Transcript A Phase Ib/II Trial of Trastuzumab-DM1 (T

A Phase Ib/II Trial of Trastuzumab-DM1
(T-DM1) with Pertuzumab for Women
with HER2-Positive Locally-Advanced
or Metastatic Breast Cancer who were
Previously Treated with Trastuzumab
K. Miller,1 L. Gianni,2 F. Andre,3 V. Dieras,4 R.L. Mahtani,5
N. Harbeck,6 J.E. Huang,7 T. Shih,7 Y. Choi,7 H.A. Burris1
1Indiana
University Melvin and Bren Simon Cancer Center, Indianapolis, IN; 2Montabone Unit
for New Drug Development, Istituto Nazionale dei Tumori, Milano, Italy; 3Inst Gustave Roussy,
Villejuif, France; 4Institut Curie, Paris, France; 5Boca Raton Comprehensive Cancer Center,
Boca Raton, FL;
6Breast Center, Dept. OB & GYN, University of Cologne, Cologne, Germany; 7Genentech, Inc.,
South San Francisco, CA; 8Sarah Cannon Research Institute, Nashville, TN
ASCO 2010
T-DM1
•
T-DM1 is a HER2-targeted antibody drug conjugate composed of the cytotoxic
agent DM1 (a maytansinoid anti-microtubule agent) conjugated to the
monoclonal antibody trastuzumab (Herceptin®, Genentech, Inc. and Roche,
South San Francisco, CA) via the highly-stable thioether linker Nmaleimidomethyl) cyclohexane-1-carboxylate (MCC).
Schematic of
Trastuzumab-DM1 (T-DM1)
•
T-DM1 has shown encouraging single-agent efficacy and a good safety profile in
patients with heavily pre-treated HER2-positive (HER2+) metastatic breast
cancer (MBC) in two Phase II trials.
Includes the [N-maleimidomethyl]cyclohexane-1-carboxylate (MCC) linker. An average of 3.5 DM1 molecules are
conjugated to the Fc region of trastuzumab.
Pertuzumab
•
•
Pertuzumab (Genentech, Inc. and Roche, South San Francisco, CA), a
recombinant, humanized monoclonal antibody directed against HER2, binds
a domain of HER2 that does not overlap with the epitope recognized by
trastuzumab, inhibits ligand-activated heterodimerization with other HER
receptors, most notably HER3.
The combination of pertuzumab and trastuzumab or T-DM1 provides a
complementary mode of action that may be efficacious for treatment of
HER2-overexpressing diseases.
Combination of Pertuzumab with T-DM1 in a HER2+
Xenograft Model
• The combination T-DM1 and pertuzumab treatment shows enhanced
activity a KPL-4 trastuzumab-resistant breast tumor xenograft model.
Study TDM4373g
• This global, single-arm, Phase Ib/II study investigates the
safety and effiicacy of the combination of T-DM1 with
pertuzumab in patients with HER2-positive locally
advanced or MBC.
• In the 3+3 design, patients received pertuzumab (840
mg, Cycle 1; 420 mg, Cycle 2 and beyond) with T-DM1
(3.0 mg/kg in Cohort 1 and, in the absence of dose
limiting toxicity [DLT], 3.6 mg/kg in Cohort 2).
• Once dose escalation was complete, additional patients
were added to the expansion phase.
3+3 Study Schema for TDM4373g
DLT=dose-limiting toxicity; T-DM1=trastuzumab-MCC-DM1.
* Full-dose pertuzumab=Cycle 1 loading dose (840 mg); 420 mg all subsequent cycles.
† Patients enrolled to the initial cohort may now receive 3.6 mg/kg T-DM1 in subsequent cycles along with full-dose pertuzumab.
‡ 20 first-line and 40 relapsed (second-line and beyond) patients were to be included in this phase.
TDM4373g Objectives
Primary objectives:
• To characterize the safety and tolerability of the combination of TDM1 and pertuzumab administered every 3 weeks (q3w) to patients
with HER2-positive locally advanced or MBC
• To evaluate the pharmacokinetics of T-DM1 when T-DM1 and
pertuzumab are administered on this schedule
• To make a preliminary assessment of the efficacy of T-DM1 and
pertuzumab administered on this schedule, as measured by
objective response rate (ORR) based on investigator assessment.
