Drug Trials Snapshot: MARGENZA
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the MARGENZA Package Insert for complete information.
MARGENZA (margetuximab-cmkb)
(mar-GEN-zuh)
MacroGenics
Approval date: December 16, 2020
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
MARGENZA is a drug for treatment of metastatic HER2-positive breast cancer in adult patients who have been previously treated for their metastatic disease.
How is this drug used?
MARGENZA is an injection. It is given by a healthcare provider directly into the vein (intravenous infusion) every three weeks in combination with chemotherapy.
What are the benefits of this drug?
Patients who received MARGENZA in combination with chemotherapy lived longer without cancer progression in comparison to patients who received an approved drug trastuzumab in combination with chemotherapy.
What are the benefits of this drug (results of trials used to assess efficacy)?
Table 1 shows efficacy results. The primary endpoints were progressive disease-free survival (PFS) ) by blinded independent central (BICR) review and overall survival (OS) of MARGENZA plus chemotherapy, compared with trastuzumab plus chemotherapy.
Table 1. Efficacy Results
|
|
MARGENZA + |
Trastuzumab + |
|---|---|---|
|
Progression-free Survival a |
||
|
Number of events (%) |
130 (48.9) |
135 (50.0) |
|
Disease progression |
118 (44.4) |
125 (46.3) |
|
Death |
12 (4.5) |
10 (3.7) |
|
Median, months (95% CI) b |
5.8 (5.5, 7.0) |
4.9 (4.2, 5.6) |
|
Hazard Ratio (HR) (95% CI) c |
0.76 (0.59, 0.98) |
|
|
p-value d |
0.033 |
|
|
Objective Response for Patients with Measurable Disease a |
(n = 262) |
(n = 262) |
|
Confirmed Objective Response Rate (95% CI) |
22 (17, 27) |
16 (12, 20) |
|
Duration of Objective Response |
(n=58) |
(n=42) |
|
Median (months) (95% CI) b |
6.1 (4.1, 9.1) |
6.0 (4.0, 6.9) |
aAssessed per BICR.
bBased on Kaplan-Meier estimates.
cBased on stratified Cox Model.
dp-value based on 2-sided stratified log rank test.
CI: confidence interval; n: number of patients.
MARGENZA Prescribing Information
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: Almost all patients in the trial were women; therefore, sex differences in how well the drug worked could not be determined.
- Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in how well the drug worked among races could not be determined.
- Age: MARGENZA worked similarly in patients above and below 60 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Tables 2 and 3 show the efficacy results by age and race subgroups. Sex subgroups were not analyzed due to the fact that most of the patients in the trial were women.
Table 2. Subgroup Analyses of PFS
|
|
Number of Events/Total |
Hazard Ratio (95% CI) |
|
|---|---|---|---|
|
MARGENZA plus |
Trastuzumab plus |
|
|
|
Overall |
130/266 |
135/270 |
0.78 (0.613-0.994) |
|
Age Category |
|||
|
<60 years |
97/184 |
94/182 |
0.870 (0.665-1.156) |
|
≥60 years |
33/82 |
41/88 |
0.577 (0.360-0.923) |
|
Race Category |
|||
|
White |
104/205 |
109/222 |
0.927 (0.708-1.214) |
|
Asian |
10/20 |
8/14 |
0.401 (0.153-1.050) |
|
Black or African American |
3/16 |
6/12 |
0.182 (0.036-0.907) |
Table 3. Subgroup Analyses of OS
|
|
Number of Events/Total |
Hazard Ratio (95% CI) |
|
|---|---|---|---|
|
MARGENZA plus |
Trastuzumab plus |
|
|
|
Overall |
131/266 |
139/270 |
0.895 (0.705-1.136) |
|
Age Category |
|||
|
<60 years |
85/184 |
98/182 |
0.796 (0.595-1.065) |
|
≥60 years |
46/82 |
41/88 |
1.172 (0.769-1.787) |
|
Race Category |
|||
|
White |
115/205 |
121/222 |
0.990 (0.767-1.278) |
|
Asian |
6/20 |
4/14 |
1.151 (0.324-4.093) |
|
Black or African American |
5/16 |
6/12 |
0.541 (0.162-1.808) |
Adapted from FDA Review
What are the possible side effects?
