This is a phase Ib study to evaluate safety and tolerability of dual checkpoint inhibition
(DCI) of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT in the treatment of
oligometastatic NSCLC. This study will examine the sequential delivery of SBRT to all disease
sites followed by combination of durvalumab and tremelimumab for patients for whom the goal
is ablating all known sites of disease. We anticipate that for many patients this will be the
first line-therapy. Patients who have received prior-platinum-based chemotherapy and/or any
line of prior chemotherapy are eligible. Prior immunotherapy treatment is not allowed.
- • Patients with histologically or cytologically confirmed stage IV NSCLC not amenable
to curative surgery or radiation
- Patients may have had prior chemotherapy or be chemotherapy naïve
- Patients must have tumors that lack sensitizing EGFR mutation (e.g. exon 19
deletion or exon 21 L858R) or ALK rearrangement. If a patient has squamous
histology, then EGFR and ALK testing is not required.
- No prior treatment with cancer immunotherapy including, but not limited to, other
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 anti-
(PD-L2) antibodies, excluding therapeutic anticancer vaccines.
- Patients will have 6 or less extracranial sites, which can safely receive SBRT
between 30 - 50 Gy in 5 fractions. A site may have multiple tumor lesions within
it as long as the gross tumor volume (GTV) of the site is 8 cm or less and can be
covered in an acceptable SBRT field determined by the PI. All gross disease must
be amenable to treatment with SBRT, as allowable per normal tissue constraints.
Patients will not have had any prior radiation therapy significantly overlapping
a tumor site to be treated.
- Patients must have evaluable disease, as defined by RECIST 1.1.
- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 at enrollment
- Life expectancy of > 12 weeks
- 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.
- Patients treated metastatic lesions to the brain may be enrolled after completing
stereotactic radiosurgery (may enroll 14 days after treatment) or whole brain
radiation (may enroll 14 days after treatment) and being weaned off
corticosteroids for 14 days prior to treatment.
- Adequate normal organ and marrow function as defined below:
- Hemoglobin ≥ 9.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
- Platelet count ≥ 100 x 109/L (>100,000 per mm3)
- Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not
apply for patients with confirmed Gilbert's syndrome, who will be allowed in
consultation with their physician.
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN unless liver metastases are present, in which
case ALT and AST must be ≤ 5x ULN
- Serum creatinine CL ≥ 50 mL/min
- Female subject of childbearing potential should have a negative urine or serum
pregnancy prior to receiving the first study treatment. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be
- Female subjects of childbearing potential should be willing to use 1 method of
highly effective birth control, 2 methods of effective birth control, be
surgically sterile, or abstain from heterosexual activity for the course of the
study through 180 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have
not been free from menses for > 1 year.
- Evidence of post-menopausal status or negative urinary or serum pregnancy test
for female pre-menopausal patients. Women will be considered post-menopausal if
they have been amenorrheic for 12 months without an alternative medical cause.
The following age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle- stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥ 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced oophorectomy with last menses >1 year ago, had
chemotherapy-induced menopause with > 1 year interval since last menses, or
underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
- Patient must be willing and able to provide written informed consent for the
- • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Previous enrolment in the present study
- Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(eg, hormone replacement therapy) is acceptable.
- Major surgical procedure (as defined by the Investigator) within 14 days prior to
the start of study treatment.
- Patients with untreated spinal cord compression. Patients with spinal cord
compression may be enrolled if stable after completing surgery (may enroll 14
days after surgery) or radiation (may enroll 14 days after radiation) and must be
off corticosteroids for at least 14 days prior to the start of study treatment.
- Patients with untreated brain metastasis. Patients with metastatic lesions to the
brain may be enrolled after completing stereotactic radiosurgery or whole brain
radiation (may enroll 14 days after radiation and must be off corticosteroids for
at least 14 days prior to the start of study treatment.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
anti-CTLA4 inhibitor including tremelimumab
- Patients with a known targetable EGFR mutation or ALK rearrangement
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease ≥2 years
- Non-metastatic prostate adenocarcinoma, or treated superficial non-invasive
- Adequately treated carcinoma in situ without evidence of disease (eg, cervical
cancer in situ)
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
- 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 of registration
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470
ms. Abnormality must be confirmed on 3 ECGs.
- Current or prior use of immunosuppressive medication within 14 days before the
first dose of durvalumab or tremelimumab
The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg,
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
- Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis with the
exception of diverticulosis, celiac disease or other serious gastrointestinal chronic
conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis
syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease,
rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the
start of treatment. The following are exceptions to this criterion:
- Patients with vitiligo or alopecia,
- Grave's disease,
- Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement,
- Psoriasis not requiring systemic treatment (within the past 2 years),
- 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 physician
- Patients with celiac disease controlled by diet alone
- History of active primary immunodeficiency
- History of allogeneic organ transplant
- Active infection, including tuberculosis (clinical evaluation), hepatitis B, hepatitis
C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies). Active
hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg)
result. Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is
negative for HCV ribonucleic acid (RNA).
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to the first dose of IP.
Note: Patients, if enrolled, should not receive live vaccine during the study and up
to 30 days after the last dose of IP.
- Any condition or uncontrolled intercurrent illness that, in the opinion of the
Investigator, would interfere with the evaluation of IP or interpretation of patient
safety or study results, including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirement, substantially increase risk of incurring AEs
from durvalumab or tremelimumab, or compromise the ability of the patient to give
written informed consent
- Subjects with uncontrolled seizures.
- Female patients who are pregnant or breast-feeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 180 days after the last dose of durvalumab and tremelimumab combination
therapy or 90 days after the last dose of durvalumab monotherapy.
- History of hypersensitivity to IP or comparator agents
- History of medically diagnosed pneumonitis or interstitial lung disease