Pembrolizumab in Elderly Patients With Advanced Lung Cancer

This is a multi-center phase II trial of intravenous (IV) Pembrolizumab MK-3475 in subjects older than 70 years with advanced Non-small cell Lung Cancer (NSCLC) expressing Programmed death-ligand 1 (PD-L1). 82 patients will be enrolled in this trial to examine the efficacy, the impact on geriatric assessments, the quality of life and the self-reported outcomes.

Subjects will receive MK-3475 at a fixed dose of 200 mg every 3 weeks (Q3W) (Figure 1). Subjects will be evaluated every 9 weeks (63 ± 7 days) with radiographic imaging to assess response to treatment. QoL and Self-reported Health Questionnaires, as well as geriatric follow-up will be performed at the same intervals. Investigators will make all treatment-based decisions using immune-related Response Criteria (irRC). However, for determination of overall response rate (ORR) and progression-free survival (PFS), the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used. 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 4.0. Treatment with MK-3475 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, noncompliance with trial treatment or procedure requirements, or administrative reasons.

After the end of treatment, each subject will be followed for a minimum of 30 days for adverse event monitoring (serious adverse events will be collected for up to 90 days after the end of treatment unless the subject starts a new anticancer therapy between days 31 and 90). Subjects will have post-treatment follow-up for disease status, including initiating a non-study cancer treatment and experiencing disease progression, until death, withdrawing consent, or becoming lost to follow-up.

Participation in this trial will be dependent upon supplying tumor tissue from a newly obtained formalin-fixed specimen from locations not radiated prior to biopsy. The specimen will be evaluated at a central laboratory facility for expression status of Programmed death-ligand 1(PD-L1) in a prospective manner. Only subjects whose tumors express Programmed death-ligand 1(PD-L1) as determined by the central laboratory facility will be eligible for inclusion in this study.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histological or cytological documented stage III B or IV squamous and non-squamous non-small-cell lung cancer previously untreated.
2. Epidermal Growth Factor receptor (EGFR) and Anaplastic lymphoma kinase (ALK) have to be wild-type.
3. The subject must be willing and able to provide written informed consent/assent for the trial.
4. Patients must be aged more than 70 years, on day of signing informed consent.
5. Measurable disease (at least 1 lesion) based on RECIST criteria v1.1. Patients will not be eligible if this lesion was irradiated before inclusion.
6. Be willing to provide tissue from a newly obtained core or excision biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
7. PD-L1 expression ≥ 1%
8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Scale.
9. Screening laboratory values must meet the following criteria (Table 1, see protocol), all screening laboratory tests should be performed within 8 days of treatment initiation.
10. Male subjects of childbearing potential must 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.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose over 10 mg of prednisone or equivalent, or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has a known history of active Tuberculosis Bacillus
4. Hypersensitivity to Pembrolizumab or any of its excipients.
5. Has had any prior anti-cancer therapy for his or her metastatic NSCLC. In the case of patients who have progressed to a metastatic stage after having been treated for early stage NSCLC, chemotherapy or radiation therapy as part of this previous treatment is allowed, provided they have been completed more than three months ago. Patients who received adjuvant or neoadjuvant treatment or both for early stages will be eligible for this trial. All adverse events related to these previous treatments must have recovered (i.e., ≤ Grade 1 or at baseline).
6. Has had any previous malignancy (except non melanoma skin cancer, and cancer in situ of: bladder, gastric, colon, cervical/dysplasia, melanoma, breast), unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate if 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 at a dose over 10 mg of prednisone or equivalent, for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
8. 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., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. 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.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. Has any geriatric exclusion criteria:

    * advanced dementia (GDS ranking \>6)
    * moderate or severe functional dependence (Barthel Index \< 35)
    * Life expectancy less than one year, due to co-morbidities other than lung cancer.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C Virus RNA \[qualitative\] is detected).
16. 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.
17. Evidence of interstitial lung disease.