• Provision to sign and date the informed consent form.

• Stated willingness to comply with all study procedures and be available for the duration of the study.

• Participant is ≥ 18 years of age.

• Participant has histologic or cytologic confirmation of locally advanced (unresectable) or metastatic NSCLC with a known (and documented) ALK, ROS1, or RET fusion based on approved diagnostic testing methods specified below. Not that NGS testing is required for all participants, but screening if any of the test below are positive.

• a. IHC: For ALK NSCLC only using the ALK D5F3 antibody b. FISH with ≥15% of 100 cells sampled constituting positivity c. NGS using a CLIA-certified test

• Participants must have clinical progression on at least one prior FDA-approved TKI. They must be on a TKI at the same dose for at least 8 weeks without radiographic progression or clinical intolerance of the TKI prior to enrolling on this study. TKIs that will be considered include (but not limited to):

∙ ALK fusions - alectinib, brigatinib, lorlatinib

‣ ROS1 fusions - entrectinib, lorlatinib

‣ RET fusions - selpercatinib, pralsetinib

• Participants must have at least 1 measurable lesion by RECIST v1.1 criteria using computed tomography (CT) scan or magnetic resonance imaging (MRI).

∙ Measurable CNS lesions ≥10mm must be captured as overall and intracranial RECIST target lesions. CNS lesions 5-9mm may be included in the intra-cranial data set alone but must be listed as non-target lesions.

‣ Measurable, treated brain metastases (≥ 10mm) growing after whole-brain radiotherapy (WBRT) or resection are allowed as target lesions, but lesions growing after stereotactic radiosurgery (SRS) are allowed as target lesions only if radiation necrosis or pseudoprogression is ruled out.

• Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0-2

• Participant has a life expectancy of greater than 12 weeks, per investigator discretion.

• Participant can ingest oral medications.

⁃ Participant has received the final dose of any of the following treatments/procedures with the specified minimum intervals before the first dose of study drug (unless in the opinion of the Sponsor-Investigator, the medication will not interfere with the study or compromise participant safety).

⁃ Chemotherapy 21 days Antibody-drug conjugate (ADC) 28 days Immune checkpoint inhibitors (ICI) 28 days Locally ablative radiotherapy 28 days Palliative radiotherapy 14 days Major surgery 28 days

⁃ Participant has adequate organ function as determined by the following laboratory values.

⁃ Absolute neutrophil count (ANC)\* ≥ 1,500/mm3 (≥ 1.5 x One times ten to the ninth/L) Platelets† ≥ 75,000/mm3 (≥ 75 x One times ten to the ninth/L) Hemoglobin† ≥ 9 g/dL Renal function: Serum creatinine ≤ 1.5 x upper limit normal (ULN) OR creatinine clearance ≥50 mL/min/1.73 m2 via Cockcroft-Gault Liver transaminases (ALT/AST) ≤ 3 x ULN

‣ 5 x ULN, if liver metastases are present on screening Bilirubin ≤ 1.5 x ULN

‣ 3.0 x ULN, if patient has Gilbert's disease Amylase and lipase ≤ 1.5 x ULN

⁃ Participants cannot be receiving growth factor support using granulocyte-stimulating colony factor (G-CSF) during the screening visit.

‣ Participants cannot receive transfusion support up to one week prior to the screening period.

⁃ Female participant of childbearing potential (defined as a sexually mature woman who has not undergone a hysterectomy \[surgical removal of the uterus\] or bilateral oophorectomy, or if ≥ 45 years old, has not been naturally postmenopausal for at least 24 consecutive months \[i.e., has had menses at any time during the preceding 24 consecutive months\]) must:

• Have 1 negative pregnancy test as verified by an Investigator prior to starting study therapy. This applies even if the subject practices true abstinence from heterosexual contact.

∙ Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use and be able to comply with a barrier method plus a hormonal method of contraception without interruption 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 3 months after discontinuation (or longer if required by local requirements) of study therapy. The method of contraception must be a barrier method plus a hormonal method to prevent pregnancy.

∙ Participants must agree to continue contraception throughout the study and continuing through 3 months after the last dose of study drug. Note: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin a highly effective method of birth control, as described above.

∙ A woman of childbearing potential must have a negative serum or urine (b- human chorionic gonadotropin \[b-hCG\]) at Screening.

∙ A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study drug.

∙ A female participant must agree not to be pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study treatment.

⁃ A man who is sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (i.e., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device \[IUD\] or intrauterine system \[IUS\]). If the subject is vasectomized, he must still use a condom (with or without spermicide), but his female partner is not required to use contraception. The subject must also not donate sperm during the study and for 6 months after receiving the last dose of study drug, even if he has undergone a successful vasectomy.