Secondary objectives:
• To estimate PFS of patients who receive T-DM1 and pertuzumab
administered on this schedule
• To assess the duration of response to T-DM1 and pertuzumab
administered on this schedule
• To assess the development of anti-therapeutic antibodies to T-DM1
Key Inclusion Criteria
• Histologically-documented locally advanced or metastatic
HER2-positive BC (HER2-positivity documented as FISH+ or
CISH+ or IHC 3+ by local laboratory assessment)
• Measurable disease
• Prior HER2-directed therapy (for patients second-line or
beyond)
• No prior T-DM1 or pertuzumab therapy
• Cardiac ejection fraction >55% by either echocardiogram
(ECHO) or multiple gated acquisition (MUGA scan).
Key Exclusion Criteria
• History of exposure to cumulative doses of anthracyclines
>500 mg/m2 doxorubicin.
• History of cardiac dysfunction.
Study Assessments
• Patients were monitored for safety and tolerability of
treatment weekly during the first 3 cycles, every cycle
thereafter, at the treatment termination visit, and during
the follow up period (30 days after ending study
treatment).
• Radiographic assessment of disease status was
conducted at screening and then every two cycles
thereafter throughout the duration of the study based on
modified RECIST criteria.
• Echocardiograms (ECHO) or multi-gated acquisition
(MUGA) scans were performed at screening, at the end of
Cycle 1, and then every three cycles thereafter.
• Any patient with a significant decline in ejection fraction or
with symptomatic congestive heart failure was withdrawn
from study treatment.
Statistical Analysis
• This report assesses safety and efficacy among
relapsed patients (n=44), who were evaluable as of
December 14, 2009.
• ORR with 95% confidence intervals (CI) were
estimated from complete or partial responses on two
consecutive occasions >4 weeks apart, through at
least 4 cycles or disease progression/death, using
the Blyth-Still-Casella method.
• Patients without a valid post-baseline tumor
assessment were counted as non-responders.
Results
• To date, 67 patients have enrolled in the study—45
relapsed patients (second-line or beyond therapy)
and 22 patients with newly diagnosed HER2-positive
MBC (first-line therapy).
• One patient did not have safety data available and
was excluded from analysis, leaving 44 relapsed
patients.
Dose-Escalation Phase
• 9 patients were enrolled in this phase.
• No dose-limiting toxicity (DLT) was observed among the
3 patients in Cohort 1 (3.0 mg/kg T-DM1 + full-dose
pertuzumab).
• Among the first 3 patients in Cohort 2 (3.6 mg/kg T-DM1
+ full-dose pertuzumab), there was 1 DLT of Grade 4
thrombocytopenia; the patient’s T-DM1 dose was
reduced to 2.4 mg/kg.
• Cohort 2 expanded to 6 patients; there were no further
DLTs.
• The expansion phase dose for T-DM1 was determined
to be 3.6 mg/kg.
Expansion Phase
• 58 patients were added in this phase.
On-Study Treatment
• All patients were treated with at least 1 cycle of
T-DM1 and pertuzumab with a median of 4 cycles of
both study drugs (range 1–9).
• 12/44 (27.3%) patients had discontinued from study
as of the data cutoff.
Demographics and Baseline Characteristics,
Relapsed Patients
Group
Median age, yr (range)
Race, n (%)
White
African-American
Asian
Sex, male, n (%)
ECOG PS, n (%)
0
1
Prior hormonal therapy, n (%)
Other systemic therapies, n (%)
Trastuzumab
Chemotherapy
Lapatinib
Biologic (not trastuzumab)
Other targeted therapy
Experimental
Cancer vaccine
Other*
Total prior systemic agents,† median (range)
Number prior systemic agents† in metastatic setting, median (range)
Median time since metastatic diagnosis, mo (range)
PS=performance status
* Includes one patient who received steroids.
† Excluding hormones
Total (n=44)
55.5 (29–74)
40 (90.9)
3 (6.8)
1 (2.3)
1 (2.3)
25 (56.8)
19 (43.2)
20 (45.5)
44 (100)
44 (100)
33 (75.0)
12 (27.3)
5 (11.4)
5 (11.4)
1 (2.3)
5 (11.4)
8 (2–16)
6 (2–14)
34.7 (5–150)
Objective Responses among Relapsed
Patients
• ORR results are from 28 patients who had been on study for at
least 12 weeks (4 cycles), or progressed or died as of the data
cutoff.
