NSCLC

Primary Objective The primary objective of this study is to determine whether the combination of MM-121 plus Docetaxel or MM-121 plus Pemetrexed is more effective than Docetaxel or Pemetrexed alone based on Overall Survival (OS) in HRG positive patients (defined as HRG ISH score of > 1+) Secondary Objectives To determine whether the combination of MM-121 plus docetaxel or MM-121 plus pemetrexed is more effective than docetaxel or pemetrexed alone in HRG positive patients (defined as HRG ISH score of > 1+) for the following clinical outcome parameters: Investigator Assessed - Progression-Free Survival (PFS) Independent Central Review – PFS Objective Response Rate (ORR) based on RECISTv1.1 Time to Progression (TTP) To describe the safety profile of MM-121 in combination with docetaxel or pemetrexed To assess health-related quality of life (HRQOL) in NSCLC To characterize the pharmacokinetic (PK) profile of MM-121 when given in combination with docetaxel or pemetrexed and of docetaxel or pemetrexed when given in combination with MM-121

MM-121

MM-121

solution for infusion

25

General:
Categorical variables will be summarized by frequency distributions (number and percentages of patients) and continuous variables will be summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum).

Primary Efficacy Analysis:
Overall Survival (OS) is the primary endpoint, and is defined as the time from the date of
randomization to the date of death from any cause. The primary efficacy will be performed on the intent-to-treat (ITT) population using a stratified log-rank test. The Kaplan-Meier method will be used to estimate median OS for each treatment group. A stratified Cox proportional hazard model will be used to obtain an estimate hazard ratio and corresponding 95% confidence intervals. Stratification factors include: Prior systemic therapies (1, ≥ 2), Geographic region (US, Asia, non-US and non-Asia), and Chemotherapy backbone (docetaxel, pemetrexed).

Secondary Efficacy Analysis:
Progression Free Survival (PFS):
PFS, based on investigator assessment and independent central review, are secondary
endpoints of this study. PFS is defined as the time from randomization to the first
documented radiographical progression of disease using RECIST 1.1, or death from any
cause, whichever comes first. Details of censorship will be thoroughly explained in the
SAP. Investigator assessments and independent review of documented progressions will
be analyzed using the same population and log-rank test as the OS primary efficacy
analysis. Kaplan-Meier curves displaying median PFS and stratified Cox proportional
hazard models will be performed similarly as OS.

To be eligible for participation in the study, patients must meet the following criteria.
Patients who are assessed to be HRG negative do not complete any screening procedures
beyond HRG assessment.
a) Patients with cytologically or histologically documented NSCLC that is presenting as
either:
Stage IV (metastatic disease) or
Stage IIIB disease not amenable to surgery with curative intent or
Recurrent or progressive disease following multimodal therapy (chemotherapy, radiation therapy, surgical resection or definitive chemoradiation therapy for locally advanced or metastatic disease)
b) Disease progression or evidence of recurrent disease during or after the last systemic
therapy as documented by radiographic assessment
c) Received one prior platinum-based chemotherapy regimen for advanced or metastatic
disease
d) Received nivolumab or other approved anti-PD-1 or anti-PD-L1 therapy where available and clinically indicated
e) Clinically eligible for intended chemotherapy, docetaxel or pemetrexed, once every three weeks per the investigator’s judgment
f) Must have:
Available recent tumor specimen, collected following completion of most recent
systemic therapy OR
A lesion amenable to either core needle biopsy or fine needle aspiration
g) A positive in-situ hybridization (ISH) test for heregulin with a score of >1+, as
determined by centralized testing
h) ECOG performance status (PS) of 0 or 1
i) Screening ECG without clinically significant abnormalities
j) Women of childbearing potential, as well as fertile men and their partners, must be
willing to abstain from sexual intercourse or to use an effective form of contraception
(an effective form of contraception is an oral contraceptive or a double barrier method
or as defined by country-specific guidelines) during the study and for 90 days following the last dose of study drug(s), or greater, as in accordance with the label requirements or institutional guidelines for docetaxel/pemetrexed.
k) ≥ 18 years of age
l) Able to provide informed consent, or have a legal representative able and willing to
do so

To be eligible for randomization, patients must not meet any of the following criteria:
a) Known Anaplastic Lymphoma Kinase (ALK) gene rearrangement
b) For adenocarcinoma patients only: Presence of exon 19 deletion or exon 21 (L858R)
substitution of the EGFR gene
c) Pregnant or lactating
d) Prior radiation therapy to >25% of bone marrow-bearing areas
e) Received >3 prior systemic anti-cancer drug regimens for locally advanced and/or
metastatic disease
Any type of maintenance therapy, e.g. pemetrexed maintenance following first line treatment with cisplatin and pemetrexed, is not considered a separate line of therapy.
f) Prior treatment with an anti-ErbB3 antibody
g)Patients who have received prior docetaxel for advanced/ metastatic disease are not
eligible for the docetaxel-containing chemotherapy backbone
h) Patients who have received prior pemetrexed for advanced/metastatic disease and/or
maintenance therapy are not eligible for the pemetrexed-containing chemotherapy
backbone
i) Received other recent antitumor therapy including:
Investigational therapy administered within the 28 days or 5 half-lives, whichever is shorter, prior to the first scheduled day of dosing in this study.

Radiation or other standard systemic therapy within 14 days prior to the first scheduled dose in this study, including, in addition (if necessary), the timeframe for resolution of any actual or anticipated toxicities from such radiation.

j) CTCAE grade 3 or higher peripheral neuropathy for patients considered for the
docetaxel backbone
k) Presence of an unexplained fever > 38.5°C during screening visits that does not resolve prior to the first day of dosing. If the fever and active infection have resolved prior to randomization, the patient will be eligible. At the discretion of the investigator, patients with tumor fever may be enrolled.
l) Clinically active CNS metastasis
m) Use of strong CYP3A4 inhibitors for patients considered for the docetaxel backbone
n) Any other active malignancy requiring systemic therapy
o) Known hypersensitivity to any of the components of MM-121 or previous CTCAE grade 3 or higher hypersensitivity reactions to fully human monoclonal antibodies.
p) History of severe hypersensitivity reactions to docetaxel or pemetrexed
q) Known hypersensitivity to polysorbate (Tween) 80 or arginine
r) Inadequate bone marrow reserve as evidenced by：
ANC < 1,500/µl or
Platelet count < 100,000/µl or
Hemoglobin < 9 g/dL
s) Serum/plasma creatinine > 1.5 x ULN for patients receiving docetaxel or a creatinine
clearance < 45 mL/min for patients receiving pemetrexed
t) For patients receiving pemetrexed: Aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) > 2.5 x ULN (> 5 x ULN if liver metastases are present)
u) For patients receiving docetaxel:
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x ULN concomitant with Alkaline phosphatase (AP) > 2.5 x ULN
Serum/plasma total bilirubin > ULN
v) Clinically significant cardiac disease, including: symptomatic congestive heart failure,
unstable angina, acute myocardial infarction within 12 months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes)
w) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active
human immunodeficiency virus (HIV) infection, active hepatitis B infection or active
hepatitis C infection
x) Patients who are not appropriate candidates for participation in this clinical study for
any other reason as deemed by the investigator