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Ipilimumab and Nivolumab as First-Line Therapy in Treating Patients with Stage IV Non-small Cell Lung Cancer

Trial Status: Temporarily Closed to Accrual

This phase II trial studies how well ipilimumab and nivolumab work as first-line therapy in treating patients with stage IV non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

  • Histologically confirmed stage IV NSCLC, with no prior systemic anti-cancer therapy of any kind (including EGFR and ALK inhibitors), prior definitive chemoradiation for locally advanced disease is permitted as long as the last administration of chemotherapy or radiation (whichever was given last) occurred at least 6 months prior to enrollment; prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months prior to initiating study treatment
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam * Note: presence of measurable disease must be in at least one lesions that has not been previously irradiated
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN, OR AST(SGOT)/ALT(SGPT) =< 5 x institutional ULN if liver metastases are present
  • Serum creatinine =< 1.5 x institutional ULN, OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with serum creatinine levels above 1.5 x institutional ULN
  • Ability to understand and the willingness to sign a written informed consent document
  • Participants must be able and willing to undergo a pre-treatment tumor tissue biopsy; participants must also be willing to undergo an on-treatment tumor tissue biopsy if clinically feasible
  • Participants must have a tumor tissue sample available (formalin-fixed paraffin embedded [FFPE] tissue block or unstained slides); may be newly obtained or obtained within 6 months prior to enrollment (without systemic therapy given after the sample was obtained); participants without sufficient archival tissue may be enrolled following successful completion of the pre-treatment tumor tissue biopsy; tissue must be a core needle biopsy, excisional, or incisional biopsy; fine needle aspirates (FNA) or malignant effusions are not adequate; bone biopsies without a soft tissue component are not adequate
  • The effects of nivolumab and ipilimumab on the developing human fetus are unknown; for this reason, women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception from the time of signing consent, and for 23 weeks after their last dose of protocol-indicated treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol who are not azoospermic who are sexually active with WOCBP must agree to follow instructions for acceptable contraception from the time of signing consent, and for 31 weeks after their last dose of protocol-indicated treatment

Exclusion Criteria

  • Participants with known EGFR mutations or ALK rearrangements; all subjects must have been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they are known to have a KRAS mutation * Note: molecular testing is not required for squamous NSCLC
  • Participants who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways
  • Participants who received prior non-central nervous system (CNS) directed palliative radiation therapy within 7 days of the date of study entry
  • Participants who are receiving any other investigational agents
  • Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to study entry. Subjects must be either off corticosteroids, or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first study treatment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or nivolumab
  • Participants with previous malignancies are excluded unless a complete remission was achieved at least 2 years prior to first treatment and no additional therapy is required or anticipated to be required during the study period as judged by the treating investigator; exceptions include non-melanoma skin cancers, and in situ cancers of any type (e.g. bladder, gastric, colon, cervical/dysplasia, melanoma, or breast carcinoma in situ)
  • Participants with any other active malignancy requiring concurrent intervention
  • Participants with an active, known, or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
  • Participants with a condition requiring systemic treatment with corticosteroids of > 10 mg daily prednisone (or equivalent), or subjects requiring other immunosuppressive medications within 14 days of first treatment. Inhaled, topical, ophthalmologic, local steroid injections, and adrenal replacement steroid > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease
  • Participants with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity in the opinion of the treating investigator
  • Participants with a known history of testing positive for human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)
  • Participants with known positive test for hepatitis B or C indicating acute or chronic infection
  • Participants with >= grade 2 peripheral neuropathy
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because ipilimumab and nivolumab are both agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ipilimumab or nivolumab, breastfeeding should be discontinued if the mother is treated with ipilimumab or nivolumab. A negative serum pregnancy test is required prior to study entry


Beth Israel Deaconess Medical Center
Contact: Deepa Rangachari
Phone: 617-667-1580
Brigham and Women's Hospital
Contact: Mark Awad
Phone: 617-632-3468
Dana-Farber Cancer Institute
Contact: Mark Awad
Phone: 617-632-3468
Massachusetts General Hospital Cancer Center
Contact: Justin F. Gainor
Phone: 617-724-4000
Steward Saint Elizabeth's Medical Center
Contact: Christopher Scott Lathan
Dana-Farber / Brigham and Women's Cancer Center at Milford Regional
Contact: Michael Constantine
South Weymouth
Dana-Farber / Brigham and Women's Cancer Center at South Shore
Contact: Rajitha Sunkara


I. Assess the overall response rate (ORR) of ipilimumab and nivolumab in non-small cell lung cancer (NSCLC) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.


I. Evaluate immunologic correlates of response and primary resistance to ipilimumab and nivolumab therapy in NSCLC.

II. Evaluate immunologic correlates of acquired resistance to ipilimumab and nivolumab in NSCLC, with acquired resistance defined as participants who experience an objective radiologic response or stable disease per RECIST 1.1 criteria followed by disease progression.

III. Assess the progression-free survival (PFS) rate, duration of response (DoR), and overall survival (OS) of the combination utilizing RECIST 1.1 criteria.


Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days and then every 3 months for up to 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Mark Awad

  • Primary ID 17-566
  • Secondary IDs NCI-2018-00433
  • ID NCT03425331