Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in the Treatment of HER2+ Metastatic Breast Cancer

An evaluation of efficacy, as measured by progression-free survival (PFS) assessed by
independent review and overall survival (OS), of margetuximab plus chemotherapy compared with
trastuzumab plus chemotherapy in patients with advanced HER2+ breast cancer who have received
at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of
having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy
in the metastatic setting, and who have received at least one, and no more than three, lines
of therapy overall in the metastatic setting. A non-randomized sub-study cohort of
approximately 78 patients will be enrolled to evaluate the safety of a reduced margetuximab
infusion rate in patients receiving margetuximab either as monotherapy or in combination with
chemotherapy.

Inclusion Criteria:

- Histologically-proven metastatic or locally-advanced relapsed/refractory HER2+ breast
cancer based on the most recently available tumor biopsy collected from the patient.
Tumors may be estrogen receptor (ER)/progesterone receptor (PgR) positive or negative.

- Have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic
setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line
of anti-HER2 directed therapy in the metastatic setting. In either case, patients must
have received prior treatment with pertuzumab, in the (neo)adjuvant or metastatic
setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 therapies are
allowed.

- Prior treatment with at least one, and no more than three, lines of therapy overall in
the metastatic setting. Patients must have progressed on or following, the most recent
line of therapy.

- Resolution of all chemotherapy or radiation-related toxicities to ≤ Grade 1

- Life expectancy ≥ 12 weeks

- Acceptable laboratory parameters

- Women of childbearing potential must have negative pregnancy test performed within 14
days of randomization and on the first day of treatment. All subjects must agree to
use an effective form of contraception for the duration of study treatment and for 7
months after the last dose of study drug.

Infusion sub-study prior therapy requirements: Same as above, except:

- Must have received 4 or more prior lines or therapy in the metastatic setting

- Must have received prior trastuzumab, pertuzumab, and T-DM1

Exclusion Criteria:

- Known, untreated brain metastasis. Patients with signs or symptoms of brain metastasis
must have a CT or MRI performed within 4 weeks prior to randomization to specifically
exclude the presence of radiographically-detected brain metastases

- History of uncontrolled seizures within 6 months of randomization

- History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation

- History of clinically significant cardiovascular disease

- Clinically-significant pulmonary compromise, including a requirement for supplemental
oxygen use to maintain adequate oxygenation

- Any condition that would be a contraindication to receiving trastuzumab as described
in the approved local label or a condition that would prevent treatment with the
physician's choice of chemotherapy