KEYNOTE-054: Adjuvant pembrolizumab beat placebo in high-risk resected melanoma

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

 

Like the EORTC 18071 trial, KEYNOTE-054 (EORTC 1325) enrolled adults with completely resected stage III cutaneous melanoma. Patients with stage IIIa disease were high-risk, with sentinel node tumors exceeding 1-mm diameter per Rotterdam criteria. Stage IIIB or IIIC patients had no in-transit metastases. In all, 1,015 patients received up to 18 doses of pembrolizumab (200 mg infused every 3 weeks) or placebo for approximately 1 year. Relapsers could either repeat pembrolizumab or cross over to the pembrolizumab arm.

Treatment-related adverse events occurred in 78% of pembrolizumab patients and 66% of placebo recipients. As in prior studies, the most frequent adverse effects of pembrolizumab included fatigue or asthenia (37%), skin reactions (28%), diarrhea (19%), arthralgia (12%), nausea (11%), and dyspnea (6%). Rates of immune-related adverse events of any grade were 37% versus 9%. The most common immune-related adverse event was endocrinopathy (23%), specifically hypothyroidism (14%) and hyperthyroidism (10%). Grade 3 or higher toxicities affected 15% of pembrolizumab recipients and most often consisted of colitis (2%), endocrine disorders (1.8%), or hepatobiliary disorders (1.4%). Myositis caused the only pembrolizumab-related death.

Patients and clinicians await KEYNOTE-054 readouts on distant metastasis-free survival and overall survival. In past trials of adjuvant interferon alfa or ipilimumab for high-risk melanoma, RFS and overall survival closely correlated, Dr. Eggermont noted. KEYNOTE-54 can be expected to produce similar findings unless post-relapse therapy – including crossover to the pembrolizumab arm – narrows the survival advantage of adjuvant treatment, he added.

Merck makes pembrolizumab and funded the trial. Dr. Eggermont disclosed ties to Actelion, Agenus, Bayer, BMS, Incyte, ISA Pharmaceuticals, HalioDX, Merck-Serono, MSD, Nektar, Novartis, Pfizer, and Sanofi outside the submitted work.

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

 

Like the EORTC 18071 trial, KEYNOTE-054 (EORTC 1325) enrolled adults with completely resected stage III cutaneous melanoma. Patients with stage IIIa disease were high-risk, with sentinel node tumors exceeding 1-mm diameter per Rotterdam criteria. Stage IIIB or IIIC patients had no in-transit metastases. In all, 1,015 patients received up to 18 doses of pembrolizumab (200 mg infused every 3 weeks) or placebo for approximately 1 year. Relapsers could either repeat pembrolizumab or cross over to the pembrolizumab arm.

Treatment-related adverse events occurred in 78% of pembrolizumab patients and 66% of placebo recipients. As in prior studies, the most frequent adverse effects of pembrolizumab included fatigue or asthenia (37%), skin reactions (28%), diarrhea (19%), arthralgia (12%), nausea (11%), and dyspnea (6%). Rates of immune-related adverse events of any grade were 37% versus 9%. The most common immune-related adverse event was endocrinopathy (23%), specifically hypothyroidism (14%) and hyperthyroidism (10%). Grade 3 or higher toxicities affected 15% of pembrolizumab recipients and most often consisted of colitis (2%), endocrine disorders (1.8%), or hepatobiliary disorders (1.4%). Myositis caused the only pembrolizumab-related death.

Patients and clinicians await KEYNOTE-054 readouts on distant metastasis-free survival and overall survival. In past trials of adjuvant interferon alfa or ipilimumab for high-risk melanoma, RFS and overall survival closely correlated, Dr. Eggermont noted. KEYNOTE-54 can be expected to produce similar findings unless post-relapse therapy – including crossover to the pembrolizumab arm – narrows the survival advantage of adjuvant treatment, he added.

Merck makes pembrolizumab and funded the trial. Dr. Eggermont disclosed ties to Actelion, Agenus, Bayer, BMS, Incyte, ISA Pharmaceuticals, HalioDX, Merck-Serono, MSD, Nektar, Novartis, Pfizer, and Sanofi outside the submitted work.

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

 

Like the EORTC 18071 trial, KEYNOTE-054 (EORTC 1325) enrolled adults with completely resected stage III cutaneous melanoma. Patients with stage IIIa disease were high-risk, with sentinel node tumors exceeding 1-mm diameter per Rotterdam criteria. Stage IIIB or IIIC patients had no in-transit metastases. In all, 1,015 patients received up to 18 doses of pembrolizumab (200 mg infused every 3 weeks) or placebo for approximately 1 year. Relapsers could either repeat pembrolizumab or cross over to the pembrolizumab arm.

Treatment-related adverse events occurred in 78% of pembrolizumab patients and 66% of placebo recipients. As in prior studies, the most frequent adverse effects of pembrolizumab included fatigue or asthenia (37%), skin reactions (28%), diarrhea (19%), arthralgia (12%), nausea (11%), and dyspnea (6%). Rates of immune-related adverse events of any grade were 37% versus 9%. The most common immune-related adverse event was endocrinopathy (23%), specifically hypothyroidism (14%) and hyperthyroidism (10%). Grade 3 or higher toxicities affected 15% of pembrolizumab recipients and most often consisted of colitis (2%), endocrine disorders (1.8%), or hepatobiliary disorders (1.4%). Myositis caused the only pembrolizumab-related death.

Patients and clinicians await KEYNOTE-054 readouts on distant metastasis-free survival and overall survival. In past trials of adjuvant interferon alfa or ipilimumab for high-risk melanoma, RFS and overall survival closely correlated, Dr. Eggermont noted. KEYNOTE-54 can be expected to produce similar findings unless post-relapse therapy – including crossover to the pembrolizumab arm – narrows the survival advantage of adjuvant treatment, he added.

Merck makes pembrolizumab and funded the trial. Dr. Eggermont disclosed ties to Actelion, Agenus, Bayer, BMS, Incyte, ISA Pharmaceuticals, HalioDX, Merck-Serono, MSD, Nektar, Novartis, Pfizer, and Sanofi outside the submitted work.

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.