Lani
06-11-2007, 11:51 PM
remember the article I posted on herceptin-pertuzumab-iressa combination "curing" mice of her2+ breast cancer
This is the result of a trial of just herceptin and pertuzumab in metastatic her2+ bc patients who have already progressed on herceptin
Note the hypomagnesemia--a described complication of antibodies blocking egfr (her1)--I had not seen it described in those blocking her2, but perhaps it is because pertuzumab, unlike herceptin, is able to block her1/2 dimerization:
HER2 Dimerization Inhibitor Pertuzumab in Combination With Trastuzumab Demonstrated Efficacy in Metastatic Breast Cancer Following Trastuzumab Progression
Multicenter phase II study
Combination of pertuzumab and trastuzumab demonstrated promising clinical benefit in patients with HER2-positive metastatic breast cancer who have progressed on trastuzumab
39% clinical benefit rate in 33 evaluable patients
Accrual ongoing
Planned recruitment: 58 patients
Combination well tolerated
Adverse events predominantly grade 1 or 2
1 occurrence (2%) of modest decline in left ventricular ejection fraction (LVEF)
Planned biomarker studies ongoing
Pertuzumab
HER2 dimerization inhibitor
Monoclonal antibody
Binds to different HER2 epitope than trastuzumab
First in a new class of HER2-targeted therapies
Potent inhibitor of HER-induced signaling
Preclinical models support complementary mechanisms of action for pertuzumab and trastuzumab
Potential for increased efficacy with combination
Current phase II study evaluated efficacy and tolerability of pertuzumab and trastuzumab in women with metastatic breast cancer who have progressed on trastuzumab
Summary of Study Design
Eligibility
HER2-positive metastatic breast cancer
Centrally confirmed by immunohistochemistry 3+ staining or by fluorescence in situ hybridization amplication
Measurable disease by Response Evaluation Criteria in Solid Tumors
? 3 previous breast cancer therapies (adjuvant and metastatic) and/or previous trastuzumab therapy
Disease progression on trastuzumab as most recent metastatic therapy
Baseline LVEF ? 55%
No decline in LVEF to < 50% during previous trastuzumab therapy
Treatment
Trastuzumab
4-mg/kg loading dose followed by 2 mg/kg once weekly or
8-mg/kg loading dose followed by 6 mg/kg every 3 weeks
Pertuzumab
840-mg loading dose followed by 420 mg every 3 weeks
Treatment initiated within 9 weeks of last dose of previous trastuzumab therapy
Outcome analysis
Primary endpoints
Efficacy
Complete response (CR) and partial response (PR) rates
Stable disease (SD)
Clinical benefit (overall response rate + SD)
Safety
Monitored by internal data and safety monitoring board
Secondary endpoints
Biomarker analysis
Baseline Characteristics
Characteristic
Pertuzumab + Trastuzumab
(n = 42)
Median age, yrs (range)
54 (34-85)
ECOG PS, %
0
74
1
19
ER positive, %
45
Involved metastatic sites, %
Visceral
79
Lung
43
Liver
50
Bone
33
Lymph nodes
43
Soft tissue
29
ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor.
Main Findings
As of April 2007
42 evaluable for safety
33 evaluable for efficacy
Response to therapy
Outcome, %
Pertuzumab + Trastuzumab
(n = 33)
CR
3.0
PR
15.2
Overall response rate
18.2
SD for 6 mos
21.2
Overall clinical benefit
39.4
SD < 6 mos
30.3
Disease progression
30.3
Other Outcomes
Adverse events
Grade 3 diarrhea in 1 patient
All other adverse events grade 1 or 2
Toxicity (All Grades), %
Pertuzumab + Trastuzumab
(n = 42 )
Diarrhea
57
Skin (nonrash)
35
Mucositis
33
Pain
33
Nausea and vomiting
33
Rash
28
Fatigue
31
Single occurrence (2% incidence)
Deep vein thrombosis
Decreased LVEF
14% decrease by local assessment, 9% decrease by central assessment
Patient asymptomatic
Hypersensitivity
Hypertension
Hypomagnesemia
Reference
Baselga J, Cameron D, Miles D, et al. Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Illinois. Abstract 1004.
