An Open-Label, Randomized, Phase 3 Trial of Nivolumab versus Investigator*s Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer

Subjects with advanced NSCLC represent a great unmet medical need. Current
platinum based chemotherapy (standard of care for first line therapy) provide
patients with approximately 10 month median survival, and a 5 year survival
rate of less than 5%.
Nivolumab has shown substantial activity in previously treated NSCLC patients.
However, the potential benefit of nivolumab monotherapy over standard of care
first-line chemotherapy is not yet known. The current platinum-based first line
chemotherapy regimens have similar clinical activity and well characterized
safety profiles. Nivolumab has a different safety profile, characterized by
liver toxicity, pneumonitis, diarrhea, and endocrinopathies, which are mostly
low grade and manageable with the use of corticosteroids.
In order to assess the potential benefit of nivolumab monotherapy over current
first-line chemotherapy, a randomized trial comparing nivolumab monotherapy to
investigator*s choice chemotherapy in subjects with stage IV or recurrent NSCLC
is needed.
Preliminary data suggest that PD-L1+ tumor expression may be associated with
response to nivolumab. Therefore, to increase the potential benefit to risk
ratio, this study will select only those subjects with PD-L1 tumor expression.

The study will look at patients with advanced Non-Small Cell Lung Cancer
(NSCLC) whose tumours express a certain type of protein called PD-L1. The
research aims to compare a new drug called nivolumab against Investigator's
choice of chemotherapy to see which treatment helps patients, who are strongly
PD-L1 positive, live longer without their disease getting worse, this is known
as progression free survival (PFS).

This is an open-label, 2-arm, randomized, Phase 3 study in adult male and
female subjects with chemotherapy-naive stage IV or recurrent non-small cell
lung cancer with PD L1+ tumor expression. PD-L1 status will be determined by
immunohistochemical (IHC) staining of PD-L1 protein. This will be performed on
the submitted tumor sample prior to randomization.
Subjects will be randomized 1:1 into one of the two treatment arms. They will
be stratified by PD-L1 expression level (< 5% versus greater than or equal to
5%) and histology (squamous vs non-squamous).
Subjects will receive open-label treatment with one of the following:
• Arm A: Nivolumab 3 mg/kg IV every 2 weeks until disease progression or
unacceptable toxicity. Nivolumab treatment beyond initial investigator-assessed
RECIST 1.1 defined progression is permitted if the subject has investigator
assessed clinical benefit and is tolerating nivolumab
• Arm B: Investigator*s Choice Chemotherapy is administered in 3-week cycles
for up to a maximum of 6 cycles of IV chemotherapy. Chemotherapy treatment will
continue until disease progression, unacceptable toxicity or completion of the
6 cycles, whichever comes first. Choice of chemotherapy regimens is dependent
on NSCLC histology.
* Squamous: gemcitabine (1250 mg/m2) with cisplatin (75 mg/m2) (gemcitabine
administered Day 1 and Day 8 of each cycle); or gemcitabine (1000 mg/m2) with
carboplatin (AUC 5) (gemcitabine administered Day 1 and Day 8 of each cycle);
or paclitaxel (200 mg/m2) with carboplatin (AUC 6).
* Non-Squamous: pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or
carboplatin (AUC 6). Non squamous subjects who have stable disease or response
after Cycle 4 are permitted to continue pemetrexed alone as maintenance therapy
until disease progression or unacceptable toxicity.
Subjects who progress on or after chemotherapy may be eligible to receive
optional crossover nivolumab, as long as they meet certain protocol specific
criteria. There is a separate ICF Addendum for consenting patients onto the
crossover nivolumab.
After treatment in either Arm A or B subjects will enter the follow-up phase of
the study. Subjects will have 2 visits within the first 3 months after stopping
treatment. The remaining follow-up visits can be conducted over the phone and
will occur every 3 months.
The duration of the study from start of enrolment to analysis of the primary
PFS endpoint is expected to be 33 months. The study will end once additional
survival follow-up has concluded.

The medicinal interventions include nivolumab or Investigator's choice of:
gemcitabine, cisplatin, carboplatin, pemetrexed and paclitaxel. All of these
compounds will be supplied by the sponsor.

Nivolumab is given intravenously every 2 weeks continuing will depend on the
subject*s response to the medicine. The other investigator choice
chemotherapies will be given intravenously every 3 weeks for up to a maximum of
6 cycles.

As part of the trial, patients will be expected to attend multiple clinic
visits, where they will undergo physical examinations, vital sign measurements
(including oxygen saturation levels), blood tests for safety assessment,
pregnancy testing (for females of child bearing potential), and monitoring for
adverse events. In addition, every 6 weeks (from week 6 until week 48) and then
every 12 weeks, patients will undergo radiographic assessment of their tumours
(by CT or MRI) until disease progression or treatment discontinuation whichever
occurs later. Blood will also be collected at certain visits for research
purposes (PK, immunogenicity and biomarker studies). The frequency of visits
and number of procedures carried out during this trial would typically be
considered over and above standard of care. These procedures are conducted by
medically trained professionals and every effort will be made to minimise any
risks or discomfort to the patient. Treatment for cancer often has side
effects, including some that are life threatening. An independent Data
Monitoring Committee will be utilised in this trial.