This study is for patients with non-resectable, recurrent, or metastatic well or moderately differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

The study will be conducted in two stages: 1) Safety Run-In and 2) Expanded Cohort.

1. Safety run-in: The first stage will include a safety run-in of 6 patients treated with pembrolizumab 200 mg intravenous (IV) every 3 weeks and lanreotide depot 90mg subcutaneous (SQ) every 3 weeks. Up to 6 patients at the Duke Cancer Institute will be accrued at the starting dose level. If one or less subject meets treatment-related discontinuation criteria (as specified in the protocol) during Cycle 1, then the study will proceed to the second stage, Expanded Cohort.
2. Expanded Cohort: Patients will be treated with pembrolizumab 200mg IV every 3 weeks and lanreotide depot 90mg SQ every 3 weeks as determined by the Safety Run-In Cohort.

Inclusion Criteria:

1. Willing and able to provide written informed consent for the trial.

2. At least 18 years of age on day of signing informed consent.

3. Non-resectable, recurrent, or metastatic well- or moderately-differentiated gastroenteropancreatic neuroendocrine tumor (GEP-NETs) with disease progression within the last 12 months. (Patients who have received prior local therapy, including but not limited to embolization, chemoembolization, radiofrequency ablation, radiation therapy, are eligible provided that measurable disease falls outside the treatment field or within the field but has shown an increase of > 20% in the size. Prior local therapy must be completed at least 4 weeks prior to the baseline scan.)

4. Prior somatostatin analogue therapy. (Patients should receive the first dose of study drug no sooner than 4 weeks from the last dose of somatostatin analogue.)

5. At least one measurable lesion based on RECIST version 1.1.

6. Agrees to provide available archived tumor tissue specimen. (Patients who do not have available archived tumor must agree to have core or excisional biopsy of a tumor lesion obtained up to 42 days prior to the first dose of study drug, if safely accessible. If archived tissue is not available and the tumor is not amenable to safe biopsy, subject is still eligible to participate.)

7. ECOG performance status of 0 or 1.

8. Adequate organ function defined as:

   • Absolute neutrophil count (ANC) ≥ 1,500 /mcL
   • Platelets ≥ 100,000 /mcL
   • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
   • Serum creatinine OR calculated creatinine clearance (CrCL) per institutional standard (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
   • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
   • Albumin ≥ 2.5 mg/dL

9. Negative serum pregnancy test within ≤ 7 days prior to the first dose of study drug, for women of childbearing potential only.

10. Female subjects agree to use two birth control methods, be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug.

11. Male subjects agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug.

Exclusion Criteria:

1. Tumor mitotic rate >20/10 hpf and/or Ki67 index >20% (if available).
2. 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 study drug.
3. 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 study drug.
4. Known history of active TB (Bacillus Tuberculosis).
5. Hypersensitivity to pembrolizumab or lanreotide or any of their excipients.
6. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
7. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
8. Prior major surgery within 2 weeks prior to the first dose of study drug or who has not recovered adequately from the toxicity and/or complications from the intervention.
9. 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.
10. 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 the first dose of study drug. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
11. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
12. Known history of, or any evidence of active, non-infectious pneumonitis.
13. Active infection requiring systemic therapy.
14. 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 physician.
15. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. 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 study drug.
17. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
18. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
20. Live vaccine within 30 days of planned start of study drug regimen. 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.
21. History of intolerance to somatostatin analogues.

Up to 25 months for adverse events; up to 59 months for all-cause mortality