Ipilimumab and Nivolumab in Patients With Anti-PD-1-axis Therapy-resistant Advanced Non-small Cell Lung Cancer.

Approximately 20 percent of unselected patients with advanced non-small cell lung cancer
(NSCLC) and progression during or after standard first line chemotherapy will experience
tumor response to nivolumab. Treatment options for patients who are not responsive to
programmed death 1 (PD-1) axis inhibitor therapy are limited, and the mechanisms of primary
resistance are poorly understood.

The combination of nivolumab and ipilimumab is currently FDA approved for the treatment of
advanced melanoma based on superiority to either agent alone5. The results of a phase I study
evaluating combination therapy with nivolumab and ipilimumab in patients with advanced NSCLC
(NCT01454102) were presented at the annual American Society of Clinical Oncology (ASCO)
meeting in 20166. Dosing of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6
weeks yielded an objective response rate (ORR) by Response Evaluation Criteria in Solid
Tumors (RECIST) v1.1 of 39%, with one-year survival rate of 69% and grade 3-4
treatment-related adverse event rate of 33%. These results prompted an ongoing phase III
study comparing this regimen to standard first line chemotherapy, nivolumab monotherapy or
combination therapy with chemotherapy and nivolumab for patients with advanced NSCLC
(NCT02477826).

The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab
after primary resistance to anti-PD-1 axis therapy can lead to objective radiographic tumor
regression. It is hypothesized that ipilimumab will enable more effective immune priming in
some patients, resulting in the trafficking of tumor-specific cytotoxic T cells to the tumor,
as well as depletion of tumor-permissive T regulatory cells. With concurrent nivolumab, PD-1
inhibition in the tumor will enable effective anti-tumor attack by tumor-specific T cells.
Serial tumor biopsies and blood collections will allow interrogation of changes in the tumor
microenvironment (and periphery) that support this hypothesis.

The investigators will primarily enroll patients who have experienced progression of NSCLC
after anti-PD-1- axis therapy without initial response to such therapy ('primary
resistance'). A smaller cohort of patients with acquired resistance to anti-PD-1 axis therapy
(i.e. progression after initial response) will additionally be accrued.

Inclusion Criteria

A. Signed Informed Consent B. Ability to comply with the protocol C. Age ≥18 years D.
Histologically or cytologically documented, locally advanced or metastatic (i.e., Stage
IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the
American Joint Committee /AJCC staging system) E. ECOG performance status of 0 to 2 F.
Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can be counted
as target lesions if clearly progressing after radiation.

G. Chemotherapy-naive and treated patients will be eligible, with no limit on number of
prior therapies. Patients with NSCLC known to harbor an ALK rearrangement, or EGFR mutation
known to be sensitive to FDA-approved tyrosine kinase inhibitors (TKI), are only eligible
after experiencing disease progression (during or after treatment) or intolerance to an FDA
approved EGFR TKI or ALK TKI, respectively.

1. Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR T790M tumor
must have received prior osimertinib

2. Patients with crizotinib-treated ALK rearranged NSCLC must have received a next
generation ALK inhibitor (e.g. ceritinib, alectinib or brigatinib) H. Prior palliative
radiotherapy must have been completed at least 2 weeks before the first dose of study
drug.

I. Anti- PD-1 Axis therapy (anti-PD-1 or anti-PD-L1, e.g. nivolumab, pembrolizumab,
atezolizumab, durvalumab, avelumab) must be the most recent systemic anti-tumor treatment
received in all patients, with documented progressive disease. Last administration of
anti-PD-1 axis therapy must have been at least 3 weeks before the first dose of study drug.

a. Patients to be enrolled to the primary cohort (primary resistance) must have had
progressive disease or stable disease less than 24 weeks as the best clinical response to
anti-PD-1-axis monotherapy b. Patients to be enrolled to the exploratory cohort (acquired
resistance) must have had stable disease for at least 24 weeks, partial response, or
complete response as the best clinical response to anti-PD-1-axis monotherapy, with
subsequent progression of disease J. At least one tumor amenable to incisional, excisional,
core or forceps (transbronchial) biopsy. Patients must be willing to undergo tumor biopsies
before starting trial therapy, and 9 to 10 weeks after initiation of therapy.

a. If the initial biopsy will be excisional, the excised tumor cannot be counted as a
target lesion and there must be another lesion amenable to incisional, excisional, core or
forceps biopsy. In this scenario, the second biopsy can only be excisional if the lesion to
be excised is not a target lesion. b. Cytology tumor specimens (e.g. from fine-needle
biopsies, or drainage of pleural/ pericardial or ascites fluid) are not acceptable.
Biopsies of bone lesions that do not have a soft tissue component are also not acceptable
(i.e. decalcified tumor samples are not acceptable).

