YERVOY Concentrate for solution for infusion Ref.[8371] Active ingredients: Ipilimumab

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: L01XC11

Mechanism of action

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell immune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function, which may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete T-regulatory cells at the tumour site, leading to an increase in the intratumoral T-effector/T-regulatory cell ratio which drives tumour cell death.

Pharmacodynamic effects

In patients with melanoma who received ipilimumab, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. In Phase 2 studies, this increase was dose-dependent. In MDX010-20 (see section 5.1), ipilimumab at 3 mg/kg with or without gp100 increased ALC throughout the induction dosing period, but no meaningful change in ALC was observed in the control group of patients who received an investigational gp100 peptide vaccine alone. In peripheral blood of patients with melanoma, a mean increase in the percent of activated HLA-DR+ CD4+ and CD8+ T cells was observed after treatment with ipilimumab, consistent with its mechanism of action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ T cells and a smaller, but significant, mean increase in the percent of effector memory (CCR7- CD45RA-) CD8+ T cells also was observed after treatment with ipilimumab.

Clinical efficacy and safety

Ipilimumab in combination with nivolumab

For additional information on clinical efficacy and safety associated with the dosing recommendations of nivolumab when administered as monotherapy following combination therapy with ipilimumab, please refer to the nivolumab SmPC.

Based on modelling of dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or 3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significant differences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in advanced melanoma and RCC.

Clinical trials with ipilimumab monotherapy

Melanoma

Overall survival (OS) advantage of ipilimumab at the recommended dose of 3 mg/kg in patients with previously-treated advanced (unresectable or metastatic) melanoma was demonstrated in a Phase 3 study (MDX010-20). Patients with ocular melanoma, primary CNS melanoma, active brain metastases, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were not included in the MDX010-20 clinical trial. Clinical trials excluded patients with ECOG performance status >1 and mucosal melanoma. Patients without liver metastasis who had a baseline AST >2.5 x ULN, patients with liver metastasis who had a baseline AST >5 x ULN, and patients with a baseline total bilirubin ≥3 x ULN were also excluded.

For patients with a history of autoimmune disease, see also section 4.4.

MDX010-20

A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) melanoma who had previously been treated with regimens containing one or more of the following: IL-2, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive ipilimumab 3 mg/kg + an investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg/kg monotherapy, or gp100 alone. All patients were HLA-A2*0201 type; this HLA type supports the immune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutation status. Patients received ipilimumab every 3 weeks for 4 doses as tolerated (induction therapy).

Patients with apparent tumour burden increase before completion of the induction period were continued on induction therapy as tolerated if they had adequate performance status. Assessment of tumour response to ipilimumab was conducted at approximately Week 12, after completion of induction therapy.

Additional treatment with ipilimumab (re-treatment) was offered to those who developed PD after initial clinical response (PR or CR) or after SD (per the modified WHO criteria) >3 months from the first tumour assessment. The primary endpoint was OS in the ipilimumab+ gp100 group vs. the gp100 group. Key secondary endpoints were OS in the ipilimumab + gp100 group vs. the ipilimumab monotherapy group and in the ipilimumab monotherapy group vs. the gp100 group.

A total of 676 patients were randomized: 137 to the ipilimumab monotherapy group, 403 to the ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 doses during induction. Thirty-two patients received re-treatment: 8 in the ipilimumab monotherapy group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of follow-up ranged up to 55 months. Baseline characteristics were well balanced across groups. The median age was 57 years. The majority (71-73%) of patients had M1c stage disease and 37-40% of patients had an elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previously treated brain metastases.

The ipilimumab-containing regimens demonstrated a statistically significant advantage over the gp100 control group in OS. The hazard ratio (HR) for comparison of OS between ipilimumab monotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p=0.0026).

By subgroup analysis, the observed OS benefit was consistent within most of the subgroups of patients (M [metastases]-stage, prior interleukin-2, baseline LDH, age, sex, and the type and number of prior therapy). However, for women above 50 years of age, the data supporting an OS benefit of ipilimumab treatment were limited. As the subgroups analysis includes only small numbers of patients, no definitive conclusions can be drawn from these data.

Median and estimated rates of OS at 1 year and 2 years are presented in Table 8.

Table 8. Overall survival in MDX010-20:

^a gp100 peptide vaccine is an experimental control

In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for patients with SD and those with PD, respectively. At the time of this analysis, medians were not reached for patients with CR or PR.

For patients who required re-treatment, the BORR was 38% (3/8 patients) in the ipilimumab monotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of patients in these analyses, no definitive conclusion regarding the efficacy of ipilimumab re-treatment can be drawn.

