Clinical Trials /

Genetic Predictors of Benefit to Pembrolizumab



The primary objective is to determine if mutation load underlies sensitivity to pembrolizumab alone and in combination with chemotherapy.

Related Conditions:
  • Bladder Carcinoma
  • Esophageal Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Lung Adenocarcinoma
  • Non-Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility


<span class="go-doc-concept go-doc-keyword">Genetic</span> Predictors of Benefit to <span class="go-doc-concept go-doc-intervention">Pembrolizumab</span>


  • Brief Title: Genetic Predictors of Benefit to Pembrolizumab
  • Official Title: Identifying Genetic Predictors of Durable Clinical Benefit to Pembrolizumab in Advanced or Recurrent Cancers
  • Clinical Trial IDs

    NCT ID: NCT02710396

    ORG ID: AAAQ5450

    Trial Conditions

    Carcinoma, Non-Small-Cell Lung

    Cancer of the Head and Neck

    Urinary Bladder Neoplasms

    Esophageal Squamous Cell Carcinoma

    Carcinoma, Transitional Cell

    Trial Interventions

    Drug Synonyms Arms
    Pembrolizumab Keytruda, MK-3475, Lambrolizumab Pembrolizumab

    Trial Purpose

    The primary objectives are to determine if tumor genetics (non-synonymous mutation burden >
    200 mutations and mutational smoking signature [transversion high]) can predict durable
    clinical benefit (DCB) to pembrolizumab. The secondary objective is to determine if a
    combined genetic and immune (PD-L1, immune signature) analysis can predict durable clinic
    benefit better than either test alone. Our exploratory objectives are to identify and
    validate candidate neoantigens in vitro; and explore mechanisms of resistance to

    Detailed Description

    The adaptive immune response mechanism can be co-opted by tumor cells leading to immune
    resistance and tumor growth. Recent success of anti-PD-1 antibodies (anti-PD-1) across a
    broad range of tumors suggests that this immune resistance can be reversed [Brahmer-Phase I,
    Brahmer-Clinical, Topalian-Safety, Brahmer-Harnessing]. Although responses have been
    observed to anti-PD-1, it is a subset of patients who have durable benefit. Biomarker
    analysis to date has focused on co-inhibitory molecule and T cell subsets in the tumor
    microenvironment leading to a useful classification ranging from highly immunogenic to
    immunologically ignorant tumors that can define to some degree sensitivity and resistance to
    anti-PD-1 [Taube-Colocalization]. This approach has been relatively successful however it
    does not define the specific antigenic targets that exist. A growing body of literature
    would suggest tumor specific neoantigens underlie sensitivity to anti-PD-1 and mutation
    burden stochastically increases the likelihood of neoantigen formation [Matsushita-Cancer,
    DuPage-Endogenous, DuPage-Expression, Castle-Exploiting]. Although responses are higher in
    more genetically damaged tumors, there are many paths to inducing DNA damage leading to
    adaptive immune resistance (viral mediated, DNA repair defects, carcinogen induced)
    [Schumacher-Neoantigens]. In published work to date in non-small cell lung cancer, the
    non-synonymous mutation burden and mutational smoking signature is highly predictive of
    durable clinical benefit (DCB) to pembrolizumab (defined as objective complete or partial
    response or stable disease for at least 6 months) [Rizvi-Cancer]. In this biomarker trial,
    we will explore the relationship between the genetic landscape of smoking carcinogen induced
    tumors and DCB to pembrolizumab. A systematic prospective analysis in smoking carcinogen
    induced tumors (NSCLC, HPV negative head and neck, esophageal and bladder cancers) will be
    performed to elucidate the underlying biology of sensitivity and resistance.

    Trial Arms

    Name Type Description Interventions
    Pembrolizumab Experimental Subjects with advanced or recurrent cancers receiving Pembrolizumab every 3 weeks for up to 2 years. Pembrolizumab

    Eligibility Criteria

    Inclusion Criteria:

    - Be willing and able to provide written informed consent/assent for the trial.

    - Advanced or recurrent non-small cell lung cancer, HPV negative head and neck cancer,
    transitional cell bladder cancer or squamous esophageal cancer.

    - NSCLC patients may be chemotherapy nave or pre-treated. For NSCLC patients with lung
    adenocarcinoma, tumors must be epidermal growth factor receptor (EGFR) and Alkaline
    phosphatase (ALK) wild-type; if a Kirsten rat sarcoma (KRAS) mutation is detected,
    EGFR and ALK testing is not required.

    - HPV negative head and neck cancer, transitional cell bladder cancer and squamous
    esophageal cancer patients must have received at least one prior line of therapy for
    their disease; treatment may include surgery, radiation, chemotherapy and/or a
    biologic agent.

    - 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.

    - Be willing to undergo tumor biopsies pre-treatment and at Cycle 2 Day 8 (C2D8) (+/- 7
    days). For patients who progress after DCB, also repeat biopsy at progression.

    - 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 (Section
    8.4.4). 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

    - Demonstrate adequate organ function as defined below, all screening labs should be
    performed within 10 days of treatment initiation.


    - Absolute neutrophil count (ANC): 1,500 /mcL

    - Platelets: 100,000 / mcL

    - Hemoglobin: 9 g/dL or 5.6 mmol/L


    - 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


    - 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


    - 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

    - 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

    - 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., HCV RNA
    [qualitative] is detected).

    - Has a known history of active TB (Bacillus Tuberculosis)

    - Has received a live vaccine within 30 days prior to the first dose of trial

    - History of allergy or hypersensitivity to any component of the treatment.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of subjects with non small-cell lung cancer who receive durable clinical benefit to pembrolizumab.

    Number of subjects with other smoking related cancers (HPV negative head and neck, esophageal and bladder cancers) who receive durable clinical benefit to pembrolizumab.

    Secondary Outcome Measures

    Trial Keywords

    Carcinoma, Non-Small-Cell Lung

    Non-Small Cell Lung Cancer

    Non-Small-Cell Lung Carcinoma

    Nonsmall Cell Lung Cancer


    Cancer of Neck

    Neoplasms, Head and Neck

    Cancer of the Head

    Cancer of the Head and Neck

    Head, Neck Neoplasms

    Bladder Cancer

    Bladder Neoplasms

    Malignant Tumor of Urinary Bladder

    Urinary Bladder Cancer

    Esophageal Squamous Cell Carcinoma

    Carcinoma, Transitional Cell