AAPS NBC 2014
Pharmacokinetics of
Trastuzumab and
Bevacizumab in Gastric
Cancer
Chunze Li, Angelica Quartino, Kelong Han, David
Allison, Amit Garg, Ranvir Mangat, Bert Lum
Jin Jin, Sandhya Girish, Jennifer Visich, Amita Joshi
©2012, Genentech
Outline
v  Compare the PK of trastuzumab (ToGA) and bevacizumab
(AVAGAST) in metastatic gastric cancer (mGC) to other solid tumors
v  In-depth data analysis: Would any existing covariate relationships
explain the faster clearance of mAbs in mGC?
•
•
Patient and disease characteristics
Subgroup analysis
v  Possible mechanisms for the faster clearance of mAbs in mGC
•
•
HER2 target related mechanism
Non-target related mechanism
v  Summary
©2012, Genentech
2
Trastuzumab concentration is lower in mGC (ToGA)
compared to metastatic breast cancer (mBC) patients
ToGA study design
Dose regimen: 6 mg/kg Q3W (8
mg/kg loading dose)
PopPK approach Mean±SE Observed Ctrough
mBC
mGC (ToGA)
Time (days)
PopPK Model Prediction
Observed
Median Observed Conc.
Time (weeks)
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Trastuzumab Conc (µg/mL)
Trastuzumab Conc (µg/mL)
6 mg/kg q3w (8 mg/kg loading dose), n=266
*Base model was used in simulation for trastuzumab
Assessment report for herceptin. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Assessment_Report_-_Variation/human/000278/
WC500074921.pdf
Lower trastuzumab concentrations are associated with shorter overall
survival (ToGA Trial)
•  Patients at the Lowest quartile (Cmin <11.8 µg/mL) had 7-10 months Shorter
Median survival time
•  The poor outcomes of patients with low PK in the ToGA trial has led to the PMR/
FUM trial, HELOISE to study the impact of a higher trastuzumab IV dose
©2012, Genentech
Yang J and Wang Y et al, J Clin Pharmacol, 53:160-166, 2012
Bevacizumab exposure was lower in mGC as compared to other solid
tumor
5
200
2
5
10 20
50
7.5 mg/kg q3w, n=162
1
AVAGAST study design
Bevacizumab Plasma Concentration (ug/mL)
Bevacizumab PK in AVAGAST 0
10
20
30
40
Time after Last Dose (Days)
PopPK Model Prediction
Observed
©2012, Genentech
Kelong Han, Jin Jin, Mauricio Maia, John Lowe, Martina A. Sersch, David E. Allison, AAPS J, 2014
50
Summary – mAb PK in GC
Would any existing covariate relationships explain the
lower exposure of mAb in mGC?
q  Do mGC patients have the same covariate distribution as other cancer
patients?
q  Would mGC patients have similar exposure with other cancer patients,
after accounting for single covariate?
q  Would combination of multiple significant covariates identified by popPK
model explain the mAb PK differences between mGC and other solid
tumors?
©2012, Genentech
6
Summary – Historical PopPK
Factors that May be Correlated with mAb PK
Demographic data
•  BW is the most important covariate for the mAb PK
•  Age and race do not affect mAb PK
Patient health status and disease severity
•  Albumin and baseline tumor size are often identified as statistically significant
covariates for mAb PK in oncology
•  HER2 ECD is often identified as a significant covariate for Her-2 molecules, but
its impact on the mAb exposure is small and not clinically relevant
•  CRP appears to be correlated with the PK of mAb, but has not been consistently
evaluated across molecules.
•  ECOG is not identified as a significant covariate on mAb PK, though ECOG
status may show correlation with the mAb PK as ECOG is correlated with other
covariates.
•  Prior gastrectomy is identified as a statistically significant covariate for
trastuzumab PK in ToGA, but its effect on trastuzumab exposure is small.
•  HER2+ expression levels does not appear to be correlated with mAb PK at
clinical relevant doses.
Liver enzymes
•  Liver enzymes, such as ALT, AST and ALK, are occasionally identified as
significant covariates for mAb PK, but their impact on the mAb exposure are
usually very small and not of clinical relevance.
