SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.
Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types.
Immune-related Adverse Events (irAEs) are commonly observed following treatment with ICIs. An association between irAEs and improved outcomes has been reported, among patients with malignant melanoma and lung cancer, treated with ICIs such as anti-CTLA-4 and anti-PD-1 antibodies. It however remains unclear whether immune-related Adverse Events (irAEs) indicate drug activity in patients treated with ICIs.
The European Organization for Research and Treatment of Cancer (EORTC) 1325/(KEYNOTE-054) trial is a randomized, double-blind, placebo-controlled Phase III study which enrolled 1019 patients with completely resected, Stage IIIA, IIIB or IIIC Melanoma. Patients were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV every three weeks (N=514) or placebo (N=505) as adjuvant therapy, for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. KEYTRUDA® 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.
This study met the Primary end point of Recurrence-Free Survival (RFS), in this high-risk Stage III melanoma patients. KEYTRUDA® was associated with significantly longer Recurrence-Free Survival (RFS) compared to placebo in the overall intent-to-treat population, with a 1-year RFS rate of 75.4% versus 61.0% respectively (HR for recurrence or death=0.57; P<0.001). This suggested that the risk of recurrence or death in the total population was 43% lower in the KEYTRUDA® group than in the placebo group.
The authors in this publication investigated the association between immune-related Adverse Events (irAEs) and Recurrence-Free Survival (RFS) in the KEYNOTE-054 clinical trial, adjusting for age, sex and stage of the disease and also investigated the influence of systemic steroid use on outcome. Of 1011 patients who received treatment with KEYTRUDA® therapy or placebo, 61.5% were men and 38.5% were women. About 25% were 65 years and older and 37% of patients were younger than 50 years. The onset of the first irAE occurred within the first 6 months of treatment for majority of the patients who experienced an irAE and the common irAEs included endocrine disorders such as hypothyroidism or hyperthyroidism, and vitiligo. The incidence of irAEs was 37.4% in the KEYTRUDA® group and 9% in the placebo group, and in each treatment group, the incidence of irAEs was similar for men and women, for younger and older patients, and across different disease stages.
Consistent with previously published results in the intent-to-treat population, a prolonged RFS was observed in the KEYTRUDA® group compared with the placebo group, among patients who started the treatment allocated at the time of randomization (HR=0.56). The occurrence of an irAE was associated with a longer RFS in the KEYTRUDA® group (HR=0.61; P=0.03), but not in the placebo group (HR=1.37; P=0.21). Compared with the placebo arm, the reduction in the hazard of recurrence or death was substantially higher (P=0.03) after the onset of an irAE (HR=0.37), than without or before the onset of an irAE (HR=0.62), in patients who started KEYTRUDA® treatment. Similar results were obtained in each sex group and when only endocrine AEs were considered. Steroid are known to be immune-suppressive and treatment with KEYTRUDA® was less effective when steroids were used after the onset of an irAE.
It was concluded from this secondary analysis that the occurrence of an irAE was associated with a longer Relapse-Free Survival, among patients treated with KEYTRUDA®.
Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo. A Secondary Analysis of a Randomized Clinical Trial. Eggermont AM, Kicinski M, Blank CU, et al. JAMA Oncol. 2020;6:519-527.
