Inclusion Criteria:

PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) ? Tissue available for biomarker testing (any brain metastasis tissue and extracranial site from any prior resection or biopsy).

REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)

• Participants must have histologically confirmed metastatic disease to the brain from any solid tumor. Note: this includes patients that have controlled extracranial disease with progressive intracranial metastasis, as well as patients that have progressive intracranial and extracranial disease.

• New or progressive brain metastases are defined as any one of the following:

  • Untreated measurable lesions in patients who have received surgery and/or stereotactic radiosurgery (SRS) to one or more other lesions.
  • Residual or progressive lesions after surgery if asymptomatic.
  • Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then whose lesions have progressed by BM-RANO criteria or there are new lesions, are eligible. Lesions treated with SRS may be eligible if there is unequivocal evidence of progression.
  • Patients who have not previously been treated with cranial radiation (e.g. WBRT or SRS) are eligible, but such patients must be asymptomatic or neurologically stable from their CNS metastases.
• Measurable CNS disease (> 10 mm).
• Ability to obtain magnetic resonance imaging (MRI)s.
• No surgery within 2 weeks prior to or after registration.

• No chemotherapy within 14 days prior to registration (Note: for abemaciclib arm, a 21-day chemotherapy washout is required).

  • For melanoma, patients must have progressed after prior immune checkpoint blockade or for BRAF positive melanoma, BRAF/MEK inhibitors.
  • For lung cancer, EGFR mutant patients must have failed EGFR therapies
  • For HER2-positive breast cancer patients, patients must have received at least one prior HER-2 directed therapy in the metastatic setting.
  • For triple negative breast cancer (TNBC), patients must have received at least one chemotherapy in the metastatic setting.
  • For estrogen receptor (ER)/progesterone receptor (PR)+ breast cancer, patients must have received at least one endocrine therapy in the metastatic setting.
  • Breast cancer patients who have received ribociclib or palbociclib are eligible as long as there is documentation of CDK4 pathway alteration on a biopsy at the point of progression post-ribociclib or palbociclib.
• Tissue available for sequencing (any brain metastasis tissue and extracranial site from any prior resection or biopsy that was resected as part of clinical care). If the patient does not have any evidence of extracranial disease, brain metastasis tissue is sufficient for eligibility.
• Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K pathway in both a brain metastasis and extracranial site.
• Not pregnant and not nursing, because this study involves investigational agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required (Note: for abemaciclib arm, pregnancy test is required =< 7 days prior to registration).
• No known leptomeningeal involvement.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function.
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's disease.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN).
• Creatinine =< 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min.
• No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Concurrent radiation to symptomatic non-target sites within neural axis is allowed (provided there is at least one untreated target lesion).
• Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7 days prior to registration. Baseline doses and changes in steroid dosing will be captured.
• No concurrent administration of anticancer therapies (except for endocrine therapy or continuation of hormonal therapy or trastuzumab in breast cancer patients). No chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the study (Note: For abemaciclib arm, a 21-day chemotherapy washout is required).
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to registration on the study.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR GDC-0084 ARM

• Urine protein to creatinine (UPC) ratio < 1 or urine protein =< 1.
• Recent acute myocardial infarction in the last 6 months or current angina pectoris are excluded. Patients with symptomatic bradycardia should have an electrocardiogram at baseline. If QT interval > 470 msec, the patient is excluded.
• Patients with uncontrolled type I or II diabetes mellitus should be excluded. Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to registration.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ENTRECTINIB ARM

? Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump inhibitors (PPIs), and/or antacids are prohibited.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM

• Hemoglobin >= g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.
• Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade =1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and registration (provided the patient did not receive radiotherapy).
• Patients who received adjuvant radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and registration.
• For females of childbearing potential: A female of childbearing potential, must have a negative serum pregnancy test within 7 days prior to registration and agree to use a highly effective contraception method during the treatment period and for 3 weeks following the last dose of abemaciclib. Contraceptive methods may include an intrauterine device [IUD] or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection. Cases of pregnancy that occur during maternal exposures to abemaciclib should be reported. If a patient or spouse/partner is determined to be pregnant following abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation.
• Patients with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is not required for enrollment.
• Patients with personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest, are excluded.

Criteria

Inclusion Criteria:

PRE-REGISTRATION:

• Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.

• Three or fewer (i.e. 0 to 3) unresected brain metastases (as defined on the post operative magnetic resonance imaging [MRI]) at the time of screening.

  o Note: Dural based metastases (e.g. commonly seen in breast cancer) are eligible.

• Unresected lesions must measure < 4.0 cm in maximal extent on the contrasted post-operative treatment MRI brain scan. The unresected lesions will be treated with SRS as outlined in the treatment section of the concept.

  o Note: The metastases size restriction does not apply to the resected brain metastasis.

• One brain metastasis must be completely (gross total resection) resected =< 30 days prior to pre-registration.

  o NOTE: May not have had resection of more than one brain metastasis.

• The resected brain metastasis must measure 2 cm or larger on the pre-operative MRI.
• Resection cavity must measure < 5.0 cm in maximal extent and the resection must be complete (gross total resection) on the post-operative MRI obtained =< 30 days prior to pre-registration.
• Karnofsky performance status of >= 60.

• For women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to pre-registration is required.

  • Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment.
  • A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Ability to complete an MRI of the head with contrast.
• The brain metastasis must be located > 5 mm of the optic chiasm and outside the brain stem.
• Must not have any prior whole brain radiation therapy.

• Past radiosurgery to other lesions is allowed.

  o NOTE: The surgically resected lesion cannot be the same location treated in the past with radiosurgery (i.e. repeat radiosurgery to the same location/lesion is not allowed on this protocol).

• May not have primary germ cell tumor, small cell carcinoma, or lymphoma.

• No evidence of leptomeningeal metastasis (LMD).

  o NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.

• Must be fluent in English, Spanish, or French.

REGISTRATION:

? Completion of all baseline electronic patient-reported outcome (ePRO) quality of life measures (or booklet quality of life measures) and Montreal Cognitive Assessment (MoCA).