Clinical Trials

Inclusion Criteria:

• Be willing and able to provide written informed consent for the trial. The subject may also provide consent/assent for FBR; however, the subject may participate in the main trial without participating in FBR.
• Be at least 18 years of age on the day of signing informed consent.
• Have a histologically or cytologically confirmed diagnosis of Stage IV metastatic NSCLC (AJCC version 8).
• Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesion.
• Have a life expectancy of at least 3 months.
• Have an ECOG Performance Status of 0 or 1.
• Have adequate organ function.
• Specimens must be collected within 10 days prior to the start of trial treatment.
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Tumor demonstrates PD-L1 expression in ≥ 50% of tumor cells (TPS ≥ 50%) as assessed by IHC as determined by an FDA-approved test (22C3 Pharm IHC PharmDx [Dako] assay) at a central laboratory. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
  • Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual).
• Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
• A female subject is eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applies: (1) is not considered to be a woman of childbearing potential (WOCBP) as described in Section 12.5 or (2) is a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatment(s) (MK and or any active comparator/combination).
• A male subject must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
  • Note: As of amendment 06, contraception is no longer required for male participants. Sperm donation is also acceptable.

Exclusion Criteria:

• Has received prior systemic chemotherapy/other targeted or biological antineoplastic therapy treatment for their Stage IV metastatic NSCLC.
  • Note: Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease.
• Tumor harbors an EGFR-sensitizing (activating) mutation or an ALK translocation. Note: EGFR-sensitizing mutations are those mutations that are amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatinib. Subjects with nonsquamous histologies will not be randomized until EGFR mutation status and/or ALK translocation status is available in source documentation at the site. For subjects enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR mutation and ALK translocation will not be required as this is not SOC and is not part of current diagnostic guidelines.
• Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.
  • Note: Subjects who have entered the Follow-up Phase of an investigational trial may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
• Has received prior radiotherapy within 2 weeks of start of trial treatment or received lung radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• The subject’s NSCLC can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation.
  • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting trial treatment.
• Tumor specimen is not evaluable for PD-L1 expression.
• Is receiving systemic steroid therapy ≤ 7 days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication:
  • Corticosteroid use on study after Cycle 1 for management of AEs, SAEs, and events of clinical interest (ECIs), as a premedication for IV contrast allergies/reactions or if considered necessary for a subject’s welfare, is allowed;
  •  Subjects who receive daily steroid replacement therapy serve as an exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or hydrocortisone equivalent doses) is an example of replacement therapy;
  • Subjects who use inhaled steroids for the control of asthma serve as an exception to this rule.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known untreated CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (i.e., without evidence of progression for at least 4 weeks by repeat imaging [note that the repeat imaging should be performed during study screening]), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.
• Has a history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
• Has had an allogeneic tissue/solid organ transplant.
• Has received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus CalmetteGuérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Has an active infection requiring systemic therapy.
• Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus (HCV) RNA [qualitative] is detected) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
• Has a known history of active tuberculosis (TB; Bacillus Tuberculosis).
• 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 cooperating with the requirements of the trial.
• Is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the Screening Visit (Visit 1) through 120 days after the last dose of pembrolizumab or 90 days after the last dose of ipilimumab.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients and/or to ipilimumab and/or any of its excipients. Subjects with known ROS1 mutation: if treatment and testing for ROS1 is approved and accessible.