MARGENZA may cause serious side effects, including weakening of the heart, a harm to unborn baby and infusion reactions.
The most common side effects include fatigue, nausea, diarrhea, and vomiting.
What are the possible side effects (results of trials used to assess safety)?
Table 4 below summarizes common adverse reactions at all grades of severity. This was based on safety population defined as all patients who received at least 1 dose of trial drug.
Table 4. Adverse Reactions Occurring in ≥ 5% of Patients on the MARGENZA Treatment Arm in the Trial
|
Adverse Reaction
|
MARGENZA + Chemotherapy |
Trastuzumab + Chemotherapy |
||
|---|---|---|---|---|
|
All Grades |
Grade 3 or 4 |
All Grades |
Grade 3 or 4 |
|
|
General disorders and administration site conditions |
||||
|
Fatigue/Asthenia |
57 |
7 |
47 |
4.5 |
|
Pyrexia |
19 |
0.4 |
14 |
0.4 |
|
Gastrointestinal disorders |
||||
|
Nausea |
33 |
1.1 |
32 |
0.4 |
|
Diarrhea |
25 |
2.3 |
25 |
2.3 |
|
Vomiting |
21 |
0.8 |
14 |
1.5 |
|
Constipation |
19 |
0.8 |
17 |
0.8 |
|
Abdominal paina |
17 |
1.5 |
21 |
1.5 |
|
Skin and Subcutaneous tissue |
||||
|
Alopecia |
18 |
0 |
15 |
0 |
|
Palmar-plantar erythrodysesthesia |
13 |
0 |
15 |
3 |
|
Nervous System Disorders |
||||
|
Headacheb |
19 |
0 |
16 |
0 |
|
Peripheral neuropathyc |
16 |
1.1 |
15 |
2.3 |
|
Respiratory, thoracic and mediastinal disorders |
||||
|
Cough |
14 |
0.4 |
12 |
0 |
|
Dyspnea |
13 |
1.1 |
11 |
2.3 |
|
Metabolism and nutrition disorders |
||||
|
Decreased appetite |
14 |
0.4 |
14 |
0.4 |
|
Musculoskeletal and connective tissue disorders |
||||
|
Arthralgia/Myalgia |
14 |
0.4 |
12 |
0.8 |
|
Extremity pain |
11 |
0.8 |
9 |
0 |
|
Injury, poisoning and procedural complications |
||||
|
Infusion-related reaction |
13 |
1.5 |
3 |
0 |
aIncludes abdominal pain, abdominal discomfort, lower abdominal pain and upper abdominal pain
bIncludes headache and migraine
cIncludes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, and neuropathy
MARGENZA Prescribing Information
Were there any differences in side effects among sex, race and age?
- Sex: Almost all patients in the trial were women; therefore, differences in side effects between men and women could not be determined.
- Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in side effects among races could not be determined.
- Age: The occurrence of overall side effects was similar in patients younger than 65 years and those 65 years and older. More severe side effects (grade 3-4) were seen more frequently in patients above 65 years. Also, heart toxicity side effects were seen more commonly in patients 65 years and older.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Analysis of side effects by subgroup was limited to age and race due to the fact that most of the patients in the trial were women. Presented is pooled safety population consisting of all patients from drug development program who received MARGENZA at recommended dose (15mg/kg every three weeks).
Table 5. Summary of Treatment-Emergent Adverse Events (TEAEs) by Age
|
|
MARGENZA |
|
|---|---|---|
|
<65y |
≥65y |
|
|
Any TEAEs, n (%) |
229 (97.4) |
59 (98.3) |
|
Grade 3 or 4, n (%) |
115 (48.9) |
37 (61.7) |
|
Cardiotoxicity n (%) |
42 (17.9) |
21 (35) |
Table 6. Summary of Treatment-Emergent Adverse Events (TEAEs) by Race
|
|
MARGENZA |
|
|---|---|---|
|
White |
All Other |
|
|
Any TEAEs, n (%) |
206 (96.7) |
82 (100) |
|
Grade 3 or 4, n (%) |
103 (48.4) |
49 (59.8) |
|
Cardiotoxicity |
53 (24.9) |
10 (12.2) |
FDA review and Clinical Trial Report
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved MARGENZA based primarily on evidence from one clinical trial (NCT02492711) of 536 patients 27 to 86 years old with HER2-positive, metastatic breast cancer who had been previously treated for their metastatic disease. The trial was conducted at 166 sites in the United States and 16 other countries.
