Ipilimumab

The open-label, three-arm, North American Intergroup trial E1609 (NCT01274338) compared two doses of ipilimumab with HDI as adjuvant therapy in high-risk patients with melanoma.[23] A total of 1,670 patients with resected disease (defined by the American Joint Committee on Cancer, 7th edition, as stage IIIB, IIIC, M1a, or M1b) were randomly assigned (1:1:1) to ipi3 or ipi10 every 3 weeks for four doses (induction), followed by the same dose every 12 weeks for four doses (maintenance), or HDI 20 million units/m2 per day, 5 days per week for 4 weeks (induction), followed by 10 million units/m2 daily subcutaneously every other day, 3 days per week for 48 weeks (maintenance).[23][Level of evidence A1] The trial was designed with two coprimary end points, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03−86.6). Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death. The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because the CheckMate 238 trial demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.

The open-label, three-arm, North American Intergroup trial E1609 (NCT01274338) compared two doses of ipilimumab with HDI as adjuvant therapy in high-risk patients with melanoma.[23] A total of 1,670 patients with resected disease (defined by the American Joint Committee on Cancer, 7th edition, as stage IIIB, IIIC, M1a, or M1b) were randomly assigned (1:1:1) to ipi3 or ipi10 every 3 weeks for four doses (induction), followed by the same dose every 12 weeks for four doses (maintenance), or HDI 20 million units/m2 per day, 5 days per week for 4 weeks (induction), followed by 10 million units/m2 daily subcutaneously every other day, 3 days per week for 48 weeks (maintenance).[23][Level of evidence A1] The trial was designed with two coprimary end points, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03−86.6). Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death. The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because the CheckMate 238 trial demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.

Ipi3 significantly improved OS compared with HDI (HR, 0.78; 95% repeated CI, 0.61−0.99; P = .044), but not RFS (HR, 0.85; 95% CI, 0.66−1.09; P = .065).

The open-label, three-arm, North American Intergroup trial E1609 (NCT01274338) compared two doses of ipilimumab with HDI as adjuvant therapy in high-risk patients with melanoma.[23] A total of 1,670 patients with resected disease (defined by the American Joint Committee on Cancer, 7th edition, as stage IIIB, IIIC, M1a, or M1b) were randomly assigned (1:1:1) to ipi3 or ipi10 every 3 weeks for four doses (induction), followed by the same dose every 12 weeks for four doses (maintenance), or HDI 20 million units/m2 per day, 5 days per week for 4 weeks (induction), followed by 10 million units/m2 daily subcutaneously every other day, 3 days per week for 48 weeks (maintenance).[23][Level of evidence A1] The trial was designed with two coprimary end points, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03−86.6). Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death. The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because the CheckMate 238 trial demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.

Ipi10 did not significantly improve OS or RFS compared with HDI (HR, 0.88; 95.6% CI, 0.69−1.12 and exploratory HR, 0.84; 99.4% CI, 0.65−1.09, respectively).

The open-label, three-arm, North American Intergroup trial E1609 (NCT01274338) compared two doses of ipilimumab with HDI as adjuvant therapy in high-risk patients with melanoma.[23] A total of 1,670 patients with resected disease (defined by the American Joint Committee on Cancer, 7th edition, as stage IIIB, IIIC, M1a, or M1b) were randomly assigned (1:1:1) to ipi3 or ipi10 every 3 weeks for four doses (induction), followed by the same dose every 12 weeks for four doses (maintenance), or HDI 20 million units/m2 per day, 5 days per week for 4 weeks (induction), followed by 10 million units/m2 daily subcutaneously every other day, 3 days per week for 48 weeks (maintenance).[23][Level of evidence A1] The trial was designed with two coprimary end points, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03−86.6). Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death. The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because the CheckMate 238 trial demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.

Salvage treatments were used in 69.7% of patients after ipi3, 51.6% of patients after ipi10, and 86.2% of patients after HDI.

The open-label, three-arm, North American Intergroup trial E1609 (NCT01274338) compared two doses of ipilimumab with HDI as adjuvant therapy in high-risk patients with melanoma.[23] A total of 1,670 patients with resected disease (defined by the American Joint Committee on Cancer, 7th edition, as stage IIIB, IIIC, M1a, or M1b) were randomly assigned (1:1:1) to ipi3 or ipi10 every 3 weeks for four doses (induction), followed by the same dose every 12 weeks for four doses (maintenance), or HDI 20 million units/m2 per day, 5 days per week for 4 weeks (induction), followed by 10 million units/m2 daily subcutaneously every other day, 3 days per week for 48 weeks (maintenance).[23][Level of evidence A1] The trial was designed with two coprimary end points, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03−86.6). Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death. The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because the CheckMate 238 trial demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.

