SUMMARY: The American Cancer Society’s estimates that for 2021, about 106,110 new cases of melanoma will be diagnosed in the United States and 7,180 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.
Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. The current standard of care for patients following resection of high-risk Stage II disease is observation, even though patients with Stage IIB and IIC disease presenting with high-risk features (depth of invasion, T-category, ulceration) have 5 and 10 year melanoma-specific survival similar to that of patients with Stage IIIA and IIIB disease.
KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. The FDA in 2019, approved KEYTRUDA® for the adjuvant treatment of patients with melanoma, with involvement of lymph node(s) following complete resection (Stage III). The present study was conducted to evaluate the role of adjuvant immunotherapy in patients with high risk Stage II melanoma.
KEYNOTE-716 is a randomized, double-blind, Phase III trial, in which 976 patients aged 12 years or older, with completely resected cutaneous Stage IIB or IIC melanoma, and no lymph node involvement, were randomly assigned 1:1 to receive KEYTRUDA® 200 mg (2 mg/kg for pediatric patients) or placebo, every 3 weeks for 17 cycles (up to 1 year). Patients were stratified by T category 3b, 4a, 4b (adults) and with a separate stratum for pediatric patients. Approximately 65% had Stage IIB disease and 35% had Stage IIC disease. There was no prespecified analysis for PD-L1 or BRAF status in this study, as there was inconsistent and small amounts of tissue available for testing. This was the first part (Part 1) of this double-blind study. The Primary endpoint was Relapse Free Survival (RFS) per investigator assessment, and Safety. The second part (Part 2) of this study was open-label design, and adults and pediatric patients were eligible to receive up to 35 additional cycles of treatment, only if they had recurrence after receiving the placebo or completed 17 cycles of KEYTRUDA®. Patients in the KEYTRUDA® group who experienced disease recurrence within 6 months of completing the treatment were excluded from Part 2 of the study. Secondary end points included Distant Metastasis-Free Survival, Overall Survival (OS) and Quality of Life. The researchers herein reported the results at the interim analysis of Part 1 of this study, and Part 2 data are not yet mature.
At median follow up of 14.4 months, the study met its Primary end point of RFS at the first protocol-specified analysis. KEYTRUDA® significantly prolonged RFS compared to placebo (HR=0.65; P=0.00658). At the time of this analysis, 11.1% of patients on KEYTRUDA® had a recurrence, compared to 16.8% of those receiving placebo. The 12-month RFS rate was 90.5% for KEYTRUDA® versus 83.1% for placebo. Median RFS was Not Reached in either group at the time of this analysis. Quality of Life scores were similar between the KEYTRUDA® and placebo groups at all time points.
It was concluded that adjuvant KEYTRUDA® for resected Stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo, and was associated with significantly prolonged Relapse Free Survival and a favorable benefit-risk profile. KEYNOTE-716 is the first randomized Phase III trial of an anti-PD-1 therapy in resected Stage II melanoma, and these findings represent an important milestone for this patient group.
LBA3_PR – 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. Luke JJ, Rutkowski P, Queirolo P, et al. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741.