The goal of this clinical research study is to learn if local consolidation treatment (LCT--
surgery and/or radiation) plus immunotherapy (ipilimumab and nivolumab) is more effective
than ipilimumab and nivolumab alone in treating patients with metastatic (has spread)
non-small cell lung cancer (NSCLC) who have not previously received immunotherapy.
This is an investigational study. LCT is FDA approved and commercially available for the
treatment of NSCLC. Nivolumab and ipilimumab are FDA approved and commercially available for
treatment of many types of cancer. It is considered investigational to use nivolumab and
ipilimumab to treat metastatic NSCLC.
The study doctor can explain how the study drugs and LCT are designed to work.
Up to 270 participants will be enrolled in this study. All will take part at MD Anderson.
1. Age >/= 18
2. Histologically or cytologically confirmed non-small cell lung cancer. If a diagnostic
biopsy is available, a pre-treatment biopsy is not required. Patients with a suspected
lung cancer may be consented, but pathology must be confirmed prior to initiating
treatment on study. Neuroendocrine carcinomas (e.g. SCLC, carcinoid tumors) are not
eligible. Carcinomas with neuroendocrine differentiation are eligible.
3. Stage IV (according to AJCC 8th edition).
4. Signed and dated written informed consent prior to admission to the study in
accordance with ICH-GCP guidelines and to the local legislation.
5. For lung adenocarcinoma patients, patients must be wild-type for EGFR and ALK. For
patients with histologies other than adenocarcinoma, EGFR and ALK status is not
required. Adenocarcinoma patients may be consented prior to the EGFR and ALK status
being known, but EGFR and ALK status must be determined prior to initiating therapy.
EGFR and ALK status may be determined using either tumor- or plasma-based,
CLIA-certified assays. For patients with NSCLC, not otherwise specified (NOS),
EGFR/ALK testing is not required, as the frequency of alterations is exceedingly rare
in this histology. Also, note that patients with ROS1/RET alterations can be enrolled,
as TKIs/crizotinib aren't established as first line therapy for patients with these
6. One prior line of chemotherapy and/or targeted agents for metastatic disease are
permitted. This chemotherapy can include maintenance therapy, as long as it was given
in the front line setting. In addition, prior antiangiogenic therapy (e.g.
bevacizumab) is permitted if used as frontline treatment.
7. Patients must have organ and marrow function as defined below: a) Performance Status
of 0 or 1 if using ECOG/Zubrod. b) Screening laboratory values must meet the following
criteria and should be obtained within 14 days prior to randomization/registration i)
WBC >/= 2000/µL ii) Neutrophils >/= 1500/µL iii) Platelets >/= 100 x 10 ^3/µL iv)
Hemoglobin > 9.0 g/dL v) Serum creatinine </=1.5 x ULN or creatinine clearance (CrCl)
>/= 50 mL (if using the Cockcroft-Gault formula): Female CrCl = (140 - age in years) x
weight in kg x 0.85 ÷ 72 x serum creatinine in mg/dL; Male CrCl = (140 - age in years)
x weight in kg x 1.00 ÷ 72 x serum creatinine in mg/dL vi) AST/ALT </= 3 x ULN vii)
Total Bilirubin </= 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)
8. Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. Appropriate methods of contraception are as follows. Women will be
instructed to adhere to contraception for a period of 26 weeks after the last dose of
investigational product. Men receiving nivolumab and who are sexually active with
WOCBP will be instructed to adhere to contraception for a period of 35 weeks after the
last week of nivo/ipi. Note: WOCBP is defined as any female who has experienced
menarche and who has not yet undergone surgical sterilization (hysterectomy or
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically
as 12 months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 55 must have a documented
negative serum or urine test.
9. Women of childbearing potential must have a negative serum or urine pregnancy test
within 48 hours prior to the start of nivolumab.
10. Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 35
weeks after the last dose of investigational product Women who are not of childbearing
potential (ie, who are postmenopausal or surgically sterile) as well as azoospermic
men do not require contraception.
11. Subjects with brain metastases are eligible if metastases have been treated and there
is no MRI evidence of disease progression for 4 weeks after treatment is complete and
within 28 days prior to the first dose of nivolumab. Subjects with asymptomatic brain
metastases are eligible, though if treated with radiation or surgery the above
criteria apply regarding a 28-day washout and MRI to assess for progression after 4
12. Subjects may receive radiotherapy for symptomatic metastases prior to enrollment
provided that there is at least one other non-irradiated lesion amenable to LCT at the
time of enrollment. When feasible, stereotactic body radiation therapy (SBRT) or other
hypofractionated techniques are strongly encouraged.
1. Systemic immunotherapy for metastatic NSCLC. Immunotherapy agents include, but are not
limited to, agents targeting the PD1/PD-L1 axis (e.g. nivolumab, pembrolizumab,
atezolizumab, durvalumab) or CTLA-4 (ipilimumab, tremelimumab) pathways.
2. Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3
weeks prior to the initiation of study treatment; the following exceptions are
allowed: Hormone-replacement therapy or oral contraceptives
3. Women must not be breastfeeding.
4. Patients excluded with any prior treatment of pneumonitis requiring corticosteroids.
5. Unwillingness or inability to follow the procedures required in the protocol.
6. Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results.
7. Prior malignancy active within the previous 2 years. Patients with locally curable
cancers that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
with local control measures (surgery, radiation) are eligible.
8. Patients should be excluded if they have an active, known or suspected autoimmune
disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger.
9. Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration (i.e.
disease-modifying antirheumatic drugs). Inhaled or topical steroids and adrenal
replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of
active autoimmune disease. Note that subjects are permitted to use topical, ocular,
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
absorption). Physiologic replacement doses of systemic corticosteroids are permitted,
even if >10 mg/day prednisone equivalents. A brief course of corticosteroids for
prophylaxis (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions
(e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
10. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution.
11. Patients should be excluded if they are known to be positive for hepatitis B virus
surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody)
indicating acute or chronic infection.
12. Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
13. History of allergy to study drug components.
14. History of severe hypersensitivity reaction to any monoclonal antibody.
15. Prisoners or subjects who are involuntarily incarcerated.
16. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (infection disease) illness.
17. Psychological, familial, sociological or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule.
18. Any condition that, in the opinion of the investigator, would interfere with the study
treatment or interpretation of the study results.