1. In the pembrolizumab arm, distant metastasis-free survival was significantly improved and the risk of recurrence remained lower than the placebo group.

2. Treatment-related adverse events of grades 3 or higher occurred more frequently in the pembrolizumab arm, with the most common in both arms the being hypertension, diarrhea, autoimmune hepatitis, rash and increased lipase.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Immune checkpoint inhibitors (ICIs) have become the standard adjuvant treatment for advanced stage melanoma patients. This study explored the efficacy and safety of adjuvant pembrolizumab (a programmed cell death 1 inhibitor) compared to placebo in stage IIB or IIC, completely resected melanoma patients; this is the 3rd interim analysis of the study at a median 27.4 month follow-up. Median distant metastasis-free survival (MFS) was not reached in either arm but pembrolizumab significantly improved distant MFS versus placebo. Pembrolizumab also provided a sustained reduction in the risk of recurrence versus placebo. Overall survival data is still immature at the time of this interim analysis. Treatment-related adverse events (TRAEs) of grades 3 or higher occurred more frequently in the pembrolizumab arm, with the most common in both arms the being hypertension, diarrhea, autoimmune hepatitis, rash and increased lipase. Limitations to this study include its crossover design but speaks to the robust nature of the benefit. The strengths of this study are its limited bias given the design and that results of the first two interim analyses were confirmed with a longer follow-up. Overall, adjuvant pembrolizumab is a strong consideration for adjuvant treatment option for stage IIB or IIC completely resected melanoma patients and the expectation is that for this disease population, it will be the standard of care.

Click to read the study in The Lancet Oncology

Relevant Reading: Immune checkpoint inhibitors: therapeutic advances in melanoma

In-Depth [randomized control trial]: This phase III trial randomly assigned 976 patients with stage IIB or IIC completely resected melanoma to receive either adjuvant pembrolizumab or placebo; 487 were in the pembrolizumab arm and 489 were in the placebo arm. At a 95% confidence interval [CI], median distant MFS was not reached in either arm. In the pembrolizumab arm, distant MFS was significantly improved versus placebo (hazard ratio [HR], 0.64; 95% CI, 0.47 to 0.88; P=0.0029) and there was continued reduction in the risk of disease recurrence (HR, 0.64; 95% CI, 0.50 to 0.84). Occurrence of TRAEs of grades 3 or higher was 17% in the pembrolizumab arm and 5% in the placebo arm. The most common TRAEs were hypertension (3% of patients in pembrolizumab arm vs 4% of patients in placebo arm), diarrhea (2% vs <1%), autoimmune hepatitis (1% vs <1%), rash (1% vs <1%) and increased lipase (1% vs 2%). Overall, adjuvant pembrolizumab improved distant metastasis-free survival and sustained reduction in the risk of disease recurrence in stage IIB or IIC completely resected melanoma patients.

Image: PD

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