Phase I Study of Repotrectinib and Osimertinib in NSCLC Patients

Inclusion Criteria: 1. Patients of age ≥18. 2. Histological or cytological confirmation of locally advanced or metastatic, non-squamous cell lung carcinoma (NSCLC) in patients who are not candidates for local curative treatment through radical surgery and/or radiotherapy. 3. Stage IV, according to Tumor-nodes-metastasis (TNM) Version 8, including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease for which there is no curative treatment (including patients who progress after chemoradiotherapy in Stage III disease). 4. Patients must have been locally diagnosed with EGFR activating mutation (including exon 18, exon 19, exon 21 and mutation T790M) based on FDA approved test (or a local equivalent laboratory developed) test (LDT)). Confirmatory central review will be performed for all patients, in case of discrepancy on EGFR status, central review will prevail. 5. Eastern cooperative oncology group (ECOG) performance status 0-1. 6. Existence of measurable or evaluable disease (according to RECIST 1.1 criteria). 7. Patients with asymptomatic central nervous system (CNS) metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the following criteria: * Patients requiring steroids at a stable or decreasing dose (≤ 12 mg/day dexamethasone or equivalent) for at least 14 days are eligible. Patients on stable doses of levetiracetam (same dose for 14 days) are eligible to be enrolled. * A minimum of 14 days must have elapsed from the completion of whole brain radiation treatment (WBRT) before the start of treatment with repotrectinib, and all side effects (with the exception of alopecia) from WBRT are resolved to CTCAE grade ≤ 1. 8. Having available tumor tissue samples, via a biopsy or surgical resection of the primary tumor or metastatic tumor tissue, within 60 days prior to the start of treatment. 9. Life expectancy ≥12 weeks, as determined by a physician. 10. Adequate hematological function, defined as: absolute neutrophil count (ANC) \>1.5 x 109/L, platelet count \>100.0 x 109/L, and hemoglobin \>9.0 g/dL (transfusion allowed at baseline). 11. Adequate liver function, defined as: total bilirubin \<1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \<2.5 x ULN. 12. Adequate renal function, defined as: calculated (Cockcroft-Gault formula) or measured creatinine clearance \>50 mL/min and proteinuria \<2+ (dipstick). 13. Ability to take part in all study procedures, per investigators. 14. Prior cytotoxic chemotherapy and prior immunotherapy (e.g., anti-PD-1, anti-programmed death ligand 1 (PDL1), anti-T cell immunoglobulin and mucin domain- containing protein 3 (TIM3), anti-OX40) for advanced or metastatic disease is allowed if: * At the time of starting treatment with repotrectinib, at least 14 days or 5 half-lives (whichever is shorter) must have elapsed after discontinuation of prior therapy (or at least 42 days for prior nitrosoureas, mitomycin C, and liposomal doxorubicin). * All side effects from prior treatments must have resolved to grade ≤ 1 (NCI CTCAE Version 5.0) with the exception of alopecia or other side effects that the investigator does not consider to be a risk to patient safety. * Patients with advanced solid tumors harboring ALK, ROS1, neurotrophic tyrosine kinase (NTRK) 1, 2, or 3 rearrangements are eligible if at the time of starting treatment at least 14 days or 5 half-lives (whichever is shorter) have elapsed after discontinuation of prior therapy. * There is no limit to the number of prior chemotherapies, immunotherapy, or TKI regimens. 15. All women of childbearing potential (WOCBP), must agree to use highly effective contraception methods during the study treatment period and for at least 2 months after the last dose of EGFR TKI. Male partners of female (WOCBP) patients agree to use condoms during the study and for 2 months after the last dose. Male patients with female partners of WOCBP should use condom protection for 6 months in addition to their female partner (WOCBP) using highly effective contraceptive methods for 4 months after the last dose. Sexually active men, and women of childbearing potential, who are unwilling to use a contraception method are not eligible for the study. 16. Provision of written informed consent, signed and dated by the patient and the investigator, before any study interventions are performed. 17. Part B expansion cohorts only (after the RP2D has been identified): * Disease progression following osimertinib with no evidence of tertiary EGFR mutation (i.e., C797S) or MET amplification. * Disease progression following first or second generation EGFR TKI (for example, erlotinib,gefitinib, afatinib, dacomitinib) regardless of T790M status. Exclusion Criteria: 1. Prior exposure to repotrectinib. 2. Diagnosis with any other lung cancer subtype apart from adenocarcinoma including patients with mixed NSCLC with predominantly squamous cell cancer, or with any small-cell lung cancer component, or a tertiary mutation. 3. Presence or history of any other primary malignancy other than NSCLC within 5 years prior to enrollment into the study. 4. Patients with a history of adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma may be included in the study. 5. Presence of only one measurable or evaluable tumor lesion that has already been resected or irradiated prior to enrollment in the study. 6. Known presence of EGFR exon 20 insertion mutation based on most recent applicable molecular testing. 7. Clinically significant cardiovascular disease (either active or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2. 8. Any of the following cardiac criteria: * Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) \> 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec) * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval 9. Known active infections requiring ongoing treatment (bacterial, fungal, viral including HIV positivity). 10. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption. 11. Peripheral neuropathy ≥ grade 2. 12. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis. Patients with a history of prior radiation pneumonitis are not excluded. 13. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise the protocol objectives in the opinion of the Investigator. 14. For Part B expansion cohorts only (after the RP2D has been identified), presence of a tertiary EGFR mutation (i.e., GFR C797S) mutations and hepatocyte growth factor receptor (MET) amplification. 15. Current use or anticipated need for drugs that are known to be strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or inducers.