1. Written informed consent and any locally-required authorization (EU Data Privacy
Directive in the EU) obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations.
2. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
3. Age > 18 years at time of study entry.
4. ECOG performance status 0-1.
5. Expected life expectancy of ≥ 6 months.
6. Patients with measurable disease (at least one uni-dimensionally measurable target
lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors
(RECIST 1.1) are eligible. For patients in Group A, non-measurable and measurable
lesions may be chosen for irradiation. However, in order to allow for evaluation of
abscopal effects, patients in Group A must have at least one measurable lesion beside
the lesion planned to be irradiated. Lesions planned to be irradiated may not be
defined as a measurable target lesion. Radiographic tumor assessment must be performed
within 28 days before initiation of study treatment.
7. Target Lesions may be located in a previously irradiated field if there is documented
(radiographic) disease progression in that site.
8. Patients with metastatic non-squamous non-small cell lung cancer in 2nd-line and
3rd-line treatment and:
1. no necessity of radiotherapy or
2. the necessity of radiotherapy of a metastatic bone lesion or soft tissue lesion.
- Patients with intrathoracic metastases or intrathoracic progressive disease
will be included if radiotherapy of the lung parenchyma is NOT required
- Subjects with symptomatic brain metastases are eligible if metastases have
been treated and there is no magnetic resonance imaging (MRI) evidence of
progression for 12 weeks after treatment is complete and within 28 days
prior to the first dose of nivolumab administration. There must also be no
requirement for immunosuppressive doses of systemic corticosteroids (> 10
mg/day prednisone equivalents) for at least 2 weeks prior to study drug
administration. Moreover, patients with stable (asymptomatic) brain
metastases that do not require local therapy with WBI (whole brain
irradiation) can be included.
9. Patients who will receive study therapy after acceptable prior therapy as specified
below are eligible:
a) Patients who will receive study therapy as 2nd-line or 3rd-line of treatment:
• Patients must have experienced disease recurrence or progression during or after one
prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease.
First line therapy is defined as therapy used to treat advanced disease. Each
subsequent line of therapy is preceded by disease progression. A switch of an agent
within a regimen in order to manage toxicity does not define the start of a new line
of therapy. Subjects must have received at least 2 cycles of platinum doublet based
chemotherapy before discontinuation for toxicity.
Experimental therapies when given as separate regimen are considered as separate line
Maintenance therapy following platinum doublet-based chemotherapy is not considered as
a separate regimen of therapy and could comprise continuation of one or more of the
agents used in the first-line therapy regimen or switch to another non cross-resistant
agent. The initiation of maintenance therapy requires the lack of progressive disease
with front-line therapy.
Treatment given for locally advanced disease is not considered as a line of therapy
for advanced disease. Subjects with recurrent disease > 6 months after
platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given
for locally advanced disease, who also subsequently progressed during or after a
platinum doublet-based regimen given to treat the recurrence, are eligible.
• Patients who received platinum-containing adjuvant, neoadjuvant or definitive
chemoradiation therapy given for locally advanced disease, and developed recurrent
(local or metastatic) disease within 6 months of completing therapy are eligible.
Adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation
therapy) followed by recurrent or metastatic disease within 6 months of completing
therapy is considered as first line therapy for advanced disease.
10. A formalin fixed, paraffin-embedded (FFPE) tumor tissue block (archival or recent) or
a minimum of 15 unstained slides of tumor sample (slices must be recent and collected
on slides provided by the sponsor) must be available for biomarker (PD-L1) evaluation.
Biopsy should be excisional, incisional or core needle. Fine needle aspiration is
11. Prior therapies and surgeries are allowed if completed 2 weeks (for minor surgery) or
12 weeks (for palliative radiotherapy for bone pain), respectively prior to start of
treatment and patient recovered from toxic effects.
12. Subjects must have recovered from the effects of major surgery or significant
traumatic injury at least 14 days before the first dose of study treatment.
13. Adequate blood count, liver-enzymes, and renal function (obtained no later than 14
days prior to start of treatment):
- WBC ≥ 2000/μL
- Neutrophils ≥ 1500/μL
- Platelets ≥ 100 x10^3/μL
- Hemoglobin > 9.0 g/dL
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
the Cockcroft-Gault formula)
- AST/ALT ≤ 3 x ULN
- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)
14. Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of nivolumab.
15. Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of nivolumab or radiotherapy.
16. 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 31
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).
1. Previous malignancy (other than NSCLC), which either progresses or requires active
treatment. Subjects with previous malignancies (except non-melanoma skin cancers, and
the following in situ cancers: bladder, gastric, colon, cervical/dysplasia,
endometrial, melanoma, or breast) are excluded unless a complete remission was
achieved at least 2 years prior to study entry AND no additional therapy is required
or anticipated to be required during the study period.
2. Brain metastases mandating active treatment in terms of WBI (whole brain irradiation).
Subjects with brain metastases are eligible if metastases have been treated and there
is no magnetic resonance imaging (MRI) evidence of progression for 12 weeks after
treatment is complete and within 28 days prior to the first dose of nivolumab
administration. There must also be no requirement for immunosuppressive doses of
systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks
prior to study drug administration.
3. Known activating EGFR mutation or a known ALK translocation.
4. Prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.
5. Patients with symptomatic interstitial lung disease.
6. Any previous treatment with a an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T‑cell co-stimulation
or immune checkpoint pathways
7. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue
must have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration
of study drug.
8. Patients should be excluded if they have an active, known or suspected autoimmune
disease. NOTE: 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. NOTE:
Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone
equivalents are permitted in the absence of active autoimmune disease.
10. Patients should be excluded if they are positively tested for hepatitis B virus
surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody)
indicating acute or chronic infection
11. Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12. History of severe hypersensitivity reactions to other monoclonal antibodies or any
13. Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control
(failure rate of less than 1% per year)
14. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) ≤14 days prior to the first dose of study
15. Any other serious or uncontrolled medical disorder, active infection, physical exam
finding, laboratory finding, altered mental status, or psychiatric condition that, in
the opinion of the investigator, would limit a subject's ability to comply with the
study requirements, substantially increase risk to the subject, or impact the
interpretability of study results.
16. Previous enrollment in the present study.
17. Involvement in the planning and/or conduct of the study (applies to both BMS
[Bristol-Myers Squibb GmbH & Co. KGaA] staff and/or staff of sponsor and study site)
18. Patient who might be dependent on the sponsor, site or the investigator.
19. Patient who has been incarcerated or involuntarily institutionalized by court order or
by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.