Clinical Research Directory

Inclusion Criteria: * Age ≥ 18 years * Radiographic or histologically confirmed melanoma brain metastasis (MBM) and be planning to undergo or have undergone SRS for treatment, the decision on SRS should be based on institutional standards and location characteristics. A maximal number of lesions allowed at initial SRS should be determined by institutional standard, but the all lesions must measure =\< 3.0 cm in maximal extent, and total volume to be treated must measure \< 30 mL on the contrast-enhanced diagnostic magnetic resonance imaging (MRI) brain scan. Patients must be asymptomatic from their brain metastases at conclusion of SRS therapy prior to starting study drug * Treatment-naive or currently on therapy for systemic disease as long as there is exhibited control of systemic disease at time of MBM development. If MBM diagnosis coincides with initial diagnosis, patients may be treatment-naive with systemic disease * In patients naive to treatment, the choice of initial therapy will be left up to the treating physician. If in their clinical judgement, single agent anti-PD1 (aPD1) plus SRS is deemed the appropriate therapy then these patients may proceed to enrollment and inclusion of CA-4948 with their regimen. If in the treating physician's judgement, patient would benefit from use of combination immunotherapy with CTLA-4/aPD1 therapy, then patient must complete induction with CTLA-4/aPD1 therapy and proceed to maintenance aPD1 therapy prior to enrollment. The timing of SRS in these patients should coincide with the conclusion of induction dual agent therapy (either during or following last cycle of CTLA-4/aPD1 therapy) to then allow for a 3-week washout from last dose of CTLA-4 inhibitor exposure received prior to starting on study drug with CA-4948 and pembrolizumab * Completion of induction is defined as either completing the planned 4 doses of CTLA-4/aPD1 therapy or if the CTLA-4 inhibitor is discontinued after any of the initial 3 doses of therapy due to toxicity. In the event for stopping due to toxicity, then patients may still be eligible for study inclusion as long as this toxicity would not prevent them from continuing on aPD1 therapy as planned systemic treatment and no other rules for exclusion have been met below. In these patients, the timing of SRS should be consistent as above and the washout period from time of last CTLA-4 inhibitor must be at least 3 weeks prior to initiating on study drug. If a longer period of washout is required due to toxicity and safe resumption of immunotherapy, patients may still be enrolled as long as they meet the timing requirements from time of SRS to initiation of therapy as outlined below * In patient who develop MBM while previously having received treatment for metastatic melanoma at other systemic locations, previous treatment with dual checkpoint inhibitor therapy (CTLA-4/aPD1 or LAG-3/aPD-1) or single agent immunotherapy therapy will be allowed, as long as at the time of SRS to these MBM lesions the patient is planned to receive aPD1 therapy as long as the above criteria are met and the patients systemic disease is displaying at least stable disease (SD) on last surveillance imaging performed * SD is determined by clinician judgement at time of study enrollment. In patients on systemic single agent aPD1 there is no washout necessary in this case and patients can start pembrolizumab and study drug at next scheduled cycle of treatment following completion of SRS as long as all other rules have been met for enrollment * Previous oral BRAFi/MEKi treatment will also be allowed, as long as at the time of MBM treatment with SRS the patient is planned to initiate aPD1 therapy and not continue on BRAFi/MEKi. A washout period of 14 days from last dose of BRAFi/MEKi to initiation of study drug is required * Treatment of symptomatic MBM with corticosteroids is allowed while receiving CA-4948, but in order to start aPD1 therapy, patient must be on =\< 10mg of oral prednisone daily or equivalent * Able to tolerate an MRI * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, or 1, (Karnofsky \>= 70%), if patients performance status is borderline with =\< 1 to =\< 2, special consideration can be made and discussed with study principal investigator (PI) for possible enrollment. These patients should be deemed to have a decrease in their performance status linked with an acute process that is expected to improve with initiation of therapy. This is to allow for patients who have initial decline from event that caused their brain metastasis presentation that is expected to improve with short course of steroid treatment and stereotactic radiosurgery. For those with borderline performance status that is not related to acutely reversible intracranial changes expected to improve than these patients will not be allowed * Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L \[Hemoglobin criterion must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks\] (obtained =\< 30 days prior to registration) * Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained =\< 30 days prior to registration) * Platelets ≥ 100,000/mm\^3 (obtained =\< 30 days prior to registration) * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin no lower than the ULN if total bilirubin \> 