• Patients must be 18 years or older.

• Patients must be willing and able to provide informed consent.

• In the dose escalation, patients must have histologically documented locally advanced, unresectable, or metastatic melanoma or TNBC that has progressed on treatments that are known to prolong survival or for which no standard treatment is available or refused such therapy. Presence of active brain metastases is not required. Patients with active metastases as defined below can be eligible in the dose escalation.

• In the dose expansion, patients must have histologically documented locally advanced, unresectable, or metastatic melanoma or TNBC that has progressed on treatments that are known to prolong survival or for which no standard treatment is available or refused such therapy.

∙ Melanoma patients without brain metastases who have progressed on an anti-PD-1 or anti-PD-L1-based regimen.

‣ Melanoma patients with active and untreated brain metastases who have progressed on an anti-PD-1 or anti-PD-L1-based regimen.

‣ TNBC patients (defined as ER \<1%, HER2 0, 1+, 2+, and fluorescence in situ hybridization negative) with active untreated brain metastases. Prior treatment with anti-PD-1/anti-PD-L1 is not required.

• All patients must have had a brain magnetic resonance imaging (MRI) scan in the previous 28 days to confirm eligibility for the following cohorts:

∙ Dose escalation and dose expansion Cohort 1: Confirmed absence of untreated brain metastases in patients with histologically confirmed advanced melanoma. Prior surgery for brain metastases must have been completed at least 4 weeks prior study treatment initiation, whole brain radiation therapy must have been completed at least 3 weeks prior to study treatment initiation, and stereotactic radiosurgery must have been completed within 7 days prior to study treatment initiation.

‣ Dose escalation and dose expansion Cohorts 2 and 3: At least one confirmed measurable untreated brain lesion ≥ 0.5 cm and \< 3.0 cm in the longest axis.

• Has measurable disease based on the RECIST v1.1.

• Has adequate organ function as defined in Table 2:

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4).

• Has a life expectancy of at least 12 weeks.

⁃ Able to swallow and retain orally administered medication.

⁃ In the dose expansion, patients with EC disease must be willing to provide tissue from a newly obtained, safely accessible core or excisional biopsy lesion at pre-treatment and at least one time point while on study treatment. Correlative biopsies will be optional in the dose escalation portion of the study. Newly obtained biopsy is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of study treatment on Day 1 without intervening systemic therapy.

⁃ Women of childbearing potential (WOCBP) should have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

⁃ Alpelisib and pembrolizumab can cause fetal harm when administered to a pregnant woman. Therefore, WOCBP must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of screening through 4 months after the last dose of study treatment. Refer to Pregnancy Assessment Policy MD Anderson Cancer Center (MDACC) Institutional Policy # CLN1114. This includes all female patients between the onset of menses and 55 years unless the patient presents with an applicable exclusionary factor such as one of the following:

• Postmenopausal (no menses in ≥ 12 consecutive months)

∙ History of hysterectomy or bilateral salpingo-oophorectomy

∙ Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range and have received whole pelvic radiation therapy)

∙ History of bilateral tubal ligation or another surgical sterilization procedure

⁃ Approved methods of birth control are as follows: hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation or hysterectomy, patient/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the study and the study treatment washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

⁃ Male patients with partner(s) of childbearing potential must agree to use adequate contraception from the time of screening through 4 months after the last dose of study treatment.