Avelumab and Stereotactic Ablative Radiotherapy in Non-responding and Progressing NSCLC Patients

Lung cancer is the leading cause of cancer deaths worldwide. More than half of lung cancer
patients present with metastatic disease at diagnosis, with a median survival of only 10-12
months. In recent years the development of more efficacious therapies for metastatic
non-small cell lung cancer (NSCLC) based upon an improved understanding of the underlying
tumor biology has resulted in an improvement in median overall survival by several months.
However, survival remains poor for most patients and there remains an urgent unmet need for
novel treatment strategies to improve survival for these patients.

Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody. In phase I studies, avelumab
was well-tolerated at a dose of 10 mg/kg IV Q2 weeks with the most frequently observed
treatment related adverse events including fatigue, infusion-related reactions, nausea,
chills, diarrhea, and pyrexia. However, many patients will not respond to checkpoint
inhibition, and developing strategies to further improve the efficacy and extend the benefit
of these treatments to non-responding and progressing patients is an area of substantial
need. Among NSCLC patients, approximately 80% of patients will not respond to a checkpoint
inhibitor as monotherapy.

Combinatorial strategies may increase response rates. Radiotherapy is an intriguing partner
therapy, with preclinical and clinical studies confirming the immunomodulatory effects of
radiotherapy. There is particularly interest in the use of radiotherapy in patients who have
failed a checkpoint inhibitor as monotherapy as this approach will isolate the effects of
radiation in enhancing response rates.

Stereotactic ablative radiotherapy (SAR) (also known as stereotactic body radiotherapy or
SBRT) has emerged as a potentially curative treatment option for patients with early stage,
medically inoperable non-small cell lung cancer and as a safe and effective local treatment
for metastatic lesions.

The investigators hypothesize that local radiotherapy can augment the systemic effects of
avelumab in NSCLC patients previously refractory to a checkpoint inhibitor previously used as
standard-of-care treatment. This proposal seeks to gain insight into the clinical and
biological efficacy of this combination.

Inclusion Criteria:

1. Signed informed consent.

2. Ability to comply with the protocol.

3. Adults >18 years of age with histologically proven stage IV non-small cell lung
cancer.

4. At least two sites of measurable disease as defined by RECIST 1.1; one of which must
be amenable to treatment with SAR and accessible for a mandatory pre-treatment biopsy
and a post- treatment biopsy at physician discretion. If a pulmonary nodule is being
considered for SAR it must range in size from 1-5 cm.

5. Have provided written consent for protocol directed biopsies.

6. Patients with treated supratentorial metastases are allowed if stable, the patient is
off steroids or on a stable or decreasing dose of ≤10 mg daily prednisone (or
equivalent) and no evidence of intracranial hemorrhage.

7. Archival tumor sample available. A minimum of 10 unstained slides. No fine needle
aspiration (FNAs) allowed or tumor tissue from bone.

8. ECOG performance status score of 0 or 1 (Appendix 1).

9. Life expectancy ≥ 3 months.

10. Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 14 days of the first study treatment:

1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and
hemoglobin ≥ 9 g/dL (may have been transfused)

2. Liver function tests meeting the following criteria: total bilirubin level ≤ 1.5
× the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST
and ALT levels ≤ 5 × ULN (for subjects with documented metastatic disease to the
liver).

3. INR and aPTT <1.5 × ULN (for patients on anticoagulation they must be receiving a
stable dose for at least 1 week prior to randomization)

4. Creatinine clearance >30 mL/min by Cockcroft-Gault formula (or local
institutional standard method).

11. No history of severe hypersensitivity reactions to other mAbs.

12. No other active malignancy.

13. No active autoimmune disease or a history of known or suspected autoimmune disease
except as detailed in the exclusion criteria below.

14. No chemotherapy or radiotherapy within the past 28 days.

15. Any number of prior treatments is allowed. Must have failed at least one treatment
regimen for metastatic disease and must have failed platinum-based chemotherapy
(including as treatment for localized disease) or be deemed ineligible for
platinum-based therapy by the treating medical oncologist.

16. Most recent prior regimen was a PD-1 inhibitor (nivolumab or pembrolizumab) with
progression. Last dose must have been delivered within 90 days of enrollment.

17. Highly effective contraception for both male and female subjects if the risk of
conception exists. (Note: The effects of the trial drug on the developing human fetus
are unknown; thus, women of childbearing potential and men able to father a child must
agree to use 2 highly effective contraception, defined as methods with a failure rate
of less than 1% per year. Highly effective contraception is required at least 28 days
prior, throughout and for at least 60 days after avelumab treatment.

18. Negative serum pregnancy test at screening for women of childbearing potential.

Exclusion Criteria:

1. Patients whose tumors contain activating EGFR mutations or ALK rearrangement should be
excluded from this study, unless disease has progressed on all available, approved
therapies targeting the EGFR mutation or ALK rearrangement.

2. All subjects with brain metastases, except those meeting the following criteria:

1. Brain metastases that have been treated locally and are clinically stable for at
least 2 weeks prior to enrollment

2. No ongoing neurological symptoms that are related to the brain localization of
the disease (sequelae that are a consequence of the treatment of the brain
metastases are acceptable)

3. Subjects must be either off steroids or on a stable or decreasing dose of <10mg
daily prednisone (or equivalent)

3. Leptomeningeal disease.

4. Uncontrolled pleural or pericardial effusion or ascites that would require recurrent
drainage.

5. Uncontrolled tumor related pain.

6. Uncontrolled hypercalcemia.

7. Pregnant and lactating women.

8. Uncontrolled concomitant disease.

9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
Association Classification Class II), or serious cardiac arrhythmia requiring
medication

10. Significant acute or chronic infections including, among others:

1. Known history of testing positive test for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)

2. Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV
antibody tested positive)

11. Oral or IV antibiotics within 2 weeks prior to enrollment.

12. Active tuberculosis

13. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE
v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
features of partially controlled asthma).

14. Known hypersensitivity or allergy to any component of the avelumab formulation.

15. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent:

1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
not requiring immunosuppressive treatment are eligible

2. Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at
doses ≤ 10 mg or 10 mg equivalent prednisone per day

3. Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable

16. Patients with a prior allogeneic bone marrow transplantation or prior solid organ
transplantation.

17. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. A
history of radiation pneumonitis in the radiation field (fibrosis) is permitted.