©2012, Genentech
7
Summary – mAb PK in GC
8
Patient Characteristics in HER2+ mGC vs mBC
BW (kg) Gender: Male ( %) Age (year) Race: Asian (%) Albumin (g/L) ALK (U/L) ALT (SGPT, U/L)) AST (SGOT, U/L) Her-2 ECD (ng/mL) Baseline tumor size (cm) ECOG: % (n) for ECOG =>2 Metastatic Gastric Cancer (ToGA) N Median (range) 294 62 (35-111) 294 226 (77%) 294 61 (23-83) 294 151 (51%) 294 38.8 (24.0-75.0) 294 97.6 (26-834) 293 25 (5-217) 294 23 (7-195) NR NR 242 8.6 (1.1-46.2) 266 26(9.8%) Metastatic Breast Cancer N Median (range) 402 65 (39-129) 402 0 (0%) 402 54.0 (22-82) 402 128 (31.8%) 395 42.0 (32.0-51.0) 400 85 (16-589) 401 30 (7-262) 400 28.0 (10.0-148) 368 24.7 (0.847-3245) 351 7.9 (1-42.2) 402 •  Apparent differences were observed for the following demographic
characteristics between mGC and mBC: gender, race and ECOG.
•  Her-2 ECD was not measured in ToGA
©2012, Genentech
3(0.74%) Patient Characteristics in mGC vs Other Solid Tumors in
Bevacizumab Trials
BW (kg) Gender: Male ( %) Age (year) Race: Asian (%) Albumin (g/L) Baseline tumor size (cm) ECOG: % (n) for ECOG =>2 Metastatic Gastric Cancer
(AVAGAST)
N
Median (range)
162
60 (36-100)
162
109 (67%)
162
58 (28-81)
162
101 (62%)
162
39 (27-48)
162
10.2 (1.6-48.5)
162
11 (6.0%)
9
Other solid tumor N 533 533 533 533 533 533 Median (range) 74 (49-114)
233 (43.8%)
59 (21-88)
0%
37 (29-44)
NR
533 10 (1.8%)
Differences were observed for the following demographic characteristics:
gender, race and ECOG.
©2012, Genentech
Kelong Han, Jin Jin, Mauricio Maia, John Lowe, Martina A. Sersch, David E. Allison, AAPS J, 2014"
Summary – mAb PK in GC
Gender and race do not affect Trastuzumab and
Bevacizumab clearance in mGC
Trastuzumab
Gender 10
5
CL (mL/day/kg)
15
10
5
CL (mL/day/kg)
10
15
Race
Reference line
for mBC
Female
Male
Non-Asian
MBC
Asian
CL (mL/day/kg)
CL (mL/day/kg)
Bevacizumab
Reference line
Female
©2012, Genentech
Male
Asian
Non-Asian
Kelong Han, Jin Jin, Mauricio Maia, John Lowe, Martina A. Sersch, David E. Allison, AAPS J, 2014"
MBC
Summary – mAb PK in GC
Trend of higher CL in patients with higher ECOG, but CL for mGC
patients with ECOG of 0 are still higher than other cancers
Trastuzumab
11
CL (mL/day/kg)
10
15
5
ECOG
Reference line
for mBC
PS 0
PS 2
CL (mL/day/kg)
Bevacizumab
PS 1
Reference line
PS 0
©2012, Genentech
PS 1
PS 2
Kelong Han, Jin Jin, Mauricio Maia, John Lowe, Martina A. Sersch, David E. Allison, AAPS J, 2014"
Angelica and Kelong Summary – mAb PK in GC
Trend of higher CL in patients with more metastatic sites and
without prior gastrectomy
12
55
CL (mL/day/kg)
CL (mL/day/kg)
10
15
10
15
CL (mL/day/kg)
CL (mL/day/kg)
10
15
10
15
55
Trastuzumab
1-4 metastatic lesions
MBC
No Prior Gastrectomy
Prior Gastrectomy
NO
YES
Prior Gastrectomy
MBC
CL (mL/day/kg)
CL (mL/day/kg)
Bevacizumab
>4 metastatic lesions
1-4
>4
Number of Metastatic sites
Reference line
for mBC
Reference line
Number of Metastatic sites
©2012, Genentech
Prior Gastrectomy
Kelong Han, Jin Jin, Mauricio Maia, John Lowe, Martina A. Sersch, David E. Allison, AAPS J, 2014"
Angelica and Kelong Summary – mAb PK in GC
No Single Covariate can Explain the PK Difference between mGC and Other Solid
Tumors (Albumin example)
Trastuzumab
Reference line
for mBC
g/L
<30< 30g/L
>= 30 g/L
≥30g/L
CL (mL/day/kg)
CL (mL/day/kg)
CL (mL/day/kg)
10
15
55
10
15
MBC
MGC
MBC
Baseline Albumin (g/L)
Reference line
<30 g/L
