The primary objective is to determine if mutation load underlies sensitivity to pembrolizumab
alone and in combination with chemotherapy. This will be a 3-arm, multi-center, open-label,
non-randomized biomarker trial in patients with advanced, treatment-naive NSCLC. Patients
will receive 1 of 3 possible cohorts as per investigator's discretion. Patients with
non-squamous histology may receive any of the 3 cohorts; patients with squamous histology may
receive either cohorts 1 and 2.
Somatic mutations leading to cancer are related to endogenous or exogenous DNA damaging
processes. The resultant mutations can be separated into two categories - (i) mutations that
provide selective advantage for clonal expansion and (ii) mutations that do not result in
growth advantage. The latter have been termed passenger mutations, while the former are
referred to as driver mutations. It is widely believed that the number of driver mutations in
a cancer sample is limited to a handful, usually two or more but less than ten. In contrast,
the genome of a cancer can harbor more than a million somatic mutations most of which are
considered to be passengers.
Several studies have shown that the passenger mutations may not be oncogenic drivers but may
be of importance in adaptive immune resistance of a tumor. In particular the relevant
mutations are likely to be the nonsynonymous exonic mutations in tumors; these may give rise
to novel proteins that differ from their wild type counterparts and are immunogenically more
relevant. The study will explore if there is a relationship between the genetic mutations and
the success of pembrolizumab.
Inclusion Criteria:
- NSCLC patients of all histologies may enroll to Cohorts 1 and 2. Only patients of
non-squamous histologies may enroll to Cohort 3. If enrollment to a cohort is
completed, enrollment may continue to other open cohorts.
- Be willing and able to provide written informed consent/assent for the trial.
- Chemotherapy naïve NSCLC patients.For NSCLC patients with lung adenocarcinoma, tumors
must be Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK)
wild-type; if a Kirsten Ras (KRAS) mutation is detected, EGFR and ALK testing is not
required.
- Diagnosis must be documented by histology or cytology from brushings, washings, or
needle aspiration of a defined lesion but not from sputum cytology.
- Be ≥ 18 years of age on day of signing informed consent.
- Have measurable disease based on RECIST 1.1.
- Sufficient archived tumor material available (equivalent to 2 core biopsies or
greater); if insufficient archived tumor material available new tumor biopsy is
mandatory.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale.
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.
- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy.
- Demonstrate adequate organ function as defined below, all screening labs should be
performed within 10 days of treatment initiation.
-- Hematological
- Absolute neutrophil count (ANC): ≥1,500 /mcL
- Platelets: ≥100,000 / microliter (mcL)
- Hemoglobin: ≥9 g/dL or ≥5.6 mmol/L
-- Renal
- Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used
in place of creatinine or CrCl): ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for
subject with creatinine levels > 1.5 X institutional ULN
-- Hepatic
- Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤
2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
-- Coagulation
- International Normalized Ratio (INR) or Prothrombin Time (PT): ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
range of intended use of anticoagulants
- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants
Exclusion Criteria:
- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.
- Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent. Note: Subjects
with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
study. Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- Has evidence of interstitial lung disease or active, non-infectious pneumonitis.Has an
active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C
(HCV) RNA [qualitative] is detected).
- Has a known history of active tuberculosis (TB)
- Has received a live vaccine within 30 days prior to the first dose of trial treatment.
- History of allergy or hypersensitivity to any component of the treatment.
