Investigators hypothesize that addition of pembrolizumab will enhance the efficacy of carboplatin and pemetrexed in patients with EGFR-mutation-positive NSCLC, or patients with other genetic alterations, and who have disease progression following appropriate targeted therapies.

Inclusion Criteria:

• Cohort-specific:

Cohort 1- EGFR mutation positive NSCLC patients previously treated with appropriate targeted therapy with progressive and measurable disease per RECIST 1.1 criteria tumor.

Cohort 2- Other genetically altered NSCLC patients previously treated with appropriate targeted therapy with progressive and measurable tumor.

• Tumor tissue for PD-L1 assessment should be available unless PD-L1 assessment results are already available.
• Patients should not have received any systemic chemotherapy for advanced NSCLC. Patients who received 1 cycle of systemic chemotherapy for advanced NSCLC while awaiting the results of tumor molecular analysis and subsequently were switched to appropriate targeted therapy will be eligible. Patients who have received neoadjuvant, adjuvant or as part of concurrent chemotherapy and radiation are eligible if they received the chemotherapy 12 months or more before the start of study therapy.
• ECOG PS 0-1 (Eastern Cooperative Oncology Group Performance Status: an attempt to quantify cancer patients' general well-being and activities of daily life. The score ranges from 0 to 5 where 0 is asymptomatic and 5 is death.)
• Patients should have recovered to ≤ grade 1 from clinically meaningful (example alopecia is not considered clinically meaningful) adverse events related to prior treatments.
• Patients should be willing and able to provide written informed consent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Demonstrate adequate organ function
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 1 week of enrollment.
• Female subjects of childbearing potential must be willing to use an adequate method of contraception
• Male subjects of child bearing potential must agree to use an adequate method of contraception

Exclusion Criteria:

• 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. If the half-life of the drug is known then starting therapy 5 half-lives after the end of the last therapy is acceptable.
• Has a diagnosis of immunodeficiency. Patient should not be of any immunosuppressive therapy or steroids > prednisone 10mg/day or its equivalent on the day of the start of therapy.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab, carboplatin or pemetrexed 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 targeted small molecule therapy, or palliative radiation therapy within 1 week 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.
• Has a known additional malignancy that is progressing or requires active treatment or the treating physician believes will require therapy within 1 year.
• Has symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has active autoimmune disease that has required systemic treatment in the past 2 years
• Has known history of non-infectious pneumonitis that required steroids or has current pneumonitis. Has known history of interstitial lung disease.
• 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 or Hepatitis C
• Has received a live vaccine within 30 days of planned start of study therapy.