©2012, Genentech
≥30 g/L
CL (mL/day/kg)
CL (mL/day/kg)
Bevacizumab
Baseline Albumin (g/L)
Kelong Han, Jin Jin, Mauricio Maia, John Lowe, Martina A. Sersch, David E. Allison, AAPS J, 2014"
13
100
50
10
5
1
Herceptin Serum Level (ug/mL)
500 1000
Combination of Multiple Significant Covariates Identified in popPK Model
Explains Part but not All of the Lower Exposure of mAb in mGC:
Herceptin
0
21
42
63
84
105
126
147
168
Time (Days)
MBC PopPK base Model Prediction (median w 90% CI)
Observed data for ToGA trial
Median of the Observed Conc.
MBC PopPK Final Model Prediction (median)
MBC PopPK Final Model Prediction (90% CI)
©2012, Genentech
Significant
Covariates N Weight (kg) ToGA 266 62 (35-111) ALK (U/L) 97.6 (26-834) HER2+ ICH 3+ 129 (48.5%) mBC popPK 265 68 (41-131) 107 (33 -867) 191 (72.1%) 14
Hypothesis
Possible Mechanisms for Faster Clearance of mAbs in mGC
Ø  HER2 target-related mechanism
•
HER2 expression level
•  Tumor burden
•  HER2 ECD
Ø  Non-target related mechanism
•  Patient health status, disease severity and cachexia
•  Inflammation vs Cancer
•  Gastric protein leakage in mGC patients
©2012, Genentech
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Hypothesis
Her-2 Target Related Mechanism
x Her-2 expression levels
•  Her-2 expression levels appears to be similar between mGC and mBC
•  Her-2 expression levels (IHC score) was not identified as a significant covariate
for trastuzumab PK in both mGC and mBC at the therapeutic doses.
•  Accessibility of mAbs to the HER2+ tumor and HER2 receptor turn-over rate in
mBC and mGC are unknown
x Tumor bulk
•  In house data showed that tumor size is similar
? HER-2 SHED ECD
•  Assay: SHED ECD appears not to affect free mAb assay at physiologically
relevant ECD concentrations.
•  Preclinical: Antibody-ECD complex was shown to have a greater clearance than
free antibody in monkeys
•  Clinical: SHED ECD was identified as a significant covariate for the clearance of
the trastuzumab or T-DM1 in mBC, but the magnitude of the impact on PK was
relatively small and was not of clinical relevance. ECD was not collected in
ToGA.
•  Limited data showed that ECD levels were similar between mGC (JOSHUA) and
mBC
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16
Biology Results
mRNA expression of Her-2 receptors in Breast and Gastric Cancer
Relative mRNA Expression Levels
Her-2 mRNA levels in gastric cancer are similar to breast cancer if not less.
©2012, Genentech
17
Hypothesis
Her-2 Target Related Mechanism
x Her-2 expression levels
•  Her-2 expression levels appears to be similar per cell basis
•  Her-2 expression level (IHC score) was not identified as a significant covariate
for trastuzumab clearance in both mGC and mBC at the therapeutic doses.
•  Accessibility of mAbs to the HER2+ tumor and HER2 receptor turn-over rate in
mBC and mGC are unknown
x Tumor bulk
• In house data showed that baseline tumor size is similar
? HER-2 SHED ECD
• Assay: SHED ECD appears not to affect free mAb assay at physiologically relevant
ECD concentrations.
• Preclinical: Antibody-ECD complex was shown to have a greater clearance than
free antibody in monkeys
• Clinical: SHED ECD was identified as a significant covariate for the clearance of the
trastuzumab or T-DM1 in mBC, but the magnitude of the impact on PK was relatively
small and was not of clinical relevance. ECD was not collected in ToGA.
