A Phase 2, Multicenter Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases

• History of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation or an EGFR activating mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled

• Occurrence or progression of BM while receiving first-line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If BM progression occurs after osimertinib, patient will be eligible.

• At least one measurable BM by RECIST 1.1 criteria (≥ 10 mm in longest diameter). Target lesions must not have received stereotactic radiotherapy (SRS). If a subject had prior whole brain radiotherapy (WBRT), progression in any measurable BM lesion must have occurred at least 3 months after the end of WBRT. Subjects with asymptomatic brain metastases may have been enrolled without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases may have been enrolled without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant

• Subjects in Cohort A may have had asymptomatic LM detected by MRI. (Subjects with symptoms or signs attributed to LM were enrolled in Cohort B whether or not they have brain metastases)

• No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy

• ECOG Score ≤ 2

• No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred

• Adequate organ and bone marrow functions

• Serum potassium and magnesium levels above the lower limit of normal

• No coexisting medical problems of sufficient severity to limit compliance with the study

• Willing and able to sign written informed consent and able to comply with the study protocol for the duration of the study

• Women of childbearing potential (i.e., menstruating women) must have had a negative urine pregnancy test (positive urine tests confirmed by serum test)

• History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation) or, if previously treated, history of an activating EGFR mutation that had a clinical response to erlotinib, afatinib, or gefitinib in the subject being enrolled).

• Presentation with LM at initial presentation with no prior systemic treatment, or occurrence or progression of LM while receiving first-line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If LM progression occurred after osimertinib, subjects were eligible.

• Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed by the investigator to LM

• Diagnosis of LM by:

‣ Cytological evidence in cerebrospinal fluid (CSF) sample of LM due to NSCLC, and/or

⁃ Findings on gadolinium-enhanced MRI

• No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy

• Concomitant brain metastases and brain metastases previously treated with radiation therapy were allowed. (Subjects with symptoms or signs attributed to LM will be enrolled in Cohort B whether or not they have brain metastases)

• ECOG Score ≤ 2

• No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and had not recurred

• Adequate organ and bone marrow functions

• Serum potassium and magnesium levels above the lower limit of normal (LLN)

• No coexisting medical problems of sufficient severity to limit compliance with the study

• Willing and able to sign written informed consent and able to comply with the study protocol for the duration of the study

• Women of childbearing potential (i.e., menstruating women) must have had a negative urine pregnancy test (positive urine tests confirmed by serum test)

• NSCLC with EGFR activating mutation

• No prior systemic treatment for NSCLC. Treatment with systemic steroids was not considered systemic treatment for NSCLC

• No prior radiation therapy to the CNS (brain or spinal cord)

• At least one measurable BM by RECIST 1.1 criteria (≥ 10 mm in longest diameter) in a subject with asymptomatic or minimally symptomatic brain metastases who did not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.

• Subjects in Cohort C may have had asymptomatic LM detected by MRI

• ECOG Score ≤ 2

• No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred

• Adequate organ and bone marrow functions

• Serum potassium and magnesium levels above the LLN

• No coexisting medical problems of sufficient severity to limit compliance with the study.

• Willing and able to sign written informed consent and able to comply with the study protocol for the duration of the study

• Women of childbearing potential (i.e., menstruating women) must have had a negative urine pregnancy test (positive urine tests are to be confirmed by serum test)