• The median number of T-DM1 doses received was 5 (range: 2–9).
• ORR was 35.7% (10/28 patients; 95% CI, 19.3–55.9).
– All responses were confirmed partial responses.
– Among the 13 patients with stable disease, there were 2
unconfirmed responses.
Objective Responses among Relapsed
Patients (cont’d)
Cohort 1
(n=3)
Complete
response
Cohort 2 (n=25) Total (n=28)
0
0
0
Partial response
2 (66.7)
8 (32.0)
10 (35.7)
Stable disease
1 (33.3)
12 (48.0)
13 (46.4)
Progressive
disease
0
4 (16.0)
4 (14.3)
Missing
0
1 (4.0)
1 (3.6)
Safety
• The Phase I portion of the study confirmed that it was safe to
combine full doses of T-DM1 and pertuzumab.
• One Grade 5 AE (pneumonia) was reported in a patient who died
concomitantly due to disease progression, prior to first tumor
assessment; it was considered unrelated to study treatment.
• There were two Grade 4 events, both thrombocytopenia, in two
patients (including the DLT), resulting in T-DM1 dose reduction (to
2.4 mg/kg) in one patient.
• 6 patients had dose reductions due to AEs
– Grade 4 thrombocytopenia, Grade 1–2 thrombocytopenia, Grade 2
neutropenia, Grade 3 nausea and vomiting, Grade 3 elevation in
aspartate aminotransferase level, and Grade 3 elevation in aspartate
and alanine aminotransferase levels with subsequent Grade 4
thrombocytopenia after dose reduction.
• One patient discontinued both drugs due to Grade 3 left ventricular
dysfunction.
All AEs Occurring in >20% of Relapsed Patients
AEs, n (%)
Gr 1
Gr 2
Gr 3
Gr 4
Gr 5
Total
Any Events
Fatigue
44 (100)
15 (34.1)
36 (81.8)
12 (27.3)
16 (36.4)
6 (13.6)
2 (4.5)
0
1 (2.3)
0
44 (100)
23 (52.3)
Nausea
20 (45.5)
8 (18.2)
2 (4.5)
0
0
22 (50 .0)
Decreased appetite
Dysgeusia
12 (27.3)
7 (15.9)
7 (15.9)
6 (13.6)
0
0
0
0
0
0
16 (36.4)
12 (27.3)
Thrombocytopenia
9 (20.5)
5 (11.4)
3 (6.8)
2 (4.5)
0
12 (27.3)
Diarrhea
10 (22.7)
2 (4.5)
1 (2.3)
0
0
11 (25.0)
Epistaxis
Chills
8 (18.2)
9 (20.5)
3 (6.8)
1 (2.3)
0
0
0
0
0
0
11 (25.0)
10 (22.7)
Constipation
9 (20.5)
3 (6.8)
0
0
0
10 (22.7)
Cough
Pyrexia
10 (22.7)
9 (20.5)
0
2 (4.5)
0
0
0
0
0
0
10 (22.7)
10 (22.7)
Vomiting
9 (20.5)
1 (2.3)
2 (4.5)
0
0
10 (22.7)
AST increase
Dyspnea*
6 (13.6)
6 (13.6)
6 (13.6)
4 (9.1)
3 (6.8)
1 (2.3)
0
0
0
0
9 (20.5)
9 (20.5)
AST=aspartate aminotransferase
* These events were primarily attributed to pneumonia, or the disease under study (lung metastases and pleural effusions); we are continuing to monitor
these events.
Serious AEs
• 10 serious AEs occured in 7 patients:
– Pneumonia (in 2 patients, Grades 3 and 5)
– Diarrhea/fatigue/nausea/vomiting (in 1 patient, Grade 3),
– and in 1 patient each, cellulitis, dyspnea, hematuria, and URI
(Grade 3).
Conclusions
• In combination with full-dose pertuzumab (840 mg
loading/420 mg thereafter), the T-DM1 dose was
determined to be 3.6 mg/kg.
• T-DM1 + full dose pertuzumab has an encouraging
safety and tolerability profile.
– Thrombocytopenia and hepatic transaminase elevations
generally were transient, reversible, and did not occur at a
higher rate than that observed with T-DM1 alone.
•
Preliminary efficacy of this combination is promising.