in Oncology Phase 3 Trials

67 46 10 20 30 40 50 60 70 80 1997-2002 2002-2007 Success Rate (%)

Drivers of Attrition-McKinsey & Co. Report 2008  21%

4

32 15 47 6 10 20 30 40 50 Efficacy vs placebo Safety-expected Safety-unexpected Efficacy vs active Safety vs active Percent

Drivers of Attrition-McKinsey & Co. Report 2008

Drivers for Oncology Phase 3 Failure (1990-2007)

5

Poor Estimation of Efficacy from Earlier Clinical Trials

• Novel or ‘unprecedented’ mechanisms
• Empirical selection of dose and dosing

schedules

• Poor correlation between biomarkers

and clinical response

• Short, single-arm phase 2 trials with

small sample size

• Large uncertainty on survival benefit

after phase 2 trials

6

Case Study: Herceptin

• Regimen approved for HER2-overexpressing breast cancer was

selected as the Phase 3 regimen for metastatic HER2-

• verexpressing gastric cancer
• Initial assumption: median OS of 7 months for fluoropyrimidine

(capecitabine or 5-fluorouracil) and cisplatin (FC) and 10 months for Herceptin+FC

• Three interim safety analyses and one interim efficacy (50%

death, 124) analysis

• Third safety interim analysis showed combined median OS of

12 months

• New assumption: median OS of 10 months for FC and 13

months for Herceptin+FC

• Two interim efficacy analyses (50% death, 230; 75% death 345)
• Second efficacy interim analysis (348 deaths) was significant at

pre-defined significance level and was used as final analysis

• Close of study was one year after 2nd interim analysis, the time

projected to have 460 deaths (full data, OS benefit: 1.4 month)

7

Phase 3 Clinical Trial

R A N D O M I Z A T I O N

Chemotherapy (FC) Trastuzumab + FC (T+FC)

FC: Cisplatin+

capecitabine/5-FU

N=594, 1:1

Trastuzumab: 8mg/kg followed by 6mg/kg q3w

8

Trastuzumab Demonstrated Overall Survival Benefit of 1.4 Months

FC (n=296) Trastuzumab+FC (n=298) Patients with Events 227 (76.7%) 221 (74.2%) Patients without Events 69 (23.3%) 77 (25.8%) Median OS in Months (95%CI) 11.7 (10.3, 13.0) 13.1 (11.9, 15.1) Hazard ratio (95%CI) 0.80 (0.67, 0.97)

9

Steep Exposure-Survival Relationship

Patients with Cmin <12 µg/mL Had 7-10 Months Shorter Median OS

Q1:Cmin <11.8 Q2:Cmin 11.8-16.2 Q3:Cmin 16.2-21.4 Q4:Cmin >21.4

10 20 30 40 50 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Q1:Cmin <11.8 Q2:Cmin 11.8-16.2 Q3:Cmin 16.2-21.4 Q4:Cmin >21.4 Median Survival (95% CI) 7.7 (6.3-10.6) 14.1 (9.5-19.3) 15.5 (13.1-24.3) 17.9 (14.8-21.2)

Overall Survival Study Month

10

Confounding Risk Factors for Survival

Lowest exposure pts (Q1) vs. the rest pts (Q2-Q4)

10 20 30 40 50 60 70 80 90 100

ECOG Performance Status (2) Prior Gastrectomy (No) Asia (No) Number of Metastatic Sites (>2)

Q2-Q4 (N=199) Q1 (N=67)

5% 24%

Poor ECOG performance No Prior Gastrectomy

70% 87%

# of metastatic sites >2 Non-Asian

40% 62% 42% 54%

Percentage

11 10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0

Time (month) Survival Distribution FC (all) H+FC (Q1)

Median Surival (95%CI) 11.7 ( 10.5 , 13.1 ) 7.7 ( 6.5 , 10.9 )

Is Herceptin Shortening Life?

12

Percentage of High Risk Patients Before and After Matching within Low Exposure Patients

10 20 30 40 50 60 70 80 90 100

ECOG Performance Status (2) Prior Gastrectomy (No) Asia (No) Number of Metastatic Sites (>2)

Percentage

FC (N=296) H+FC (N=67)

Before Matching

10 20 30 40 50 60 70 80 90 100

ECOG Performance Status (2) Prior Gastrectomy (No) Asia (No) Number of Metastatic Sites (>2)

FC (N=67) H+FC (N=67)

After Matching

13

0.0 0.2 0.4 0.6 0.8 1.0

FC FC+Trastuzumab

Median Surival (95%CI) 12.8 ( 11.2 , 14.2 ) 15.7 ( 14.1 , 19 ) 10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0

Time (month) FC FC+Trastuzumab

Median Surival (95%CI) 12.8 ( 11.2 , 14.2 ) 15.7 ( 14.1 , 19 )

No Survival Benefit in Low Exposure Patients Compared to Matched Control

10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0

Time (month) Survival Distribution FC FC+Trastuzumab

Median Surival (95%CI) 7.5 ( 6.4 , 10.8 ) 7.7 ( 6.5 , 10.9 )

Remaining (75%) Low Exposure (25%)

8 - 5.3 = 2.7

14

Reason for Lack of Benefit in Selected Subgroup (Matched)

• Low trastuzumab exposure

(Cmin <12 ug/mL)

– Implication: higher dose may work

• Low exposure (high risk) patients

may be non-responders?

– Implication: higher dose may not work

15

Support for Higher Dose

• All patients are sensitive to higher

trastuzumab exposure

• Low exposure (high risk) patients may be

more sensitive to higher trastuzumab exposure

Per 10 ug/mL increase in Cmin

0.2 0.4 0.6 0.8 1.2 Hazard Ratio Remaining Low Exposure (75%) (25%)

0.69 0.85

Lower PK Exposure in Advanced Gastric Cancer Patients

Breast cancer pts Advanced gastric cancer pts

Ctrough

Time (weeks)

• Steady state Ctrough 24-63% lower than that in breast cancer

patients using the same dosing regimen

17

Publication

18

Summary of Case Study

• Lack of exposure-response data to justify

regimen, leading to no survival benefit for 25% population

• Lack of justification for assumed effect size

led to under-powered study

• Exposure-response (ER) and case-control

analyses provided the rationale for post marketing requirement (PMR) study for a higher dose

• Trial design (dose selection, patient

population and effect size assumption) for PMR study was based on ER and case- control analyses

19

Conclusion

• Better efficacy estimation is needed for
• ncology phase 3 trials
• Pharmacometric analyses, such as

biomarker-survival relationship, ER modeling, should be routinely conducted to support dosing regimen selection, effect size estimation, patient population selection.

• Clinical trial simulation should become the

standard procedure for phase 3 trial design

20

Acknowledgment

• Jun Yang
• Hong Zhao
• Christine Garnett
• Joga Gobburu
• Atik Rahman
• William Pierce
• Genny Schechter
• Patricia Keegan
• Jeff Summers