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

Summary

This is an open-label, 2-arm, randomized, Phase 3 study in adult (18 years) 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 programmed death-ligand 1 (PD-L1) protein in the submitted tumor sample prior to randomization; PD-L1+ status is defined as membranous staining in greater than or equal to 1% tumor cells in a minimum of 100 evaluable tumor cells. Strongly PD-L1+ status is defined as membranous staining in [GreaterThanorequalTo]greater than or equal to 5% tumor cells in a minimum of 100 evaluable tumor cells.

Subjects will be randomized 1:1 into one of the two treatment arms and stratified by PD-L1 expression level and histology (squamous vs non-squamous).

Subjects will receive open-label treatment with one of the following:
* arm a: nivolumab 3 mg/kg intravenous (iV) every 2 weeks until disease progression or unacceptable toxicity. nivolumab treatment beyond initial investigator-assessed radiographic progression per 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 non-small cell lung cancer (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 (area under the concentration-time curve -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.

Primary endpoint
The primary endpoint of this study is progression-free survival (PFS) as assessed by the independent radiology review committee (iRRC) among strongly PD-L1+ subjects, which is defined as the time from randomization to the date of the first documented tumor progression as determined by the iRRC (per ReCiST 1.1), or death due to any cause.

Secondary endpoints
Secondary endpoints include objective response rate (oRR) as determined per iRRC and overall survival for strongly PD-L1+ subjects, PFS and disease-related symptom improvement among all PD-L1+ subjects. oRR is defined as the number of subjects whose best confirmed objective response is a CR or PR, divided by the number of andomized subjects among strongly PD-L1+ subjects. Best overall response (BoR) is defined as the best response designation, as determined by the iRRC, recorded between baseline and the date of objectively documented progression per ReCiST 1.1 or the date of subsequent anticancer therapy, whichever occurs first.

Treatment Beyond Disease Progression
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, as specified in protocol Section 4.3.7.
if the doctor thinks the subject is benefitting from nivolumab treatment, but they have experienced growth of their tumor, they can continue beyond their disease progression. if subjects continue treatment with nivolumab, all foreseeable risks or discomforts and other alternative treatment options as described in the main informed consent form are applicable.

Participant Eligibility

1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule,
and laboratory testing.

2. Target Population
a) ECOG Performance Status of <= 1
b) Subjects with histologically confirmed Stage IV or recurrent NSCLC (per the 7th
International Association for the Study of Lung Cancer classification [Goldstraw 2007]),
squamous or nonsquamous histology, with no prior systemic anticancer therapy
(including EGFR and ALK inhibitors) given as primary therapy for advanced or
metastatic disease.
Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last
administration of the prior regimen occurred at least 6 months prior to enrollment.
Prior definitive chemoradiation for locally advanced disease is also permitted as long as
the last administration of chemotherapy or radiotherapy (which ever was given last)
occurred at least 6 months prior to enrollment.
c) Measurable disease by CT or MRI per RECIST 1.1 criteria; radiographic tumor
assessment performed within 28 days of randomization
i) Target lesions may be located in a previously irradiated field if there is documented
(radiographic) disease progression in that site after the completion of radiation
therapy.
d) Subjects must be PD-L1+ on IHC testing performed by the central lab during the
Screening period. Refer to Section 5.6.1 for the definition of PD-L1+.
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or minimum of
15 unstained tumor tissue sections, with an associated pathology report, must be
submitted for biomarker evaluation prior to randomization. The tumor tissue sample may
be fresh or archival if obtained within 6 months prior to enrollment, and there can have
been no systemic therapy (eg, adjuvant or neoadjuvant chemotherapy) given after the
sample was obtained. Subjects with fewer than 15 unstained slides available at baseline
(but no fewer than 10) may be eligible following discussion with BMS Medical Monitor.
Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle
biopsies, drainage of pleural effusions with cytospins, or punch biopsies are not
considered adequate for biomarker review and randomization. Biopsies of bone lesions
that do not have a soft tissue component or decalcified bone tumor samples are also not
acceptable.
e) Prior radiotherapy must have been completed at least 2 weeks prior to randomization
f) Screening laboratory values must meet the following criteria (using CTCAE v4):
i) WBC >= 2000/uL
ii) Neutrophils >= 1500/uL
iii) Platelets >= 100x103/uL
iv) Hemoglobin >= 9.0 g/dL
v) Serum creatinine <= 1.5 x ULN or calculated creatinine clearance > 50 mL/min (using
the Cockcroft-Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
vi) AST <= 3.0 x ULN
vii) ALT <= 3.0 x ULN
viii) Total Bilirubin<= 1.5 x ULN (except subjects with Gilbert Syndrome who must
have a total bilirubin level of < 3.0x ULN).
g) Subject Re-enrollment: This study permits the re-enrollment of a subject that has
discontinued the study as a pre-treatment failure (ie, subject has not been randomized /
has not been treated). If re-enrolled, the subject must be re-consented.

3. Age and Reproductive Status
a) Men and women, ages >= 18 years of age.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception from the time
of enrollment for the duration of treatment with nivolumab plus 5 half-lives of nivolumab
plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment
completion.
WOCBP must also agree to follow instructions for method(s) of contraception from the
time of enrollment for the duration of treatment with chemotherapy plus 5-half lives of
chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days post
treatment completion.
e) Men who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives
of nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks
post-treatment completion.
Men who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with chemotherapy plus 5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 90 days
post-treatment completion.
f) Azoospermic males and WOCBP who are continuously not heterosexually active are
exempt from contraceptive requirements. However they must still undergo pregnancy
testing as described in these sections
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on
the use of highly effective methods of contraception. Highly effective methods of contraception
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method
being highly effective and the other method being either highly effective or less effective as
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

* Male condoms with spermicide

* Hormonal methods of contraception including combined oral contraceptive pills, vaginal
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena by WOCBP
subject or male subject[Single Quote]s WOCBP partner

* Nonhormonal IUDs, such as ParaGard

* Tubal ligation

* Vasectomy.

* Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence
are not required to use a second method of contraception, but female subjects must continue to
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION

* Diaphragm with spermicide

* Cervical cap with spermicide

* Vaginal sponge

* Male Condom without spermicide*

* Progestin only pills by WOCBP subject or male subject[Single Quote]s WOCBP partner

* Female Condom