Patients with high-risk stage II melanoma are at significant risk for recurrence after surgical resection. In contrast to stage III melanoma, adjuvant treatment options to lower the risk for distant metastases in this setting are limited. The phase III Keynote-716 trial, assesses adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma and demonstrates a significant reduction in the risk of disease recurrence or death compared with placebo in this patient population.
Current standard of care for patients after resection of high-risk stage II melanoma is observation. Unfortunately, patients with stage IIB and IIC melanoma are at high risk of disease recurrence and survival outcomes are similar to stage IIIA and IIIB melanoma. Pembrolizumab already demonstrated to prolong recurrence-free survival (RFS) and distant metastasis-free survival vs. placebo as adjuvant treatment for stage III melanoma with sustained RFS benefit. Building on this success, the phase III double-blind Keynote-716 trial now evaluates pembrolizumab vs. placebo in patients with resected AJCC-8 stage IIB or IIC melanoma.
Keynote-716 study design
Eligible patients were aged ≥12 years and had newly diagnosed, completely resected, high-risk cutaneous stage IIB or IIC melanoma with negative sentinel lymph node biopsy and an ECOG performance status of 0 or 1. In total, 976 patients were randomised (1:1) to pembrolizumab 200 mg (2 mg/kg for paediatric patients) or placebo Q3W for 17 cycles (up to 1 year). Randomisation was stratified by T-category 3b, 4a, 4b (adults) with a separate stratum for paediatric patients. The primary endpoint was recurrence-free survival (RFS) per investigator assessment.
Baseline patient and disease characteristics were well-balanced between treatment arms. The median age of study participants was approximately 60 years and 64% of patients had stage IIB melanoma. After a median follow-up of 14.4 months, pembrolizumab significantly prolonged the RFS compared to placebo (HR[95%CI]: 0.65[0.46-0.92], p= 0.00658; median not reached for both). In total, 54 patients (11.1%) in the pembrolizumab arm and 82 patients (16.8%) in the placebo arm had a recurrence, with 23 distant recurrence events in the pembrolizumab group as compared to almost double (38 events) in the placebo group. The 12-month RFS rate was 90.5% and 83.1% in the pembrolizumab and placebo arm, respectively. Recurrence-free survival favoured pembrolizumab in all key subgroups, including T-category, age, gender, race, ECOG performance status and geographic region.
Grade ≥3 any-cause adverse events (AEs) occurred in 25.9% vs. 17.1% of patients in the pembrolizumab vs. placebo group. Grade ≥3 drug-related AEs (TRAEs) were reported in 16.1% and 4.3% of patients, respectively. TRAEs led to study discontinuation in 15.3% of patients in the pembrolizumab arm and in 2.5% of patients in the placebo arm. No deaths due to TRAEs occurred in either arm. Immune-mediated AEs occurred in 36.2% vs. 8.4% of patients in the pembrolizumab and placebo arms, respectively. The most common adverse events of interest were hypothyroidism (15.7% vs. 3.5%) and hyperthyroidism (10.4% vs. 0.6%). Most were grade 1-2 in severity. In total, 18.6% of patients in the pembrolizumab arm had an adverse event of interest requiring hormonal management, including hypophysitis (2.1%), adrenal insufficiency (2.1%) and type 1 diabetes mellitus (0.4%). Global health status and quality of life scores were similar between treatment groups at all time points.
Adjuvant pembrolizumab was associated with a significant reduction in the risk of disease recurrence or death compared to placebo in patients with resected high-risk stage II melanoma. Importantly, the incidence of distant recurrences was lower in patients in the pembrolizumab vs. placebo arms. The safety profile of pembrolizumab was consistent with that previously defined and the quality of life was maintained with adjuvant pembrolizumab. Overall, pembrolizumab thus is an effective treatment option with a favourable benefit risk profile for patients with high-risk stage II melanoma.
Luke J, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Presented at ESMO 2021; Abstract LBA3_PR.