Inclusion criteria
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 up.
3. Age ≥ 18 years at time of study entry. 4. ECOG performance status 0-1. 5. 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.
6. Target Lesions may be located in a previously irradiated field if there is documented
(radiographic) disease progression in that site.
7. 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 treatment has been completed at least 12 weeks before inclusion in
this study for group B and 2 weeks for group A. Moreover, there must be no
magnetic resonance imaging (MRI) evidence of progression 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. Patients
with stable/asymptomatic brain metastases that do not require local therapy with
irradiation (whole brain irradiation or stereotactic brain irradiation) can be
included. In ambiguous cases, consultation with the LKP or his/her delegate is
advised.
8. Patients who will receive study therapy after acceptable prior therapy as
specified below are eligible: i. Patients who will receive study therapy as
2nd-line or 3rd-line of treatment:
1. 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 of therapy.
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.
2. 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.
9. A formalin fixed, paraffin-embedded (FFPE) tumor tissue block (archival or
recent) or a minimum of 15 unstained slides of tumor sample (2-3 µm sections,
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 insufficient.
10. Prior therapies and surgeries are allowed if completed 2 weeks for minor
surgery (group A and B) or 12 weeks for any previous radiotherapy for group B,
respectively prior to start of treatment and patient recovered from toxic
effects. For group A, any prior radiotherapy not involving the lungs must be
completed 2 weeks prior to start of treatment. A prior radiotherapy involving the
lungs must be completed 12 weeks prior to start of treatment.
11. 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.
12. 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 x103/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 below):
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)
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)
13. 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.
14. Women of childbearing potential must have a negative serum pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of
nivolumab.
15. 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).
Exclusion criteria
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 irradiation (whole brain
irradiation or stereotactic brain irradiation). As stated in 3.2 point 7 b,
subjects with brain metastases are eligible if metastases have been treated and
treatment has been completed at least 12 weeks before inclusion in this study for
group B and 2 weeks for group A. Moreover, there must be no magnetic resonance
imaging (MRI) evidence of progression 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. Patients with
stable/asymptomatic brain metastases that do not require local therapy with
irradiation (whole brain irradiation or stereotactic brain irradiation) can be
included. In ambiguous cases, consultation with the LKP or his/her delegate is
advised.
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 interstitial lung disease.
6. Any previous 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
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 excipient.
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 treatment.
15. Any other serious or uncontrolled medical disorder, active infection, physical
examining, 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. History of solid organ or tissue transplantation including allogenic
hematopoietic stem cell transplantation.
17. Previous enrollment in the present study.
18. Involvement in the planning and/or conduct of the study (applies to both BMS
staff and/or staff of sponsor and study site)
19. Patient who might be dependent on the sponsor, site or the investigator.
20. Patient who has been incarcerated or involuntarily institutionalized by court
order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