K. For female patients of childbearing potential and male patients with partners of
childbearing potential, agreement (by patient and/or partner) to use a highly effective
form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when
used consistently and correctly) and to continue its use for 6 months after the last dose
of trial therapy. Highly effective contraception is one with a failure rate of <0.1%. Birth
control pills on their own do not achieve that rate.

1. Women of childbearing potential must have a negative pregnancy test (serum or urine)
within 72 hours of the start of study drug administration

2. Women who have recently given birth must no longer be breastfeeding

L. Adequate hematologic and end-organ function, defined by the following laboratory results
obtained within 14 days prior to the first study treatment:

- Neutrophils ≥1500 cells/μL (without granulocyte colony-stimulating factor support within
2 weeks prior to Cycle 1, Day 1)

- Platelets ≥75,000/μL (transfusion to achieve this level is not permitted within 2
weeks of the first study drug administration)

- Hemoglobin ≥9.0 g/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x institutional
upper limit of normal (ULN) with the following exceptions: Patients with documented
liver metastases: AST and/or ALT≤5 x ULN

- Serum bilirubin ≤1.5 x ULN (Patients with known Gilbert disease who have serum
bilirubin level ≤3 x ULN may be enrolled)

- Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min

Exclusion Criteria

A. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved
childhood asthma/atopy would be an exception to this rule. Subjects who require
intermittent use of inhaled steroids or local steroid injections would not be excluded from
the study. Subjects with hypothyroidism stable on hormone replacement, or psoriasis not
requiring systemic therapy (within the past 3 years) will not be excluded from the study.
B. Interstitial lung disease that is symptomatic or may interfere with the detection or
management of suspected drug-related pulmonary toxicity C. Subjects must not have a history
of life-threatening toxicity related to prior anti-PD-1 axis therapy a. Subjects with
history of anti-PD-1 axis therapy toxicities that are unlikely to recur with standard
countermeasures (e.g., hormone replacement after adrenal crisis) are eligible.

D. Prior treatment with anti-CTLA-4 therapeutic antibodies

E. Symptomatic or untreated CNS metastases. Patients with a history of treated asymptomatic
CNS metastases are eligible, provided they meet all of the following criteria:

1. No evidence of interim progression between the completion of CNS-directed therapy and
the start of trial therapy.

2. No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants
at a stable dose are allowed.

3. Completed stereotactic radiosurgery at least 1 week prior to Cycle 1, Day 1 or
wholebrain radiation at least 2 weeks prior to Cycle 1, Day 1 F. History of
leptomeningeal carcinomatosis G. Prior palliative radiotherapy outside the CNS within
2 weeks of the first dose of study drug.

H. Treatment with systemic immunosuppressive medications (including but not limited to,
dexamethasone at doses > 2 mg daily (or equivalent dose of other corticosteroids),
cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and
antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to initiating trial
therapy (Inhaled or topically applied steroids, and acute and chronic standard-dose NSAIDs
are permitted. Replacement steroids are also permitted).

I. Subjects must not have received vaccines containing live virus for prevention of
infectious diseases within 12 weeks prior to the first dose of study drug.

a. The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on
study without restriction.

J. Any approved systemic anti-cancer therapy, within 3 weeks prior to initiation of study
treatment; the following exception is allowed:

- TKIs approved for treatment of NSCLC discontinued > 7 days prior to Cycle 1, Day 1.
The baseline scan must be obtained after discontinuation of prior TKIs.

K. Treatment with any other investigational agent or participation in another clinical
trial with therapeutic intent within 28 days prior to enrollment; the following exceptions
are allowed:

- Unapproved/experimental TKIs discontinued 14 days prior to Cycle 1, Day 1 L. Known
infection with HIV, HBV or HCV. Patients with prior exposure to hepatitis, but no
evidence of active or chronic infection, may be eligible.

- Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by
polymerase chain reaction are eligible.

M. Active systemic infection requiring systemic antibiotic treatment within 72 hours prior
to first dose of study treatment N. Uncontrolled intercurrent illness including, but not
limited to, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric
illness/social situations that would limit compliance with study requirements O. Major
surgery or traumatic injury within 4 weeks of starting study drug P. Women who are pregnant
or lactating. Q. Any underlying medical condition that in the Principal Investigator's
opinion will make the administration of study drug hazardous to the patient or would
obscure the interpretation of adverse events.