• Limited data showed that ECD levels were similar between mGC (JOSHUA) and
mBC
©2012, Genentech
18
Clinical Results
Baseline Tumor Size in HER2+ mGC and mBC
Density Density Median
Mean
mGC appears to have similar baseline tumor size to mBC
©2012, Genentech
19
Hypothesis
Her-2 Target Related Mechanism
x Her-2 expression levels
•
•
•
Her-2 expression levels appears to be similar per cell basis
Her-2 expression level (IHC score) was not identified as a significant covariate for
trastuzumab PK in both mGC and mBC at the therapeutic doses.
Accessibility of mAbs to the HER2+ tumor and HER2 receptor turn-over rate in mBC and
mGC are unknown
x Tumor bulk
• In house data showed that baseline tumor size is similar
? HER-2 SHED ECD
• Assay: SHED ECD appears not to affect free mAb assay at physiologically relevant ECD
concentrations
•
•
•
Mean trastuzumab Ctrough ~60 µg/mL
Typical baseline HER2 ECD level 10-20 ng/mL
No assay Interference of HER2 ECD on trastuzumab assay when trastuzumab/ECD ration ≥10
• Preclinical: Antibody-ECD complex was shown to have a greater clearance than free antibody
in monkeys
• Clinical: SHED ECD was identified as a significant covariate for the clearance of the
trastuzumab in mBC, but the magnitude of the impact on PK was relatively small and was not of
clinical relevance. ECD was not collected in ToGA.
• Limited data showed that ECD levels were similar between mGC (JOSHUA) and mBC
©2012, Genentech
20
Clinical data
HER2 ECD is a Significant Covariate for Trastuzumab PK in mBC
HER 2 ECD vs trastuzumab clearance in mBC
Median level of HER2 ECD is expected to be ~80 fold higher in mGC than mBC if
HER2 ECD is the only factor to explain the PK differences (1480 ng/mL for mGC vs
~17.9 ng/mL for mBC)
©2012, Genentech
Bruno R, et al, Cancer Chemother Pharmacol, 56:361-369, 2005
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Clinical data
HER2 ECD levels were similar between HER2+ mBC and mGC
0.008
Density
0.0
0.004
Density
0.012
HER2+ mBC*
Median (range): 23.8 (5.8, 16465) ng/mL, n=214
0
500
1000
1500
2000
2500
HER2 ECD SHED
(ng/mL)
ECD
0.010
0.005
0.0
Density
0.015
HER2+ mGC
Median (range): 12.4 (5.1, 2268) ng/mL, n=30
0
500
1000
1500
2000
2500
HER2 ECD (ng/mL)
SHED ECD
•  Though data is limited, HER2 ECD levels in mGC does not appear to be much higher than
that of mBC.
•  As a result, HER2 ECD might not be the main driver for the observed PK differences
©2012, Genentech
*Please note: The top two SHED ECD data (3129 and 16465 ng/mL) was removed from the
plot to enable to see the lower concentration better
22
Hypothesis
Her-2 Target Related Mechanism
x Her-2 expression levels
•
•
•
Her-2 expression levels appears to be similar per cell basis
Her-2 expression level (IHC score) was not identified as a significant covariate for
trastuzumab PK in both mGC and mBC at the therapeutic doses.
Accessibility of mAbs to the HER2+ tumor and HER2 receptor turn-over rate in mBC and
mGC are unknown
x Tumor bulk
• In house data showed that baseline tumor size is similar
x HER-2 SHED ECD
• Assay: SHED ECD appears not to affect free mAb assay at physiologically relevant ECD
concentrations
•
•
•
Mean trastuzumab Ctrough ~60 µg/mL
Typical baseline HER2 ECD level 10-20 ng/mL
No assay Interference of HER2 ECD on trastuzumab assay when trastuzumab/ECD ration ≥10
• Preclinical: Antibody-ECD complex was shown to have a greater clearance than free antibody
in monkeys
• Clinical: SHED ECD was identified as a significant covariate for the clearance of the
trastuzumab in mBC, but the magnitude of the impact on PK was relatively small and was not of
clinical relevance. ECD was not collected in ToGA.
