Atezolizumab and Bevacizumab in Epidermal Growth Factor Receptor (EGFR) Mutant Non‐Small Cell Lung Cancer in Patients With Progressive Disease After Receiving Osimertinib

Inclusion Criteria:

1. Age ≥18 years

2. Histologic documentation of primary lung carcinoma, non‐squamous histology with EGFR exon deletion 19 or exon 21 L858R mutation

3. Stage IV disease according to the 8th Edition of the American Joint Committee on Cancer staging system

4. Disease progression on osimertinib

5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 (appendix 1)

6. Measureable disease as defined by RECIST 1.1 (appendix 2)

7. The following laboratory values obtained ≤ 30 days prior to starting study therapy

1. ANC ≥ 1, 500 / mm3

2. Platelet count, ≥ 100,000 / mm3

3. Hemoglobin ≥ 9.0 g / dL

4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

5. Serum Glutamic Oxaloacetic Transaminase (SGOT) (Aspartate Aminotransferase, AST) and Serum Glutamic Pyruvic Transaminase (SGPT) (Alanine Aminotransferase, ALT) ≤2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases.

6. Cockcroft‐Gault calculated creatinine clearance of ≥ 45 ml/min (appendix 3) or creatinine ≤1.5 x ULN

7. Urine protein/creatinine (UPC) ratio ≤1.

8. Negative pregnancy test done ≤7 days (or per institutional policy) prior to start of study therapy, for women of childbearing potential only. Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test of must have evidence of non‐child bearing potential by fulfilling one of the following criteria at screening:

1. Post‐menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments;

2. Women under 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 Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post‐menopausal range for the institution;

3. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

9. Male subjects should be willing to use barrier contraception.

10. Provide informed written consent

Exclusion Criteria:

1. Mixed, non‐small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component.

2. Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception

3. Other active malignancy ≤ 2 years prior to study cycle 1 day 1 of study therapy. EXCEPTIONS: Nonmelanotic skin cancer or carcinoma‐in‐situ of the cervix, or adequately treated stage I or II cancer. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (i.e. hormonal therapy) for their cancer.

4. History of myocardial infarction or other evidence of arterial thrombotic disease (angina), symptomatic congestive heart failure (New York Heart Association ≥ grade 2), unstable angina pectoris, or ventricular arrhythmia with ≤ 6 months

5. History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to study cycle 1 day 1 of study therapy.

6. History of bleeding diathesis or coagulopathy.

7. Inadequately controlled hypertension (systolic blood pressure of >160 mmHg or diastolic pressure >100 mmHg on anti‐hypertensive medications). Note: History of hypertensive crisis or hypertensive encephalopathy not allowed.

8. Serious non‐healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days or core biopsy ≤ 7 days prior to starting therapy

9. History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess ≤6 months prior to study cycle 1 day 1 of study therapy.

10. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.

11. History of hemoptysis ≥ grade 2 (defined as bright red blood of at least 2.5 mL) ≤ 3 months prior to cycle 1 day 1 of study therapy.

12. Symptomatic untreated brain metastases which is defined as persistent neurological symptoms or requiring ongoing use of steroids. Asymptomatic untreated brain metastases are allowed if ≤ 1 cm

13. Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral arterial thrombosis) ≤6 months prior to starting study therapy

14. Radiotherapy to any site for any reason ≤ 14 days prior to study cycle 1 day 1 of study therapy.

15. Pre‐existing and clinically active interstitial lung disease

16. Autoimmune condition requiring ongoing or intermittent systemic treatment. Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study treatment initiation. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

17. Prior therapy with anti‐PD‐1 or anti‐PD‐L1 immunotherapy,

18. Prisoners, participants who are involuntarily incarcerated, or participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness