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Study Overview
Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.
Design. International randomized phase 3 trial.
Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.
Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.
Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.
Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.
Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).
Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.
Commentary
Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].
In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.
Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.
Applications for Clinical Practice
The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.
—Daniel Isaac, DO, MS
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–55.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35.
Study Overview
Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.
Design. International randomized phase 3 trial.
Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.
Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.
Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.
Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.
Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).
Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.
Commentary
Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].
In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.
Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.
Applications for Clinical Practice
The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.
—Daniel Isaac, DO, MS
Study Overview
Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.
Design. International randomized phase 3 trial.
Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.
Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.
Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.
Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.
Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).
Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.
Commentary
Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].
In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.
Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.
Applications for Clinical Practice
The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.
—Daniel Isaac, DO, MS
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–55.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35.
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–55.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35.