Inclusion Criteria:

* The patient must have the following tumor types:

Cohort 1: Patient has unresectable and/or metastatic cutaneous melanoma. No more than 5 patients with acral melanoma may enroll in this cohort.

Cohort 2: Patient has unresectable and/or metastatic mucosal melanoma.

Cohort 3: Patient has unresectable and/or metastatic cutaneous melanoma. Patients with acral melanoma may not enroll in this cohort.

Cohort 4: Patient has unresectable and/or metastatic cutaneous melanoma. No patients with mucosal or acral melanoma may enroll in this cohort.

- The patient must have received previous treatment as follows: Cohorts 1 and 2: Patient has received anti-PD-\[L\]1 therapy with or without anti-CTLA-4 therapy, and less than or equal to one other prior regimen of systemic anti-neoplastic therapy (eg, targeted therapy, chemotherapy). Previous adjuvant and/or neoadjuvant therapy counts as one prior regimen. Patients have experienced objective response (partial response \[PR\] or CR; by RECIST 1.1 or iRECIST) or stable disease (SD; by RECIST 1.1 or iRECIST) as best overall response (BOR) to anti-PD-\[L\]1 therapy. Patients with confirmed progressive disease (by RECIST 1.1 or iRECIST) as best response may be included, if they received anti-PD-\[L\]1 therapy for a minimum of 12 weeks (eg, from first dose to last dose). Patients with BRAF mutations may or may not have received prior targeted therapy.

Cohort 3: Patients who have received anti-PD-\[L\]1 therapy with or without anti-CTLA-4 therapy or anti-lymphocyte-activation gene 3 (LAG-3) therapy, and ≤1 other prior regimen of systemic anti-neoplastic therapy (eg, targeted therapy, chemotherapy). Previous adjuvant and/or neoadjuvant therapy counts as 1 prior regimen. Patients must have experienced objective response (PR or CR by RECIST 1.1 or iRECIST) or stable disease (by RECIST 1.1 or iRECIST) as BOR to anti PD-\[L\]1 therapy. Patients with confirmed progressive disease (by RECIST 1.1 or iRECIST) as best response may be included, if they received anti-PD-\[L\]1 therapy for ≥12 weeks (from first dose to last dose). Patients with BRAF mutations may or may not have received prior targeted therapy.

Cohort 4: Patients must not have received prior systemic anticancer therapy for unresectable or metastatic melanoma. Prior adjuvant and/or neoadjuvant PD-\[L\]1 treatments are allowed if there is at least 6 months between the last dose and date of recurrence.

Cohorts 1, 2, and 3 - Patients who have received prior treatment with talimogene laherparepvec (TVEC) are allowed to enroll provided that last exposure to TVEC was ≥28 days prior to first exposure to nemvaleukin and that all injection-site reactions to TVEC have resolved. TVEC shall not be considered a prior regimen of systemic anti-neoplastic therapy, nor shall it be considered a systemic immunomodulatory agent.

* Patients must have disease that is measurable based on RECIST 1.1., that has not recently been irradiated or used to collect a biopsy.
* Cohorts 1 and 2 (required), Cohort 3 (optional), Cohort 4 (may be required, otherwise optional). Patient is willing to undergo a pretreatment tumor biopsy or provide qualifying archival tumor tissue.

Cohort 4 - Patients are required to have known tumor PD-\[L\]1 status determined by local testing using an approved assay. PD-\[L\]1 testing performed prior to enrolling on the study is acceptable if there was no intervening systemic anti-cancer therapy, and archival tissue may be used for testing provided the biopsy is ≤3 months old.

* Patient has an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and an estimated life expectancy of ≥3 months.
* Additional criteria may apply.

Exclusion Criteria:

* Patient has uveal melanoma (all cohorts) or acral melanoma (Cohort 2, Cohort 3 and Cohort 4).
* Patient has received prior interleukin (IL)-2-based or IL-15-based cytokine therapy; patient has had exposure, including intralesional, to IL-12 or analogs thereof.
* Patient requires systemic corticosteroids (\>10 mg of prednisone daily, or equivalent) however, replacement doses, topical, ophthalmologic, and inhalational steroids are permitted.
* Patient has undergone prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow transplant.
* Patient is currently pregnant, breastfeeding, or is planning to become pregnant or to begin breastfeeding during the study period or within 30 days (Cohorts 1,2, and 3) or 120 days (Cohort 4) after last study drug administration.
* Patients with active or symptomatic central nervous system metastases unless the metastases have been treated by surgery and/or radiation therapy and/or gamma knife, the subject has been tapered to a dose of 10 mg of prednisone (or equivalent) or less of corticosteroids for at least 2 weeks before the first dose, and the subject is neurologically stable. Patients with leptomeningeal disease are excluded.
* Patient has known or suspected hypersensitivity to any components of nemvaleukin (all cohorts) or to pembrolizumab (cohort 4 only).
* Patients with an uncontrollable bleeding disorder.
* Patient has QT interval corrected by the Fridericia Correction Formula values of \>470 msec (in females) or \>450 msec (in males); patient who is known to have congenital prolonged QT syndromes; or patient who is on medications known to cause prolonged QT interval on ECG.
* Patient has developed Grade ≥3 immune-related AEs (irAEs) while on prior immunotherapy, (eg, pneumonitis and nephritis) and has not recovered to ≤Grade 1 and/or are on systemic steroids within 14 days of first dose of study drug.
* Patients who have previously discontinued immunotherapy due to immune-related adverse event (irAEs) will be excluded.
* Cohort 4 only: Patient has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
* Additional criteria may apply.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/03/2024. Questions regarding updates should be directed to the study team contact.