1.5 × ULN (obtained =\< 30 days prior to registration) * Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 2.5 x ULN (=\< 5 x ULN for patients with liver involvement) (obtained =\< 30 days prior to registration) * Prothrombin time (PT)/international normalized ratio (INR)/activated partial prothrombin time (aPTT) =\< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =\< 30 days prior to registration) * Calculated creatinine clearance (CrCl) =\< 1.5 x ULN OR glomerular filtration rate (GFR) \>= 30 ml/min using the Cockcroft-Gault formula for participants with creatinine levels \> 1.5 × ULN (obtained =\< 30 days prior to registration) * Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only. A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile. Women in the following categories are not considered women of child bearing potential (WOCBP) : * Premenarchal * Premenopausal female with 1 of the following: * Documented hysterectomy * Documented bilateral salpingectomy * Documented bilateral oophorectomy * Postmenopausal female * A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. * A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required * Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment * Male and female participants agree to use a highly effective method of contraception while on study and at least 120 days following their last dose of study treatment * Male participants agree not to donate sperm from first dose of therapy until 120 days after the last dose of study treatment * Provide written informed consent * Ability to complete questionnaire(s) by themselves or with assistance * Willingness to provide mandatory blood specimens for correlative research * Willingness to provide mandatory tissue specimens for correlative research. Archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue * Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) * Participants living with HIV must have well-controlled HIV on antiretroviral therapy (ART), defined as: * Participants on ART must have a CD4+ T-cell count \>= 350 cells/mm\^3 at the time of screening * Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantification (LLOQ) (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening * It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months * Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (day 1) and agree to continue ART throughout the study * Hepatitis B screening tests are not required unless known history of hepatitis B virus (HBV) infection as mandated by local health authority * Hepatitis B positive patients: * Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to registration * Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention * History of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen * All adverse events (AEs) due to previous therapies have returned to ≤ grade 1 or baseline, with the exception of Alopecia. * ≤ Grade 2 neuropathy * ≤ Grade 2 endocrine-related AEs requiring treatment or hormone replacement * Patients who have had a recent surgery or procedure should be healed and cleared by their clinician and/or surgeon per local standards, prior to registration * Able to swallow oral medications Exclusion Criteria: * Any of the following because this study involves an investigational agent, the genotoxic, mutagenic and teratogenic effects of which on the developing fetus and newborn are unknown: * Pregnant persons * Nursing persons * Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception while on study and at least 120 days following their last dose of study treatment * Any of the following prior therapies: * Radiation therapy =\< 2 weeks prior to registration, with the exception of the described SRS that patients are mandated to receive for inclusion \[Participants must have recovered from all radiation-related toxicities, not require corticosteroids over =\< 10 mg of oral prednisone daily or equivalent, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease\] * Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection (is patient is receiving oral antibiotics for localized infection with planned end date they may enroll on study as soon as duration is complete) * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy * Or psychiatric illness/social situations that would limit compliance with study requirements * Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm * Other active malignancy that is progressing or has required active treatment =\< 3 years prior to registration. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded * Intolerance to gadolinium contrast (for MRI) * Has received a live vaccine or live-attenuated vaccine =\< 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Messenger (m)RNA Coronavirus Disease (COVID)-1 vaccines are allowed * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy =\< 7 days prior to the first dose of study drug * Has severe hypersensitivity (\>= grade 3) to pembrolizumab, CA-4948, or any of their excipients * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed * History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * History or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator * Has had an allogenic tissue/solid organ transplant * Unable to discontinue medications contraindicated to CA-4948 or pembrolizumab