This is the result of a trial of just herceptin and pertuzumab in metastatic her2+ bc patients who have already progressed on herceptin
Note the hypomagnesemia--a described complication of antibodies blocking egfr (her1)--I had not seen it described in those blocking her2, but perhaps it is because pertuzumab, unlike herceptin, is able to block her1/2 dimerization:
HER2 Dimerization Inhibitor Pertuzumab in Combination With Trastuzumab Demonstrated Efficacy in Metastatic Breast Cancer Following Trastuzumab Progression
Multicenter phase II study
Combination of pertuzumab and trastuzumab demonstrated promising clinical benefit in patients with HER2-positive metastatic breast cancer who have progressed on trastuzumab
39% clinical benefit rate in 33 evaluable patients
Accrual ongoing
Planned recruitment: 58 patients
Combination well tolerated
Adverse events predominantly grade 1 or 2
1 occurrence (2%) of modest decline in left ventricular ejection fraction (LVEF)
Planned biomarker studies ongoing
Pertuzumab
HER2 dimerization inhibitor
Monoclonal antibody
Binds to different HER2 epitope than trastuzumab
First in a new class of HER2-targeted therapies
Potent inhibitor of HER-induced signaling
Preclinical models support complementary mechanisms of action for pertuzumab and trastuzumab
Potential for increased efficacy with combination
Current phase II study evaluated efficacy and tolerability of pertuzumab and trastuzumab in women with metastatic breast cancer who have progressed on trastuzumab
Summary of Study Design
Eligibility
HER2-positive metastatic breast cancer
Centrally confirmed by immunohistochemistry 3+ staining or by fluorescence in situ hybridization amplication
Measurable disease by Response Evaluation Criteria in Solid Tumors
? 3 previous breast cancer therapies (adjuvant and metastatic) and/or previous trastuzumab therapy
Disease progression on trastuzumab as most recent metastatic therapy
Baseline LVEF ? 55%
No decline in LVEF to < 50% during previous trastuzumab therapy
Treatment
Trastuzumab
4-mg/kg loading dose followed by 2 mg/kg once weekly or
8-mg/kg loading dose followed by 6 mg/kg every 3 weeks
Pertuzumab
840-mg loading dose followed by 420 mg every 3 weeks
Treatment initiated within 9 weeks of last dose of previous trastuzumab therapy
Outcome analysis
Primary endpoints
Efficacy
Complete response (CR) and partial response (PR) rates
Stable disease (SD)
Clinical benefit (overall response rate + SD)
Safety
Monitored by internal data and safety monitoring board
Secondary endpoints
Biomarker analysis
Baseline Characteristics
Characteristic
Pertuzumab + Trastuzumab
(n = 42)
Median age, yrs (range)
54 (34-85)
ECOG PS, %
0
74
1
19
ER positive, %
45
Involved metastatic sites, %
Visceral
79
Lung
43
Liver
50
Bone
33
Lymph nodes
43
Soft tissue
29
ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor.
Main Findings
As of April 2007
42 evaluable for safety
33 evaluable for efficacy
Response to therapy
Outcome, %
Pertuzumab + Trastuzumab
(n = 33)
CR
3.0
PR
15.2
Overall response rate
18.2
SD for 6 mos
21.2
Overall clinical benefit
39.4
SD < 6 mos
30.3
Disease progression
30.3
Other Outcomes
Adverse events
Grade 3 diarrhea in 1 patient
All other adverse events grade 1 or 2
Toxicity (All Grades), %
Pertuzumab + Trastuzumab
(n = 42 )
Diarrhea
57
Skin (nonrash)
35
Mucositis
33
Pain
33
Nausea and vomiting
33
Rash
28
Fatigue
31
Single occurrence (2% incidence)
Deep vein thrombosis
Decreased LVEF
14% decrease by local assessment, 9% decrease by central assessment
Patient asymptomatic
Hypersensitivity
Hypertension
Hypomagnesemia
Reference
Baselga J, Cameron D, Miles D, et al. Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Illinois. Abstract 1004.