The development or maintenance of clinical activity following ipilimumab treatment was similar with or without the use of systemic corticosteroids.

CA184-169

A Phase 3, double-blind study enrolled patients with previously treated or untreated unresectable Stage III or Stage IV melanoma. A total of 727 patients were randomized, 362 to receive ipilimumab 3 mg/kg and 365 to receive ipilimumab 10 mg/kg every 3 weeks for 4 doses. In the ipilimumab 10 mg/kg group, the median OS (95% CI) was 16 months (11.63, 17.84) and in the ipilimumab 3 mg/kg group the median OS (95% CI) was 12 months (9.86, 13.27). Overall survival compared between Ipilimumab 10 mg/kg and 3 mg/kg groups showed HR=0.84 (95% CI: 0.70, 0.99; P-value=0.04). No statistically significant difference in progression free survival (PFS) was observed between the 10 mg/kg and the 3 mg/kg groups. (HR 0.89 with a 95% CI of 0.76, 1.04 and log-rank test P-value=0.1548). BORR was similar in the 10 mg/kg and 3 mg/kg groups. BORR in the 10 mg/kg group was 15.3% (95% CI: 11.8, 19.5) and in the 3 mg/kg group was 12.2% (95% CI: 9.0, 16.0). Ipilimumab 10 mg/kg was associated with higher rates of adverse events compared with the 3 mg/kg dose. The frequencies of serious adverse reactions in the 10 mg/kg and 3 mg/kg groups were 37% and 18%, with the 3 most common serious adverse reactions being diarrhea (10.7% vs 5.5%), colitis (8.0% vs 3.0%), and hypophysitis (4.4% vs 1.9%). Adverse events leading to discontinuation in the 10 mg/kg and 3 mg/kg groups occurred in 31% and 19% of patients, with AEs leading to death in 4 and 2 patients, respectively.

At the recommended dose of 3 mg/kg median OS was similar in the subgroup of females ≥50 years of age compared to the overall population: (11.40 vs 11.53 months). Median OS in the subgroup with brain metastases at baseline was 5.67 months at the recommended dose of 3 mg/kg.

Other studies with ipilimumab monotherapy

Melanoma

CA184332 and CA184338

OS of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N=78; randomised) and in treatment-naive patients in two retrospective observational studies (N=273 and N=157) were generally consistent. In the two observational studies, 12.1% and 33.1% of the patients had brain metastases at the time of advanced melanoma diagnosis. Median OS and estimated 1-year, 2-year, 3-year and 4-year survival rates are presented in Table 9. The estimated 1-year, 2-year and 3-year survival rates for chemotherapy-naive patients (N=78) pooled across Phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5-65.6), 31.6% (95% CI: 20.7-42.9) and 23.7% (95% CI: 14.3-34.4) respectively.

Table 9. Overall survival in observational studies:

Patients with brain metastases in study CA184332 had a median OS of 7 months (95% CI: 5.06-12.81) and patients without brain metastases had a median OS of 14.1 months (95% CI: 9.96-Not estimated).

Patients with brain metastases in study CA184338 had a median OS of 6.3 months (95% CI: 3.2-12.0) and patients without brain metastases had a median OS of 17.7 months (95% CI: 13.6–12.1).

Long term survival benefit of treatment with ipilimumab (at 3mg/kg) is demonstrated through a pooled analysis of OS data from clinical trials in patients with previously treated and treatment naive advanced melanoma (N=965). The Kaplan-Meier OS curve revealed a plateau beginning around year 3 (OS rate=21% [95% CI: 17-24]) that extended up to 10 years in some patients (see Figure 1).

Figure 1. Overall Survival with ipilimumab 3 mg/kg in pooled analysis:

Clinical trials with ipilimumab in combination with nivolumab

Melanoma

Randomised phase 3 study of receive ipilimumab in combination with nivolumab or nivolumab as monotherapy vs. ipilimumab as monotherapy (CA209067)

The safety and efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg nivolumab 3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The differences between the two nivolumab-containing groups were evaluated descriptively. The study included adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were to have ECOG performance status score of 0 or 1. Patients who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases were excluded from the study.

A total of 945 patients were randomised to receive ipilimumab in combination with nivolumab (n=314), nivolumab monotherapy (n=316), or ipilimumab monotherapy (n=315). Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks. Randomisation was stratified by PD-L1 expression (≥5% vs. <5% tumour cell membrane expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The co-primary outcome measures were progression-free survival and OS. ORR and the duration of response were also assessed.

Baseline characteristics were balanced across the three treatment groups. The median age was 61 years (range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 ≥5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 36% of patients had a baseline LDH level greater than ULN at study entry. Among patients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the three treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28- 8 pharmDx assay.