Figure 1 summarizes how many women were in the clinical trial.
Figure 1. Demographics by Sex
FDA Review
Figure 2 summarizes patients by race in the clinical trial.
Figure 2. Demographics by Race
FDA Review
Figure 3 summarizes patients by age in the clinical trial.
Figure 3. Demographics by Age
FDA Review
Figure 4 summarizes patients by ethnicity in the clinical trial.
Figure 4. Demographics by Ethnicity
FDA Review
Who participated in the trials?
The demographic characteristics of randomized population are summarized in Table 7.
Table 7. Demographic Characteristics (randomized population)
|
Number (%) of Subjects
|
MARGENZA plus |
Trastuzumab plus |
Total |
|---|---|---|---|
|
Sex, n (%) |
|||
|
Women |
266 (100.0) |
267 (98.9) |
533 (99.4) |
|
Men |
0 |
3 (1.1) |
3 (0.6) |
|
Race, n (%) |
|||
|
Asian |
20 (7.5) |
14 (5.2) |
34 (6.3) |
|
Black or African American |
16 (6.0) |
12 (4.4) |
28 (5.2) |
|
Native Hawaiian or Other Pacific Islander |
1 (0.4) |
2 (0.7) |
3 (0.6) |
|
White |
205 (77.1) |
222 (82.2) |
427 (79.7) |
|
Other |
24 (9.0) |
20 (7.4) |
44 (8.2) |
|
Age (years) |
|||
|
Mean (SD) |
54.4 (11.4) |
55.7 (11.5) |
55.1 (11.5) |
|
Median |
55.0 |
56.0 |
56.0 |
|
Min – Max |
29 – 83 |
27 – 86 |
27 – 86 |
|
Age Group (years) |
|||
|
<65 |
214 (80.4) |
207 (76.7) |
421 (78.5) |
|
65-74 |
42 (15.8) |
49 (18.1) |
91 (16.9) |
|
≥75 |
10 (3.8) |
14 (5.2) |
24 (4.5) |
|
Ethnicity |
|||
|
Hispanic or Latino |
16 (6.0) |
30 (11.1) |
46 (8.6) |
|
Not Hispanic or Latino |
217 (81.6) |
214 (79.2) |
431 (80.4) |
|
Not Reported |
33 (12.4) |
26 (9.6) |
59 (11.0) |
|
Region |
|||
|
North America-US |
110 (41.3) |
96 (35.6) |
177 (33.0) |
|
North America-Canada |
4 (2) |
6 (2.2) |
10 (1.9) |
|
Europe |
152 (57.1) |
138 (51.1) |
290 (54.1) |
|
Other |
29 (10.9) |
30 (11.1) |
59 (11.0) |
Adapted from FDA Review
How were the trials designed?
MARGENZA was studied in one trial that enrolled patients with HER2-positive, metastatic breast cancer who have been treated for their metastaic disease before.
The trial compared patients who were randomly assigned to receive either MARGENZA or trastuzumab infusions every three weeks in addition to chemotherapy. Both, the patients and the health care providers knew which treatment was being given. The treatment continued until the disease progression or the side effects became too toxic.
The trial compared the length of time patients were alive without cancer progression between the two groups.
How were the trials designed?
The safety and efficacy efficacy of MARGENZA were evaluated in one randomized, double-blind, open-label, multicenter clinical trial. All patients had a metastatic HER2-positive breast cancer and had received prior treatment with other anti-HER2 therapies. Prior radiotherapy and hormonal therapy were allowed.
Patients received MARGENZA or trastuzumab intravenously every 3 weeks in combination with chemotherapy until disease progression or unacceptable toxicity.
Major efficacy outcome measures were progression-free survival (PFS) by blinded independent central (BICR) review and overall survival (OS) of MARGENZA plus chemotherapy, compared with trastuzumab plus chemotherapy. Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) assessed by BICR.
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.