• Limited data showed that ECD levels were similar between mGC (JOSHUA) and mBC
©2012, Genentech
23
Hypothesis
Non-Target Related Mechanism
x Patient health status and disease severity
•  No apparent difference in patient characteristics observed in the mGC and
mBC, except gender, race and ECOG.
•  Gender and Race do not impact mAb PK and ECOG alone is not sufficient
to explain the PK differences
•  No single covariate can explain the PK Difference between mGC and Other
Solid Tumors
•  Combination of known significant covariates identified by popPK explains
part but not all of the lower exposure of mAb in mGC
? Acute phase response and inflammation
•  Systemic inflammation has long been associated with cancer
•  Elevated Inflammatory biomarkers observed in gastric and breast (limited) cancer.
•  Inflammatory factors, such as CRP, albumin, ESR appear to have a trend
with mAb clearance
? Gastric protein leakage of mAbs in gastric cancer patients
•
•
Gastric cancer vs gastric tissue inflammation
Passage of albumin into stomach was observed in gastric cancer patients
©2012, Genentech
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Gap Summaries
Lack of understanding the underlying biology process
•  Accessibility of mAbs to the HER2+ tumor and HER2 receptor turnover rate in mGC and mBC
•  Inflammation differences between mGC and other solid tumors (ie
mBC)
•  No direct comparison between the two cancers was reported and crosscomparison between studies is challenging.
•  Optimal inflammatory biomarkers has not been defined
•  How does inflammation lead to faster mAb clearance
•  Role of gastric protein leakage in mAb clearance in gastric cancer
•  Gastric cancer vs gastric tissue inflammation
•  Gastric protein leakage of mAb has not been directly demonstrated
•  Gastric protein leakage marker to identify the mGC patients with potentially
faster mAb clearance has not been identified
Missing information in our current and completed clinical trials
•  Inflammatory cytokines
•  acute phase proteins
©2012, Genentech
25
Summary
q  Lower exposures of trastuzumab and bevacizumab were observed in
metastatic gastric cancer (mGC), as compared to other solid tumors.
•
Lower trastuzumab concentrations are associated with poorer tumor response
and shorter survival.
The poor outcomes of patients with low PK in the ToGA trial has led to the PMR/
FUM trial to study the impact of a higher trastuzumab IV dose
Is the phenomenon mGC specific? PK of ramucirumab in mGC?
Panc: faster CL for Ganitumab (anti-IGF1R mAb) (Zhu et al 2013)
•
•
•
q  Mechanism of faster clearance in mGC was explored, but not fully
understood
•
Patient health status and disease severity explains part but not all of the
lower exposure of mAb in mGC
Inflammation and gastric protein leakage are the two possible hypothesis to
be tested
•
q  Implication on trial design
•
When should we conduct dose finding study for mAbs in gastric cancer ?
•
•
©2012, Genentech
Small phase 1b vs larger Phase 2 (multiple dose)
Endpoints: PK focused vs PK, safety and efficacy
26
Acknowledgement
Clinical Pharmacology
Bert Lum
Angelica Quartino
Kelong Han
Amit Garg
David Allison
Mark Stroh
Steve Eppler
Dan Lu
Jing Li
Ranvir Mangat
Manasa Tatipalli
Srikumar Sahasranaman
Jin Jin
Sandhya Girish
Jennifer Visich
Amita Joshi
©2012, Genentech
27
Biology
Gail Phillips
Mark Sliwkowski
Noel Dybdal
Clinical development
Ron Walker
Jennifer Eng-Wong
Assay
Ihsan Nijem
Eric Wakshull
Alyssa Morimoto
EPKPD
Andy Boswell
Cinthia Pastuskovas
Leslie Khawli
Jack (Jay) Tibbitts
GDTLs
Harald Weber (Herceptin)
Kip Benyunes (Pertuzumab)
Martina A Sersch (Avastin)
Ellie Guardino (T-DM1)
University of Buffalo
Professor Joseph Balthasar
Literature
Inflammatory Cytokines may be Elevated in Gastric Cancer
Patients (Literature Review)
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Positive Correlation between Golimumab Clearance and CRP
©2012, Genentech
Xu ZH et al, International J of Clin Pharmacol Ther, 48: 596-607, 2010
30