PFS results (with minimum follow up of 18 months) are shown in Figure 2 (all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour PD-L1 1% cut off).

Figure 2. Progression-free survival (CA209067):

Figure 3. Progression-free survival by PD-L1 expression: 5% cut off (CA209067):

Figure 4. Progression-free survival by PD-L1 expression: 1% cut off (CA209067):

The final OS analysis occurred when all patients had a minimum follow-up of 28 months. OS results at an additional analysis undertaken at a minimum follow-up of 36 months show outcomes consistent with the original analysis. OS results from this follow-up analysis are shown in Figure 5 (all randomised), Figure 6 (at the tumour PD-L1 1% cut off), and Table 10 (at the tumour PD-L1 5% cut off).

The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemic therapy was received by 31.8%, 44.3%, and 62.2% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1 therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 14.6%, 29.1%, and 44.1% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively.

Figure 5. Overall survival (CA209067) - Minimum follow-up of 36 months:

Figure 6. Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimum follow-up of 36 months:

Table 10. Summary of overall survival by PD-L1 expression: 5% cut off – CA209067 – Minimum follow-up of 36 months:

Minimum follow-up for the analysis of ORR was 28 months. Responses are summarised in Table 11.

Table 11. Objective response (CA209067):

Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR compared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and OS results at 28 months of follow-up were consistently demonstrated across subgroups of patients including baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases, and baseline LDH level. This observation was maintained with the OS results with a minimum follow-up of 36 months.

Among 128 patients who discontinued ipilimumab in combination with nivolumab due to adverse reaction after 18 months of follow-up, median PFS was 16.7 months (95% CI: 10.2, NA). Among 131 patients who discontinued the combination due to adverse reaction after 28 months of follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median OS was not reached.

Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumab regardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab and ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 11) after 28 months of follow-up, with a best overall response of complete response correlating to an improved survival rate.

After 28 months of follow-up, median durations of response for patients with tumour PD-L1 expression level ≥5% were not reached (range: 0+ - 31.6+) in the combination arm, not reached (range: 2.8 – 30.6+) in the nivolumab monotherapy arm and not reached (range: 1.4 – 30.6+) in the ipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached (range: 0+ - 33.3+) in the combination arm, not reached (range: 0+ - 32.3+) in the nivolumab monotherapy arm and 18.2 months (range: 0.0+ - 31.5+) in the ipilimumab monotherapy arm.

No clear cut off for PD-L1 expression can reliably be established when considering the relevant endpoints of tumour response and PFS and OS. Results from exploratory multivariate analyses identified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH, BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome.

Efficacy by BRAF status: After 18 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab in combination with nivolumab had a median PFS of 15.5 months (95% CI: 8.0, NA) and 11.3 months (95% CI: 8.3, 22.2), while those in the nivolumab monotherapy arm had a median PFS of 5.6 months (95% CI: 2.8, 9.3) and 7.1 months (95% CI: 4.9, 14.3), respectively. After 28 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab in combination with nivolumab had an ORR of 67.6% (95% CI: 57.7, 76.6; n=102) and 54.7% (95% CI: 47.8, 61.5; n=212), while those in the nivolumab monotherapy arm had an ORR of 36.7% (95% CI: 27.2, 47.1; n=98) and 48.2% (95% CI: 41.4, 55.0; n=218), respectively. After 28 months of follow-up, median OS was not reached in either of the nivolumab containing arms regardless of BRAF status. The OS HRs for ipilimumab in combination with nivolumab vs. nivolumab monotherapy were 0.71 (95% CI: 0.45, 1.13) for BRAF[V600] mutation-positive patients and 0.97 (95% CI: 0.74, 1.28) for BRAF wild-type patients.

Randomised phase 2 study of ipilimumab in combination with nivolumab and ipilimumab (CA209069)

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 61% (95% CI: 48.9, 72.4) in the combination arm (n=72) versus 11% (95% CI: 3.0, 25.4) for the ipilimumab arm (n=37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61% (95% CI: 49, 71), respectively, for the combination (n=73) and 53% (95% CI: 36, 68) and 44% (95% CI: 28, 60), respectively, for ipilimumab (n=37).

Renal Cell Carcinoma (RCC)

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. sunitinib (CA209214)

The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg for the treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study (CA209214). The study included patients (18 years or older) with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component. The primary efficacy population included those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status <80%, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal). This study included patients regardless of their tumour PD-L1 status. Patients with Karnofsky performance status <70% and patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients were stratified by IMDC prognostic score and region.

A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either ipilimumab 1 mg/kg (n=425) administered intravenously over 30 minutes in combination with nivolumab administered intravenously over 60 minutes every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.

Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 21-85) with 38% ≥65 years of age and 8% ≥75 years of age. The majority of patients were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 0.4 years in both the ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg and sunitinib groups. The median duration of treatment was 7.9 months (range: 1 day – 21.4+ months) in ipilimumab with nivolumab- treated patients and was 7.8 months (range: 1 days – 20.2+ months) in sunitinib-treated patients. Ipilimumab with nivolumab was continued beyond progression in 29% of patients.

The Kaplan-Meier curves for OS (with a minimum follow-up of 24 months) in intermediate/poor risk patients are shown in Figure 7.

Figure 7. Kaplan-Meier curves of OS in intermediate/poor risk patients (CA209214):

In intermediate/poor-risk patients, OS benefit was observed in the ipilimumab in combination with nivolumab arm vs. sunitinib regardless of tumour PD-L1 expression. Median OS for tumour PD-L1 expression ≥1% was not reached for ipilimumab in combination with nivolumab, and was 19.61 months in the sunitinib arm (HR=0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 expression <1%, the median OS was 34.7 months for the ipilimumab in combination with nivolumab and was 32.2 months in the sunitinib arm (HR=0.70; 95% CI: 0.54, 0.92).

CA209214 also randomised 249 favourable risk patients as per IMDC criteria to nivolumab plus ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the primary efficacy population. OS in favourable risk patients receiving nivolumab plus ipilimumab compared to sunitinib had a hazard ratio of 1.13 (95% CI: 0.64, 1.99; p=0.6710).

There are no data on the use of ipilimumab in combination with nivolumab in patients with only a non clear-cell histology in first line RCC.

Efficacy results for the intermediate/poor risk patients are shown in Table 12.

Table 12. Efficacy results in intermediate/poor risk patients (CA209214):

An updated OS analysis was performed when all patients had a minimum follow-up of 24 months (see figure 7). At the time of this analysis, the hazard ratio was 0.66; (99.8% CI 0.48-0.91) with 166/425 events in the combination arm and 209/422 events in the sunitinib arm. At 18 months, the OS rate was 74.3 (95% CI 69.8-78.2) for ipilimumab in combination with nivolumab and 59.9 (95% CI 54.9-64.5) for sunitinib. At 24 months, the OS rate was 66.5 (95% CI 61.8-70.9) for ipilimumab in combination with nivolumab and 52.9 (95% CI 47.9-57.7) for sunitinib.

Patients ≥75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and the combination of ipilimumab with nivolumab showed numerically less effect on OS (HR 0.97, 95% CI: 0.48, 1.95) in this subgroup versus the overall population. Because of the small size of this subgroup, no definitive conclusions can be drawn from these data.

Paediatric population

Study CA184070 was a multi-center, Phase 1, open-label, dose-escalation study of ipilimumab in paediatric patients ≥1 year to ≤21 years of age with measurable/evaluable, untreatable, relapsed or refractory solid malignant tumors without a curative option with standard therapy. The study enrolled 13 patients <12 of age and 20 patients ≥12 years of age. Ipilimumab was administered every 3 weeks for 4 doses and then every 12 weeks thereafter in the absence of dose limiting toxicity (DLT) and disease progression. The primary endpoints were safety and pharmacokinetics (PK). Of patients 12 years of age and older with advanced melanoma, ipilimumab 5 mg/kg was administered to three patients and ipilimumab 10 mg/kg was administered to two patients. Stable disease was achieved in two patients at the ipilimumab 5mg/kg dose, one with a duration of >22 months.

Study CA184178 was a non-randomized, multicenter, open-label Phase 2 study, in adolescent patients 12 to <18 years of age with previously treated or untreated, unresectable Stage III or Stage IV malignant melanoma. Ipilimumab was administered every 3 weeks for 4 doses. The primary efficacy endpoint was 1-year survival rate. Secondary efficacy endpoints of best overall response rate (BORR), stable disease (SD), disease control rate (DCR), and progression free survival (PFS) were based on mWHO criteria and determined by the investigator’s assessment. Overall survival (OS) was also evaluated. Tumor assessment was performed at Week 12. All patients were followed for at least 1 year. Ipilimumab 3 mg/kg was administered to four patients and ipilimumab 10 mg/kg was administered to eight patients. Most patients were male (58%) and white (92%). Median age was 15 years. Stable disease was achieved for 260 days in one patient on ipilimumab 3 mg/kg and approximately 14 months in one patient on ipilimumab 10 mg/kg. Two patients treated with ipilimumab 10 mg/kg experienced a partial response, one of which was a durable response for more than 1 year. Additional efficacy results are presented in Table 13.

Table 13. Efficacy Results in CA184178:

^a NE= not estimable