Phase Ib Study of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Non-small Lung Cancer (NSCLC) With Dual Immune Checkpoint Inhibition

Inclusion Criteria:

- 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 with 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 must be off corticosteroids for 14
days prior to start of SBRT.

- 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 <1.5 x upper limit of normal (ULN) OR creatinine clearance
(CrCl) ≥30 mL/min for subjects with creatinine levels >1.5 × institutional ULN

- 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 required

- 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 trial.

Exclusion Criteria:

- 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 SBRT.

- 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 SBRT.

- 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
bladder cancer

- 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
of disease

- 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,
intra-articular injection).

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
its equivalent

- Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)

- Active or known autoimmune disease that has required immunosuppressive systemic
treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids,
or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)
is not considered a form of systemic treatment and is allowed. The following are
exceptions to this criterion:

- Patients with vitiligo or alopecia,

- Grave's disease,

- Hypothyroidism (eg, following Hashimoto syndrome),

- Psoriasis not requiring systemic treatment (within the past 2 years)

- 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