The goal of this clinical trial is to understand if a new drug called LNS8801 can safely treat patients with melanoma. The primary question to be answered is what is the average length of time during which melanoma does not grow or spread after starting treatment with LNS8801? Researchers will compare LNS8801 taken alone or LNS8801 taken together with another drug called pembrolizumab to other therapies as decided by the treating doctor.

135 patients will be randomly (like flipping a coin) placed in 3 treatment groups.

In the first group (LNS8801 only) - Patients will take 125mg tablet of LNS8801 by mouth once per day every day for up to 2 years.

In the second group (LNS8801 + pembrolizumab) - Patients will take 125mg tablet of LNS8801 by mouth once per day plus 200 mg of pembrolizumab by IV infusion once every 3 weeks for up to 2 years.

In the third group, called Physician's Choice (PC), patients will receive chemotherapy (dacarbazine or temozolomide) or immunotherapy (pembrolizumab, nivolumab/relatlimab or nivolumab/ipilimumab) as determined by their treating physician.

How often the patient visits the clinic visits will depend on the treatment group. Besides returning to the clinic for treatment, the patient will undergo periodic safety assessments and other required study procedures such as imaging assessments.

This is a randomized, controlled, open-label, multicenter study to characterize the safety, tolerability, and antitumor effects of LNS8801 alone and in combination with pembrolizumab in treatment refractory, unresectable cutaneous melanoma patients who are homozygous for the consensus GPER protein-coding amino acid sequence (C/C) and have progressed on prior immune checkpoint inhibitor therapy, including an anti-PD-1 therapy. The C/C form of GPER is present in approximately 55% of patients.

Patients must initially consent to a prescreening blood-based genetic test only. Patients with the required genotype will then consent to full screening and treatment, and the potential physician's choice (PC) treatment will be identified. Patients will be randomized 1:1:1 between LNS8801 + pembrolizumab, LNS8801 monotherapy, and PC treatment. In the LNS8801 + pembrolizumab arm, LNS8801 will be administered every day per week, and pembrolizumab will be administered 200 mg Q3W for up to 35 cycles (approximately 2 years; Note: Physicians may modify the pembrolizumab regimen to 400 mg Q6W pembrolizumab after 6 months of treatment if appropriate). In the monotherapy arm, LNS8801 will be administered every day per week. In the PC arm, patients may receive chemotherapy (dacarbazine, temozolomide) or immunotherapy (pembrolizumab, nivolumab/relatlimab, nivolumab/ipilimumab).

Patients' randomization will be stratified by normal or elevated baseline LDH, <3 or ≥3 disease sites, and physician's determination of primary vs secondary anti-PD-1 therapy resistance per SITC guidelines; prior to randomization, the preferred PC treatment for each patient will be identified, and the patient must be willing to receive this therapy if assigned to the PC arm. At least one-third of patients in each arm must have had secondary resistance to prior anti-PD-1 therapy. Patients who are on LNS8801 + pembrolizumab combination therapy may drop one of the study medications and continue on the other for tolerability or safety reasons. For example, if a patient has an immune-related AE that warrants discontinuation of pembrolizumab, they should continue LNS8801 monotherapy. Patients may choose to remain on study drugs past progression if they are clinically stable and the treating physician believes that continued therapy is likely to benefit the patient.

Patients may continue on LNS8801 therapy past progression and initiate localized therapy if they are clinically stable and the treating physician believes that continued LNS8801 therapy is likely to benefit the patient. Safety assessments will be performed on all patients at screening, throughout their participation in the study, and at either 30 days following the last dose of study drugs if they are not taking an immune checkpoint inhibitor (ICI) or 90 days following the last dose if their treatment included an ICI. Measures of metabolic health (eg, circulating lipids, blood pressure, HbA1C) will also be recorded throughout the study.

Overall survival and reason for mortality should be assessed after the last dose of study medication, every 6 months for the first year, and then annually, until it has been 2 years since any patient has taken study medication. Any anti-cancer therapies should be recorded.

Imaging of tumors for evidence of tumor response and/or progression will be performed at screening (within 21 days of the first dose of study drug) and then every 8 weeks for the first year, every 12 weeks for the second year, and every 6 months thereafter.

Up to 135 patients will be randomized in this study.

Inclusion Criteria:

• Confirmed unresectable and/or metastatic cutaneous melanoma.
• 2 copies of the fully functional form of GPER protein-coding sequence.
• Eligible for and willing to receive 1 or more of the physician's choice (PC) therapies.
• Able to swallow tablets.
• Progressed on treatment with an anti-PD-1 monoclonal antibody (mAb) administered either as monotherapy or in combination with other therapies.
• Received an anti-CTLA-4 and/or BRAF containing regimen or is not eligible for or has declined anti-CTLA-4 and/or BRAF therapy prior to and for this study.
• Measurable disease.
• Eastern Cooperative Oncology Group Performance Status of 0 to 1.

Exclusion Criteria:

• Blue nevus subtype, mucosal, acral lentiginous, or uveal/ocular/choroidal Melanoma.
• Previous anti-cancer or investigational drug/device treatment within 4 weeks of the first dose of study drug.
• Radiotherapy within 2 weeks of starting study drug.
• Allogeneic tissue/solid organ transplant.
• Unstable autoimmune or immunodeficiency disease.
• Other concurrent health issues that would make participation or completion of the study difficult.
• Prior reaction to anti PD-1 therapy that would make treatment with pembrolizumab unadvisable.
• Other protocol-defined inclusion/exclusion criteria may apply.