Treatment-related discontinuations occurred in 34.9% of the ipi3 group and in 54.1% of the ipi10 group.

The open-label, three-arm, North American Intergroup trial E1609 (NCT01274338) compared two doses of ipilimumab with HDI as adjuvant therapy in high-risk patients with melanoma.[23] A total of 1,670 patients with resected disease (defined by the American Joint Committee on Cancer, 7th edition, as stage IIIB, IIIC, M1a, or M1b) were randomly assigned (1:1:1) to ipi3 or ipi10 every 3 weeks for four doses (induction), followed by the same dose every 12 weeks for four doses (maintenance), or HDI 20 million units/m2 per day, 5 days per week for 4 weeks (induction), followed by 10 million units/m2 daily subcutaneously every other day, 3 days per week for 48 weeks (maintenance).[23][Level of evidence A1] The trial was designed with two coprimary end points, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03−86.6). Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death. The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because the CheckMate 238 trial demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.

Three possibly treatment-related deaths occurred in the ipi3 group, five in the ipi10 group, and two in the HDI group.

In a multinational double-blind trial (EORTC 18071 [NCT00636168]), patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive either ipilimumab or placebo.[30][Level of evidence B1] Exclusion criteria comprised patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score higher than 1. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary end point was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.An updated analysis was performed at a median follow-up of 5.3 years.[22]

In a multinational double-blind trial (EORTC 18071 [NCT00636168]), patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive either ipilimumab or placebo.[30][Level of evidence B1] Exclusion criteria comprised patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score higher than 1. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary end point was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.An updated analysis was performed at a median follow-up of 5.3 years.[22]

A total of 951 patients were enrolled (475 patients to the ipilimumab arm and 476 patients to the placebo arm). The median age was 51 years, and 94% of the patients had a PS of 0.

In a multinational double-blind trial (EORTC 18071 [NCT00636168]), patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive either ipilimumab or placebo.[30][Level of evidence B1] Exclusion criteria comprised patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score higher than 1. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary end point was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.An updated analysis was performed at a median follow-up of 5.3 years.[22]

At a median follow-up of 2.7 years, there were 528 RFS events: 234 in the ipilimumab group (49%; 220 recurrences, 14 deaths) and 294 in the placebo group (62%; 289 recurrences, 5 deaths). Median RFS was 26 months for the ipilimumab group (95% CI, 19–39) versus 17 months for the placebo group (95% CI, 13–22). The HR was 0.75 (95% CI, 0.64–0.90; P < .002). The effect of ipilimumab was consistent across subgroups.

In a multinational double-blind trial (EORTC 18071 [NCT00636168]), patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive either ipilimumab or placebo.[30][Level of evidence B1] Exclusion criteria comprised patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score higher than 1. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary end point was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.An updated analysis was performed at a median follow-up of 5.3 years.[22]

Ipilimumab was discontinued because of adverse events in 52% of the patients. Patients received ipilimumab for a median of four doses; 36% of patients in the ipilimumab group stayed on treatment for more than 6 months, and 26% stayed on treatment for more than 1 year. Five patients died from drug-related events: three secondary to colitis, one with myocarditis, and one of multiorgan failure with Guillain-Barré syndrome. The most common adverse events were gastrointestinal, hepatic, and endocrine related and included rash, fatigue, and headache.

In a multinational double-blind trial (EORTC 18071 [NCT00636168]), patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive either ipilimumab or placebo.[30][Level of evidence B1] Exclusion criteria comprised patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score higher than 1. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary end point was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.An updated analysis was performed at a median follow-up of 5.3 years.[22]

The 5-year RFS rate was 40.8% in patients treated with ipilimumab and 30.3% in patients who received the placebo (HR recurrence or death, 0.76; 95% CI, 0.64–0.89; P < .001). The median RFS rate was 27.6% in patients treated with ipilimumab and 17.1% in patients who received the placebo.

In a multinational double-blind trial (EORTC 18071 [NCT00636168]), patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive either ipilimumab or placebo.[30][Level of evidence B1] Exclusion criteria comprised patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score higher than 1. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary end point was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.An updated analysis was performed at a median follow-up of 5.3 years.[22]

The 5-year OS rate, a secondary end point, was 65.4% in patients treated with ipilimumab versus 54.4% in patients who received the placebo (HRdeath, 0.72; 95.1% CI, 0.58–0.88; P = .001).