| Eligibility |
Inclusion Criteria:
1. Signed Informed Consent Form
2. Age >18 years at time of study entry
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Histologically or cytologically confirmed, stage IV NSCLC (per the Union
Internationale contre le Cancer/American Joint Committee on Cancer staging system).
5. Indication for standard-of-care second line platinum-based chemotherapy, using
cisplatin or carboplatin in combination with pemetrexed, paclitaxel, nab-paclitaxel,
vinorelbine or gemcitabine
6. Life expectancy of > 12 weeks
7. Body weight > 30 kg
8. First-line mono-immunotherapy with checkpoint inhibitors (anti-PD1/PD-L1) with a best
response of stable disease (SD) or better
9. Documented tumor PD-L1 expression status of =50%. Any existing data can be used.
10. First-line progression-free survival of at least 12 weeks after at least two
re-assessments after initiation of first-line treatment.
11. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, or
chemoradiotherapy with curative intent for non-metastatic disease must have
experienced a treatment-free interval of at least 6 months from initiation of
first-line immunotherapy since the last adjuvant chemotherapy or chemoradiotherapy
cycle.
12. Patients with a history of treated asymptomatic CNS metastases are eligible, provided
they meet all of the following criteria:
- No ongoing requirement for corticosteroids as therapy for CNS disease
- No stereotactic radiation within 7 days or whole-brain radiation within 14 days
prior to enrolment
- No evidence of interim progression between the completion of CNS-directed therapy
and the screening
- Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
midbrain, pons, medulla or spinal cord)
13. No known sensitizing mutation in the EGFR gene or evidence of an ALK fusion oncogene.
14. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can only
be considered as measurable disease if disease progression has been unequivocally
documented at that site since radiation.
15. Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 3 days prior to enrolment:
1. ANC 1500 cells/µL without granulocyte colony-stimulating factor support
2. Lymphocyte count = 500/µL
3. Platelet count = 100,000/µL without transfusion
4. Hemoglobin = 9.0 g/dL. Patients may be transfused to meet this criterion.
Transfusions are allowed throughout the study.
5. Serum bilirubin = 1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.
6. AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be =5x ULN
7. Measured creatinine clearance (CL) >60 mL/min or calculated creatinine clearance
CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-
hour urine collection for determination of creatinine clearance
Exclusion Criteria:
1. Use of immunosuppressive medication (including but not limited to prednisone,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor
[anti-TNF] agents) within 14 days prior to randomization. The following are exceptions to
this criterion:
- Patients who have received acute, low-dose, systemic immunosuppressant medications
(e.g., a one-time dose of dexamethasone for nausea) may be eligible after discussion
with the study chair.
- The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension,
and low-dose supplemental corticosteroids for adrenocortical insufficiency are
allowed.
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or
its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
Prior treatment with other immune-modulating agents (other than anti-PD-1/PD-L1) 3.
Treatment with systemic immunostimulatory agents (including but not limited to IFNs, IL-2)
within 4 weeks or five half-lives of the drug, whichever is longer, prior to randomization.
Prior treatment with cancer vaccines is allowed.
4. Involvement in the planning and/or conduct of the study (applies to both sponsor staff
and/or staff at the study site) 5. Concurrent enrolment in another clinical study, unless
it is an observational (non-interventional) clinical study or during the follow-up period
of an interventional study 6. Treatment with any other investigational agent or
participation in another clinical study with therapeutic intent within 28 days prior to
randomization 7. Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer
therapy (including second line platinum-based chemotherapy) with the exception of alopecia,
vitiligo, and the laboratory values defined in the inclusion criteria
• Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Chair.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation with
the Study Chair.
8. Any toxicity that led to permanent discontinuation of prior immunotherapy. 9. A =
grade 4 immune related AE or an immune related neurologic or ocular AE of any grade
while receiving prior immunotherapy.
10. Any concurrent chemotherapy, investigational product, biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
11. History of allogenic organ transplantation. 12. Major surgical procedure (as
defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local
surgery of isolated lesions for palliative intent is acceptable.
13. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after
consultation with the Study Chair
- Patients with celiac disease controlled by diet alone 14. Uncontrolled intercurrent
illness, including but not limited to, ongoing or active infection, symptomatic
congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac
arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions
associated with diarrhea, or psychiatric illness/social situations that would limit
compliance with study requirement, substantially increase risk of incurring AEs or
compromise the ability of the patient to give written informed consent 15. History of
another primary malignancy except
- Malignancy treated with curative intent and with no known active disease =3 years
prior to study enrolment and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease
- Adequately treated carcinoma in situ without evidence of disease 16. History of
leptomeningeal carcinomatosis 17. History of active primary immunodeficiency 18.
Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA. 19. Receipt of live or live attenuated vaccine within 30 days prior to
the first dose of IP. Note: Patients should also not receive live or live attenuated
vaccine for the pertinent time frames during and after treatment defined in the
respective study drug's SmPC or IB.
20. Known allergy or hypersensitivity to any of the study drugs or any of the study
drug excipients.
21. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to a defined timepoint after last dose of treatment (see Section 7.1 for
details) 22. A marked baseline prolongation of QT/QTc interval (e.g., repeated
demonstration of a QTc interval >450 ms); A history of additional risk factors for TdP
(e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
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