PRIMARY OBJECTIVES:
I. To determine whether local consolidative therapy (LCT; radiotherapy +/- surgical
resection, radiofrequency ablation, or cryoablation for up to 3 lesions) followed by up to 2
years of treatment with ipilimumab (1mg/Kg every 6 weeks) and nivolumab (3 mg/Kg, every 2
weeks) prolongs overall survival (OS) compared with up to 2 years treatment with ipilimumab
(1mg/Kg every 6 weeks) and nivolumab (3 mg/Kg, every 2 weeks) alone in metastatic or
recurrent non-small cell lung cancer (NSCLC) patients with non-progressive disease after 12
weeks of treatment with ipilimumab (1mg/Kg every 6 weeks) and nivolumab (3 mg/Kg, every 2
weeks).
II. Determine whether LCT followed by up to 2 years of treatment with ipilimumab (1mg/Kg
every 6 weeks) and nivolumab (3 mg/Kg, every 2 weeks) prolongs overall survival compared with
up to 2 years of treatment with ipilimumab (1mg/Kg every 6 weeks) and nivolumab (3 mg/Kg,
every 2 weeks) alone in the subgroup of patients with oligometastatic NSCLC (up to 3
metastases) with non-progressive disease after 12 weeks of treatment with ipilimumab (1mg/Kg
every 6 weeks) and nivolumab (3 mg/Kg, every 2 weeks).
SECONDARY OBJECTIVES:
I. To determine if there is a progression free survival (PFS) difference in the overall group
and the oligometastatic group in patients that receive LCT + ipilimumab/nivolumab vs.
ipilimumab/nivolumab alone.
II. To determine whether there is a PFS and (overall survival) OS difference in patients that
undergo complete vs. non-complete LCT after 12 weeks of induction treatment with ipilimumab
(1mg/Kg every 6 weeks) and nivolumab (3 mg/Kg, every 2 weeks).
III. To determine whether LCT improves time to progression of non-irradiated lesions
(TTP-NIL) and time to appearance of new metastases (TANM) in the overall study population and
the oligometastatic subgroup.
IV. To determine whether LCT improves the time to progression of target vs. non-target
lesions in the overall study population and the oligometastatic subgroup.
V. To assess whether LCT prolongs PFS and OS in squamous histology and non-squamous
histologies.
VI. To assess the safety and tolerability of nivolumab and ipilimumab with or without LCT.
VII. To assess quality of life patient reported outcomes in patients treated with nivolumab
and ipilimumab with or without LCT.
VIII To explore the association of baseline genomic and gene expression profiles (from tumor,
germline deoxyribonucleic acid [DNA], and cell free [cf] DNA) with clinical benefit and
toxicities in patients treated with nivolumab and ipilimumab with or without LCT.
IX. To explore the association of baseline immune profiles (from tumor and blood) with
clinical benefit and toxicities in patients treated with nivolumab and ipilimumab with or
without LCT.
EXPLORATORY OBJECTIVE:
I. To identify novel prognostic and predictive markers present at diagnosis, and to determine
modulation of markers by induction immunotherapy in order to inform future translational
studies.
OUTLINE:
INDUCTION PHASE: Patients receive nivolumab intravenously (IV) over 90 minutes on days 1, 15,
and 29, and ipilimumab IV over 60 minutes on day 1. Treatment repeats every 6 weeks for up to
2 courses in the absence of disease progression or unacceptable toxicity.
Patients with non-progressive disease after completion of Induction Phase are randomized to 1
of 2 arms.
ARM A: Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29 and ipilimumab IV
over 90 minutes on day 1. Courses repeat every 6 weeks for 2 years in the absence of disease
progression or unacceptable toxicity.
ARM B: Patients receive LCT consisting of surgery and/or radiation 14 days after completion
of Induction Phase. Patients then receive nivolumab and ipilimumab as in arm A beginning
within 4 weeks after LCT. Courses repeat every 6 weeks for 2 years in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 8 weeks and then every 3
months for up to 1 year.
Inclusion Criteria:
- 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. small cell lung cancer [SCLC],
carcinoid tumors) are not eligible. Carcinomas with neuroendocrine differentiation are
eligible.
- Stage IV (according to the American Joint Committee on Cancer [AJCC] 8th edition)
measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- Signed and dated written informed consent prior to admission to the study in
accordance with International Conference on Harmonization-Good Clinical Practice
(ICH-GCP) guidelines and to the local legislation.
- For lung adenocarcinoma patients, patients must not harbor any EGFR sensitizing or ALK
fusion where there are standard care therapy options available. 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, Clinical Laboratory
Improvement Amendments (CLIA)-certified assays. For patients with non-small cell lung
cancer (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 tyrosine kinase inhibitor such
as crizotinib aren't established as first line therapy for patients with these
alterations.
- 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.
- Performance status of 0 or 1 if using Eastern Cooperative Oncology Group
(ECOG)/Zubrod.
- White blood cell (WBC ) >= 2000/uL (obtained within 14 days prior to
randomization/registration)
- Neutrophils >= 1500/uL (obtained within 14 days prior to randomization/registration)
- Platelets >= 100 x 10^3/uL (obtained within 14 days prior to
randomization/registration)
- Hemoglobin > 9.0 g/dL (obtained within 14 days prior to randomization/registration)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl)
>= 50 mL (if using the Cockcroft-Gault formula) (obtained within 14 days prior to
randomization/registration)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (obtained
within 14 days prior to randomization/registration)
- Total Bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have
total bilirubin < 3.0 mg/dL) (obtained within 14 days prior to
randomization/registration)
- 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 nivolumab/ipilimumab (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.
- Women of childbearing potential must have a negative serum or urine pregnancy test
within 48 hours prior to the start of nivolumab.
- 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.
- Subjects with brain metastases are eligible if metastases are adequately treated and
subjects are neurologically stable (except for residual signs or symptoms related to
the central nervous system [CNS] treatment) for at least 2 weeks prior to the first
dose of nivolumab. In addition, 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 the first dose of nivolumab. Patients with asymptomatic, small (e.g. =<
1 cm) brain metastases are 1) eligible provided that the patient is off
corticosteroids, or on a stable or decreasing dose of =< 10 mg daily prednisone (or
equivalent) for at least 2 weeks prior to the first dose of nivolumab
- 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.
Exclusion Criteria:
- 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.
- 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
- Women must not be breastfeeding.
- Patients excluded with any prior treatment of pneumonitis requiring corticosteroids
within 60 days prior to the first dose of nivolumab
- Unwillingness or inability to follow the procedures required in the protocol.
- 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.
- 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.
- 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.
- 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.
- As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution.
- 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.
- Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- History of allergy to study drug components.
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Prisoners or subjects who are involuntarily incarcerated.
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (infection disease) illness.
- Psychological, familial, sociological or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule.
- Any condition that, in the opinion of the investigator, would interfere with the study
treatment or interpretation of the study results.
