A randomized, Phase III, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Onartuzumab (MetMAb) in Combination with Tarceva® (erlotinib) in Patients with Met Diagnostic-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Standard Chemotherapy for Advanced or Metastatic Disease

EGFR inhibitors are increasingly used as therapy for human cancers, but
development of resistance presents a challenge. Recently, genetic amplification
and over-expression of Met have been implicated in driving resistance to EGFR
inhibitors, both in NSCLC cell lines and in patients (Engelman et al. 2007).
Met or EGFR signaling reinforces activation of the other pathway. These data
suggest that Met and EGFR cooperate to drive tumor growth and survival and
therefore support a strong rationale for combining Met and EGFR inhibitors in
the clinic.

The Phase I study evaluating Onartuzumab in advanced solid malignancies (Study
OAM4224g) showed that the drug was tolerable up to 30 mg/kg, with onlya single
DLT of Grade 3 pyrexia occurring at 4 mg/kg (Moss et al. 2010).

The Phase II randomized trial of erlotinib ± Onartuzumab (IV 15 mg/kg, Q3W) in
previously treated patients with advanced NSCLC (Study OAM4558g) showed that
patients whose tumors were Met diagnostic positive had an improvement in PFS
(stratified HR = 0.53; 95% confidence interval [CI], 0.28, 0.99) and in OS
(stratified HR = 0.37; 95% CI, 0.19, 0.72), while patients who were Met
diagnostic negative showed a worse outcome in PFS (stratified HR = 1.82; 95%
CI, 0.99, 3.32) and in OS (stratified HR = 1.78; 95% CI, 0.79, 3.99) (Spigel et
al. 2011) The toxicity profile for erlotinib ± Onartuzumab treatment was
similar to that for erlotinib alone, with the exception of peripheral edema in
patients who received the combination treatment.

These results suggest that Onartuzumab should be further evaluated as second-
or third-line treatment in Met diagnostic*positive NSCLC.

Primary Objective
To determine whether the combination of Onartuzumab + * erlotinib is superior
(in terms of OS) to placebo * erlotinib after standard platinum-based
chemotherapy in patients with Met diagnostic*positive non*small cell lung
cancer (NSCLC)

Secondary Objectives
* To evaluate and compare the efficacy in terms of progression-free survival
(PFS) and (objective response rate) ORR between the two treatment groups
* To evaluate and compare the safety and tolerability of Onartuzumab +*
erlotinib versus placebo * erlotinib in patients with Met diagnostic*positive
NSCLC
* To evaluate the impact of Onartuzumab on patient reported outcome (PRO)
measures of quality of life
* To evaluate the pharmacokinetics of Onartuzumab
* To evaluate serum levels and incidence of anti-therapeutic antibodies (ATAs)
against Onartuzumab and to explore the potential relationship of the
immunogenicity response with pharmacokinetics, safety, and efficacy

This is a randomized, Phase III, multicenter, double-blind, placebo-controlled
study designed to evaluate the safety and efficacy of Onartuzumab in
combination with erlotinib as compared with treatment with erlotinib alone in
patients with incurable NSCLC identified to be Met diagnostic positive.
Tumor specimens from patients meeting eligibility criteria will be
prospectively tested for Met receptor expression by the Ventana anti-Total c
MET (SP44) rabbit monoclonal antibody IHC assay and for EGFR activating
mutation status by the RMS cobas* EGFR Mutation Test. Only patients with Met
diagnostic*positive tumors will be enrolled. Eligible patients will be
stratified by Met expression (clinical score of 2 * vs. 3 *), number of prior
lines of therapy (1 vs. 2), histology (nonsquamous vs. squamous), and epidermal
growth factor receptor (EGFR)*activating mutation status (yes vs. no).
Patients will be randomized in a 1:1 ratio to receive either Onartuzumab + *
erlotinib or placebo * erlotinib on a 21-day cycle. Approximately 490 patients
are planned to be enrolled.
Treatment will continue until disease progression, unacceptable toxicity,
patient or physician decision to discontinue, or death. Assessment for tumor
response will occur every 6 weeks with use of Response Evaluation Criteria in
Solid Tumors version 1.1 (RECIST v1.1). Tumor response data collection will
continue if the patient ends treatment prior to disease progression. Follow up
data capture, including subsequent anti-cancer therapies, will continue for
each patient until death or discontinuation from the study.
An independent Data Monitoring Committee (IDMC) will monitor safety data. One
interim analysis of efficacy and futility is planned for when approximately
67% of the total overall survival (OS) events have been observed.

- Arm A: erlotinib and Onartuzumab
- Arm B: erlotinib and placebo (an inactive substance)

On Day 1 of each cycle, the subject will receive either Onartuzumab or placebo
(depending on the treatment arm to which you are assigned) administered
intravenously (into the vein). For the first cycle, the intravenous dose of
study drug will occur over about 60 minutes; subsequent doses may be decreased
to about 30 minutes, depending on how the subject tolerates the first dose.
The dose of study drug will be based on weight at screening and will remain the
same throughout the study.
On Day 1, the subject will be given a sufficient amount of erlotinib tablets
for the entire cycle of 21 days, with instructions on how to take the drug at
home. The subject will take a 150 mg tablet by mouth with approximately 200 mL
(6*8 ounces) of water on an empty stomach every day (either 1 hour before or 2
hours after eating) for the entire time he/she is participating in the study.

Please refer to appendix A of the protocol for an overview of all study visits
and procedures.
Summary of procedures:

7x Vital signs
7x Physical examination
7x Pregnancy Test
8x Urine testing
6x Administration of study drug
3x ECG
9x Tumor assessment: CT- / MRI-scan
9x Additional blood samples
9x Quality of Questionnaires (3)

This study can have the following side-effects:

Onartuzumab side effects
The initial experience with Onartuzumab in humans was evaluated in a clinical
research study that tested the safety of increasing Onartuzumab doses in
patients. The most common side effects reported in at least 10% of the patients
receiving Onartuzumab were fatique, peripheral edema (swelling), nausea, low
blood albumin (a protein). The less common side effects reported in less than
10% of the patients receiving Onartuzumab were vomiting, loss of appetite,
muscle spasms, abdominal pain, weight gain, fever, low blood sodium, AST (liver
function test) high.
Results from a clinical research study evaluating the activity of Onartuzumab
in combination with erlotinib in patients with NSCLC showed that this
combination resulted in a higher rate (more than 10% difference) of edema
compared with erlotinib alone. Results from this study were also analyzed with
respect to the expression levels of the Met protein (i.e., levels of the Met
protein that each patient*s cells are producing). In patients whose tumors had
higher levels of the Met expression (as in this study), the addition of MetMAb
resulted in an increase (* 10% difference) in abdominal pain and edema.
The most common side effects reported in * 10% of the patients receiving
Onartuzumab in combination with erlotinib wererash, infections diarrhea,
neasea, peripheral edema (swelling), loss of appetite, shortness of breath,
acne-like dermatitis, cough, fever, anemia (low red blood cell count), insomnia
(trouble sleeping), weakness, dry skin and back pain.

Erlotinib Side Effects
Side effects that have been reported by at least 10% of patients receiving
erlotinib include skin rash, diarrhea, fatigue, loss of appetite, shortness of
breath, cough, nausea, infection, vomiting. Mouth sores, itchy skin, dry skin,
eye irritation, dry eyes and stomach pain.