Immune Checkpoint Inhibitors or BRAF/MEK Inhibitors

A phase I trial of ipilimumab in children and adolescents, at a dose of 5 mg/kg or 10 mg/kg every 3 weeks for four cycles, enrolled 12 patients with melanoma.[6]

A phase I trial of ipilimumab in children and adolescents, at a dose of 5 mg/kg or 10 mg/kg every 3 weeks for four cycles, enrolled 12 patients with melanoma.[6]

One patient had prolonged stable disease.

A phase I trial of ipilimumab in children and adolescents, at a dose of 5 mg/kg or 10 mg/kg every 3 weeks for four cycles, enrolled 12 patients with melanoma.[6]

This treatment demonstrated a similar toxicity profile as that seen in adults.

A phase II study of ipilimumab for adolescents with melanoma failed to achieve accrual goals and was closed. However, there was reported activity in patients with melanoma who were aged 12 to 17 years, with a similar safety profile as that seen in adults.[7][Level of evidence B4]

A phase II study of ipilimumab for adolescents with melanoma failed to achieve accrual goals and was closed. However, there was reported activity in patients with melanoma who were aged 12 to 17 years, with a similar safety profile as that seen in adults.[7][Level of evidence B4]

At 1 year, three of four patients who received 3 mg/kg and five of eight patients who received 10 mg/kg were alive.

A phase II study of ipilimumab for adolescents with melanoma failed to achieve accrual goals and was closed. However, there was reported activity in patients with melanoma who were aged 12 to 17 years, with a similar safety profile as that seen in adults.[7][Level of evidence B4]

Two patients who received 10 mg/kg had partial responses, and one patient who received 3 mg/kg had stable disease.

A phase II study of ipilimumab for adolescents with melanoma failed to achieve accrual goals and was closed. However, there was reported activity in patients with melanoma who were aged 12 to 17 years, with a similar safety profile as that seen in adults.[7][Level of evidence B4]

In adults with completely resected stage III cutaneous melanoma, prolonged DFS and overall survival have been seen with ipilimumab given at a dose of 10 mg/kg every 3 weeks for four doses, followed by one dose every 3 months for up to 3 years. This regimen caused little impairment in health-related quality of life.

In a phase I/II trial of nivolumab for children and young adults with relapsed or refractory solid tumors or lymphoma, patients were treated with a dose of 3 mg/kg every 14 days.[8]

In a phase I/II trial of nivolumab for children and young adults with relapsed or refractory solid tumors or lymphoma, patients were treated with a dose of 3 mg/kg every 14 days.[8]

The one patient with melanoma did not respond to therapy.

An open-label, single-arm, phase I/II trial of pembrolizumab for pediatric patients with advanced melanoma or programmed death-ligand 1 (PD-L1)–positive, advanced, relapsed, or refractory solid tumors or lymphoma reported the following:[9]

An open-label, single-arm, phase I/II trial of pembrolizumab for pediatric patients with advanced melanoma or programmed death-ligand 1 (PD-L1)–positive, advanced, relapsed, or refractory solid tumors or lymphoma reported the following:[9]

Eight patients with melanoma were enrolled, and no responses were observed in these patients.

An open-label, single-arm, phase I/II trial of pembrolizumab for pediatric patients with advanced melanoma or programmed death-ligand 1 (PD-L1)–positive, advanced, relapsed, or refractory solid tumors or lymphoma reported the following:[9]

Five of these patients were PD-L1 negative.

The Children's Oncology Group conducted a phase I/II trial of ipilimumab and nivolumab in 55 children and young adults with refractory or recurrent solid tumors.[10]

The Children's Oncology Group conducted a phase I/II trial of ipilimumab and nivolumab in 55 children and young adults with refractory or recurrent solid tumors.[10]

The study identified a recommended phase II dose of 3 mg/kg for nivolumab and 1 mg/kg for ipilimumab.

The Children's Oncology Group conducted a phase I/II trial of ipilimumab and nivolumab in 55 children and young adults with refractory or recurrent solid tumors.[10]

No patients with melanoma were enrolled in the trial. However, partial responses were seen in one patient with rhabdomyosarcoma and one patient with Ewing sarcoma.

A retrospective review identified 99 patients with melanoma (aged 18 years or younger) who were treated with systemic therapy at 15 Italian academic centers. Eighty-one patients received anti–PD-1 therapy. The median age was 14 years (range, 2–18 years), and 37 patients were aged 12 years or younger. Thirty-eight patients received anti–PD-1 therapy in the adjuvant setting.[11]

A retrospective review identified 99 patients with melanoma (aged 18 years or younger) who were treated with systemic therapy at 15 Italian academic centers. Eighty-one patients received anti–PD-1 therapy. The median age was 14 years (range, 2–18 years), and 37 patients were aged 12 years or younger. Thirty-eight patients received anti–PD-1 therapy in the adjuvant setting.[11]

Of the patients who received adjuvant anti–PD-1 therapy, the 3-year progression-free survival rate was 70.6%, and the overall survival (OS) rate was 81.1%.

A retrospective review identified 99 patients with melanoma (aged 18 years or younger) who were treated with systemic therapy at 15 Italian academic centers. Eighty-one patients received anti–PD-1 therapy. The median age was 14 years (range, 2–18 years), and 37 patients were aged 12 years or younger. Thirty-eight patients received anti–PD-1 therapy in the adjuvant setting.[11]

Of the 56 patients who received systemic therapy for advanced disease, 43 received first-line anti–PD-1–based therapy, while 12 patients received a second line, and 5 patients received a third line. Among patients who received first-line therapy with anti–PD-1 monotherapy, the objective response rate was 25%, and the 3-year OS rate was 34%.

A retrospective review identified 99 patients with melanoma (aged 18 years or younger) who were treated with systemic therapy at 15 Italian academic centers. Eighty-one patients received anti–PD-1 therapy. The median age was 14 years (range, 2–18 years), and 37 patients were aged 12 years or younger. Thirty-eight patients received anti–PD-1 therapy in the adjuvant setting.[11]

Toxicities were consistent with previous studies that included adult patients with melanoma.

Dabrafenib and trametinib have been studied in two trials for pediatric patients with BRAF V600-altered low-grade gliomas. The U.S. Food and Drug Administration (FDA) approved this combination for this indication.[12,13] The FDA has also approved this combination for the treatment of patients with melanoma.

Based on the positive results of two randomized clinical trials, the FDA approved adjuvant pembrolizumab for the treatment of patients aged 12 years and older with resected stage IIb, IIc, and III melanoma.[14,15]

Based on the positive results of two randomized clinical trials, the FDA approved adjuvant nivolumab for the treatment of patients aged 12 years and older with resected stage IIb to IV melanoma.[16,17]

Based on the positive results of one adult randomized clinical trial, the FDA approved nivolumab and ipilimumab for the treatment of children aged 12 years and older with unresectable or metastatic melanoma.[18]

Based on the positive results of one randomized clinical trial, the FDA approved nivolumab with relatlimab for the treatment of children aged 12 years and older with unresectable or metastatic melanoma.[19]

Although there have not been any prospective clinical trials using BRAF/MEK inhibitors in children and adolescents with melanoma, two adult studies have shown that the adjuvant combination of dabrafenib and trametinib results in a significantly lower risk of recurrence in patients with surgically resected stage III melanoma and in patients with previously untreated BRAF V600-altered metastatic melanoma.[20,21] The FDA granted accelerated approval to this drug combination for the treatment of patients with unresectable or metastatic melanoma who have BRAF V600E or V600K variants and for the adjuvant treatment of patients with melanoma who have BRAF V600E or V600K variants.