Pembrolizumab in First Line Treatment of Advanced NSCLC Patients With PD-L1 Low Tumors.

Study Overview
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Brief Summary
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This is a prospective, monocentric, open label, phase II trial of intravenous (IV) Pembrolizumab monotherapy in subjects previously untreated for their stage IIIB-IV, PD-L1 low non small cell lung cancer (NSCLC).

Detailed Description
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Approximately 65 subjects with PD-L1 low (PD-L1Lo), EGFR wt, EML4/ALK fusion negative NSCLC will be enrolled in this trial for examination of the biological characteristics associated to efficacy and safety of Pembrolizumab. Subjects will receive Pembrolizumab iv at dose of 200 mg every three weeks. Subjects will be evaluated every 9 weeks (63 +/- 3 days) with radiographic imaging to assess response to treatment. Subjects will continue with the assigned study treatment until RECIST-defined progression of disease, unacceptable toxicity or consent withdrawal. Treatment with Pembrolizumab will continue until two years of therapy have been administered, documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, or administrative reasons. Pembrolizumab treated subjects who obtain a confirmed Complete Response (CR) per RECIST 1.1 may consider stopping trial treatment. These subjects may be eligible for re-treatment with Pembrolizumab after they have experienced radiographic disease progression at the discretion of the investigator, this re-treatment will be the Second Course Phase.

Official Title
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Phase II Study to Test Pembrolizumab (MK-3475) in First Line Treatment of Advanced NSCLC Patients With PD-L1 Low Tumors (<50%)_ PEOPLE TRIAL (Pembrolizumab in Pd-L1 Low Expressors).

Conditions
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Non Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a confirmed diagnosis of NSCLC in stage IIIB/ IV. Do not have an EGFR sensitizing (activating) mutation or ALK translocation and have a PD-L1 low (<50%) tumor as determined by immunohistochemistry with anti-PD-L1 antibody (DAKO 22C3). Have not received prior systemic chemotherapy treatment for advanced NSCLC. Subjects with non-squamous histologies will not be enrolled until the EGFR mutation status and/or ALK translocation status is available. For patients enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR and ALK translocation will not be required . Be willing and able to provide written informed consent/assent for the trial. Be >=18 years of age on day of signing informed consent. Have measurable disease based on RECIST 1.1. Be willing to provide tissue from archived histological specimen or newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 45 days prior to initiation of treatment on Day 1. Have a performance status of 0 or 1 on the ECOG Performance Scale. Demonstrate adequate organ function All screening labs should be performed within 10 days of treatment initiation 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 (Reference Section 5.7.2). 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 No history of active malignancy requiring treatment Exclusion Criteria: The subject must be excluded from participating in the trial if the subject: Has an EGFR sensitizing mutation and/or an ALK translocation. Has a PD-L1 expression assessed as high by the central laboratory 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 a known history of active TB (Bacillus Tuberculosis). Hypersensitivity to Pembrolizumab or any of its excipients. Has had a prior anti-cancer monoclonal antibody (mAb) 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 subjects 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 or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 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 a history of non-infectious pneumonitis that required steroids or has current 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, or anti-PD-L2 agent. 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 received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>subjects with PD-L1 low (PD-L1Lo), EGFR wt, EML4/ALK fusion negative NSCLC | Drug: Pembrolizumab<br>* humanized antibody used in cancer immunotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune biomarkers | tumor infiltrating lymphocytes in patients whose tumors have a low PD_L1 expression | 3 years | 
| Immune biomarkers | infiltrating T cells that upregulate PD-1 | 3 years | 
| Immune biomarkers | inhibitory receptors such as TIM-3, LAG-3 and TIGIT | 3 years | 
| Immune biomarkers | type of cells being positive for PD-L1(neoplastic cells vs infiltrating immune cells) | 3 years | 
| Immune biomarkers | presence and phenotype of tumor-infiltrating lymphocytes in the pre-therapy lesions of patients with low expression of PD-L1 | 3 years | 
| Immune biomarkers | levels of CD3+, CD4+, CD8+ lymphocytes | 3 years | 
| Immune biomarkers | expression, in TIL, of markers of functional differentiation to cytolytic stage such as granzyme B and TIA-1, or maturation to memory stage (CD45RO) | 3 years | 
| Immune biomarkers | expression of PD1+ by TIL | 3 years | 
| Immune biomarkers | expression of PD-L1 on neoplastic cells vs immune cells | 3 years | 
| Immune biomarkers | expression of inhibitory receptors as LAG-3, TIM-3 and TIGIT | 3 years | 
| Immune biomarkers | frequency of FOXP3+ lymphocytes, as well as of CD11b+ CD33+ MDSCs, in pre-therapy lesions | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | tumor infiltrating lymphocytes in patients whose tumors have a low PD_L1 expression | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | infiltrating T cells that upregulate PD-1 | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | inhibitory receptors such as TIM-3, LAG-3 and TIGIT | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | type of cells being positive for PD-L1(neoplastic cells vs infiltrating immune cells) | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | presence and phenotype of tumor-infiltrating lymphocytes in the pre-therapy lesions of patients with low expression of PD-L1 | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | levels of CD3+, CD4+, CD8+ lymphocytes | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | expression, in TIL, of markers of functional differentiation to cytolytic stage such as granzyme B and TIA-1, or maturation to memory stage (CD45RO) | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | expression of PD1+ by TIL | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | expression of PD-L1 on neoplastic cells vs immune cells | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | expression of inhibitory receptors as LAG-3, TIM-3 and TIGIT | 3 years | 
| Immune biomarkers distribution between pre and post Pembrolizumab treatment | frequency of FOXP3+ lymphocytes, as well as of CD11b+ CD33+ MDSCs, in pre-therapy lesions | 3 years | 
| Activity endpoints | Response Duration (DoR) | from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease are objectively documented, assessed up to 3 years | 
| Activity endpoints | Objective Response Rate (ORR) | 3 years | 
| Activity endpoints | Disease Control Rate (DCR) | 3 years | 
| Effectiveness of Pembrolizumab treatment | Overall Survival (OS) will be used as effectiveness endpoint | from the time of enrollment to death due to any reasons, assessed up to 3 years | 
| Safety of Pembrolizumab treatment. | Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. A particular attention will be placed in the evaluation of potential Immune related adverse events (IrAE) | 3 years | 
| Patient Reported health status for physical, mental and social well-being | The patient Reported Outcomes Measurement Information System (PROMIS) provides measures of health status that assess physical, mental and social well-being from the patient prospective. | 3 years |