CTLA-4 inhibitor plus PD-1 inhibitor

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Arm 1: nivolumab (3 mg/kg every 2 weeks) plus placebo;

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Arm 2: nivolumab (1 mg/kg every 3 weeks) plus ipilimumab (3 mg/kg every 3 weeks for 4 doses) followed by nivolumab (3 mg/kg every 2 weeks for cycle 3 and beyond); or

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Arm 3: ipilimumab (3 mg/kg every 3 weeks for 4 doses) plus placebo.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

The prospectively defined coprimary analysis of PFS occurred after all patients had at least 9 months of follow-up. Treatment with nivolumab alone or in combination with ipilimumab resulted in significantly longer PFS than with ipilimumab alone. Results were consistent across the prespecified stratification factors. Median PFS was 6.9 months (95% CI, 4.3–9.5) with nivolumab, 11.5 months (95% CI, 8.9–16.7) with nivolumab plus ipilimumab, and 2.9 months (95% CI, 2.8–3.4) with ipilimumab.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

The prospectively specified coprimary analysis of OS was to occur at 28 months. With 467 deaths, the OS rate at this time point was 59% in the nivolumab group, 64% in the combination group, and 45% in the ipilimumab group (HRdeath for the combination vs. ipilimumab, 0.55 [98% CI, 0.42–0.72; P< .001]; HRdeath with nivolumab vs. ipilimumab 0.63 [98% CI, 0.48–0.81; P< .001]).[13]

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

In a descriptive analysis with a minimum follow-up of 36 months, the following data were found:

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1] › In a descriptive analysis with a minimum follow-up of 36 months, the following data were found:

OS rates were 52% in the nivolumab group, 58% in the combination group, and 34% in the ipilimumab group.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1] › In a descriptive analysis with a minimum follow-up of 36 months, the following data were found:

The median OS was not reached in the combination arm (95% CI, 38.2 months–not reached). Median OS in the single-agent nivolumab and ipilimumab groups were 37.6 months (95% CI, 29.1–not reached) and 19.9 months (95% CI, 16.9–24.6), respectively.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1] › In a descriptive analysis with a minimum follow-up of 36 months, the following data were found:

For the combination versus ipilimumab, the HRdeath was 0.55 (99.5% CI, 0.45–0.69; P < .001); for nivolumab versus ipilimumab, the HR was 0.65 (99.5% CI, 0.53–0.80; P < .001).

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Adverse events were highest in the combination arm and need to be monitored carefully. Grades 3 to 4 treatment-related adverse events occurred in 16.3% of patients in the nivolumab group, 27.3% of patients in the ipilimumab group, and 55% of patients in the combination group. The most frequent reason for treatment discontinuation was disease progression in the two monotherapy arms—49% with nivolumab and 65% with ipilimumab. The most frequent reason for discontinuation in the combination group was toxicity (38%).

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Four therapy-related deaths were reported, which were attributed to neutropenia (nivolumab group), colon perforation (ipilimumab group), liver necrosis, and autoimmune myocarditis (combination ipilimumab and nivolumab).

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

Analyses of PD-L1 expression level associated with OS at 3 years showed that expression levels alone are not a reliable predictor of OS.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1]

In a final analysis with a minimum follow-up of 10 years, the following data were reported:

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1] › In a final analysis with a minimum follow-up of 10 years, the following data were reported:

The 10-year OS rate was 34% in the combination group, 26% in the nivolumab group, and 16% in the ipilimumab group.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1] › In a final analysis with a minimum follow-up of 10 years, the following data were reported:

The median OS was 71.9 months (95% CI, 51.6–not reached) in the combination group, 36.9 months (95% CI, 30.7–46.6) in the nivolumab group, and 19.9 months (95% CI, 16.8–24.6) in the ipilimumab group.

Previously untreated patients. In an international double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to receive one of the following regimens:PFS and OS were coprimary end points. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy. The study was not powered to compare combination ipilimumab plus nivolumab with nivolumab. Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF pathogenic variant status (V600 variant−positive vs. wild-type), and American Joint Committee on Cancer stage. Characteristics at baseline were as follows: 74% of patients had an ECOG PS of 0; 36% had elevated LDH levels; 31.5% had BRAF pathogenic variants; and 58% had M1c disease. A minority of patients (23.6%) had PD-L1–positive tumors.[12][Level of evidence A1] › In a final analysis with a minimum follow-up of 10 years, the following data were reported:

HRdeath, compared with the ipilimumab group, was 0.53 (95% CI, 0.44–0.65) for the combination group and 0.70 (95% CI, 0.59–0.84) for the nivolumab group.[14]

Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[15][Level of evidence C3] Eligibility required no need for immediate intervention, an absence of neurological signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required. Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. The primary end point was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with a complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, 94 of whom had a minimum follow-up of 6 months; the data on that population are reported below.

Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[15][Level of evidence C3] Eligibility required no need for immediate intervention, an absence of neurological signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required. Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. The primary end point was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with a complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, 94 of whom had a minimum follow-up of 6 months; the data on that population are reported below.

Clinical benefit (in the brain) was seen in 57% of patients (95% CI, 47%–68%); 24 patients (26%) had a complete response, 28 patients (30%) had a partial response, and 2 patients (2%) had stable disease that lasted for 6 months or longer. Similar rates of objective response (50%) were seen in patients with extracranial lesions, although fewer patients had a complete response (7%).

Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[15][Level of evidence C3] Eligibility required no need for immediate intervention, an absence of neurological signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required. Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. The primary end point was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with a complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, 94 of whom had a minimum follow-up of 6 months; the data on that population are reported below.

A subgroup analysis indicated responses in both PD-L1–positive and PD-L1–negative patients (baseline status not known in 20/94 patients).

Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[15][Level of evidence C3] Eligibility required no need for immediate intervention, an absence of neurological signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required. Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. The primary end point was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with a complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, 94 of whom had a minimum follow-up of 6 months; the data on that population are reported below.

The median follow-up of the 94 patients was 14 months. Median time to intracranial response was 2.3 months (range, 1.1−10.8), and time to extracranial response was 2.1 months (range, 1.1−15.0).

Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[15][Level of evidence C3] Eligibility required no need for immediate intervention, an absence of neurological signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required. Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. The primary end point was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with a complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, 94 of whom had a minimum follow-up of 6 months; the data on that population are reported below.

The most common treatment-related adverse event of any grade in the nervous system was headache (21 patients [22%]), with 3 patients (3%) having headaches of grade 3 or 4. Other treatment-related neurological adverse events of grade 3 or 4 were brain edema (2 patients [2%]), intracranial hemorrhage (1 patient [1%]), peripheral motor neuropathy (1 patient [1%]), and syncope (1 patient [1%]). Each of these adverse events led to treatment discontinuation, and the one reported case of peripheral motor neuropathy was irreversible. The investigator determined one death to be related to the study treatment (grade 5 immune-related myocarditis).

Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[15][Level of evidence C3] Eligibility required no need for immediate intervention, an absence of neurological signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required. Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. The primary end point was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with a complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, 94 of whom had a minimum follow-up of 6 months; the data on that population are reported below.

Progression was documented in 33 patients (35%); 17 patients (18%) had intracranial progression only, 4 patients (4%) had extracranial progression only, and 12 patients (13%) had progression in both intracranial and extracranial sites.