Inclusion Criteria:

* At least 16 years of age
* Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene amplification identified through molecular assays (such as IHC and any next-generation sequencing \[NGS\] platform, reference lab NGS, or in house NGS platform) as routinely performed at The University of Texas MD Anderson Cancer Center or other similarly-certified laboratories. The minimum level of amplification is 7 copies. This rationale of amplification level is based on data from MOCLIA at The University of Texas MD Anderson Cancer Center
* Must have received prior standard therapy appropriate for tumor type and stage of disease, or, in the opinion of the investigator, is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy
* Must have at least one measurable lesion as defined by RECIST v1.1. Subjects with primary CNS tumors should meet the following criteria:

* Must have received prior treatment including radiation and/or chemotherapy, with radiation completed \> 12 weeks prior to cycle 1 day 1 (C1D1) of therapy, as recommended or appropriate for the tumor type
* Must have \>= 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging \[MRI\] and evaluable by RANO), with the size of at least one of the measurable lesions \>= 1 cm in each dimension
* Must have imaging study within 28 days before enrollment. If on steroid therapy, the dose must be stable for at least five days immediately before and during the imaging study
* Eastern Cooperative Oncology Group (ECOG) score =\< 3. If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky performance score (KPS) \>= 70 %
* Archived tumor tissue. If archival tissue is unavailable, an on-study tumor biopsy should be attempted if it can be safely performed
* Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) \< 2.5 x upper limit of normal (ULN) or \< 5 x ULN if liver function abnormalities are due to underlying malignancy
* Total bilirubin \< 2.5 x ULN, except in cases of biliary obstruction. Subjects with a known history of Gilberts disease and an isolated elevation of indirect bilirubin are eligible
* Serum creatinine \< 2.0 x ULN or estimated glomerular filtration rate \>= 30 mL/minute using the Cockcroft-Gault formula
* Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
* Willingness of men and women of reproductive potential to use two effective birth control methods, one used by the subject and another by his/her partner, for the duration of treatment and for 3 months following study completion

Exclusion Criteria:

* Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or five half-lives, whichever is shorter, and without clinically significant toxicities from that therapy
* Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK. However, subjects who received less than 28 days of such treatment and discontinued because of intolerance or toxicity are eligible
* Symptomatic or unstable brain metastases that needs corticosteroid usage. Subjects with asymptomatic brain metastases or primary CNS tumors are eligible
* Uncontrolled concurrent malignancy that would limit assessment of efficacy. Allowed diseases may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin
* Active uncontrolled systemic bacterial, viral, or fungal infection, unstable cardiovascular disease or other systemic disease that would limit compliance with study procedures. Unstable cardiovascular disease is defined as:

* Persistently uncontrolled hypertension defined as systolic blood pressure (BP) \> 150 mmHg and/or diastolic BP \> 100 mmHg despite antihypertensive therapy
* Myocardial infarction within 3 months of screening
* Stroke within 3 months of screening
* Inability to discontinue treatment with a strong cytochrome P450 (CYP450), 3A4 (CYP3A4) inhibitor or inducer prior to start of treatment
* Pregnancy or lactation