The purpose of this study is to examine the combination of osimertinib and carotuximab to assess the safety and find the recommended dose for treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). Safety and tolerability will be measured by the number of dose-limiting toxicities, according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 5, to find the maximum tolerated dose. The secondary objectives include evaluating the rate of objective response rate, duration of response, progression-free survival, and disease control rate, along with assessing biomarkers through tumor tissue and circulating tumor DNA.

Inclusion Criteria:

• Stage IV or recurrent/metastatic non-squamous NSCLC that harbors an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q, etc). Local testing for EGFR mutations is acceptable provided it was performed in a CLIA certified lab.
• Part I: Progressive disease on at least one prior EGFR TKI
• Part II, Cohort 1: Progressive disease on osimertinib or other prior EGFR TKIs
• Part II, Cohort 2: Receiving osimertinib as front line treatment for less than 12 weeks. Persistent ctDNA with EGFR mutation between weeks 6-12 from the start of osimertinib treatment.
• Age at least 18
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
• Archival tissue from a biopsy performed after progression of disease on previous EGFR TKI or willing to consent for a fresh tumor biopsy.
• Measurable disease by RECIST 1.1.
• Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable.
• Patients must have completed prior chemotherapy ≥ 3 weeks or radiotherapy ≥ 2 weeks prior to receiving study drugs.
• If the subject's most recent line of therapy is treatment with osimertinib, then all adverse events must be resolved to Grade 2 or better
• If the subject's most recent line of therapy is any other treatment than osimertinib, then all Adverse Events must be resolved to grade 1 or better, with the exception of fatigue, alopecia and neuropathy (which must resolve to CTCAE grade 2).
• Adequate organ function
• Women of childbearing potential and men must agree to use adequate contraception while on study.
• Written informed consent obtained from subject and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease.
• Small cell lung cancer histology.
• Other prior malignancy that might interfere with study endpoints per opinion of the investigator.
• Prior exposure to carotuximab or any CD105 targeted antibody.
• Any major surgical procedure within 2 weeks of starting therapy.
• Patients must not have a history of uncontrolled or poorly-controlled hypertension defined as SBP > 150 mmHg or DBP > 90 mmHg within 28 days prior to enrollment.
• Active bleeding or pathologic conditions that carries a high bleeding risk (e.g. gastric ulcers).
• Use of thrombolytics within 10 days prior to the first day of carotuximab.
• Known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, or humanized antibodies.
• A known diagnosis of Osler-Weber-Rendu syndrome.
• Ascites or pericardial or pleural effusion requiring external drainage procedures.
• New evidence of leptomeningeal disease.
• Acute cardiovascular event within the past 6 months.
• Pregnancy or breastfeeding.