Adjuvant Pembrolizumab for High-Risk Stage II Melanoma: Efficacy and Safety Examined

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Adjuvant pembrolizumab reduced the risk of disease recurrence in adults and children aged 12 years and older with high-risk stage II melanoma vs placebo, according to a late-breaking interim analysis of the phase III KEYNOTE-716 trial presented by Jason J. Luke, MD, and colleagues at the European Society for Medical Oncology (ESMO) Congress 2021 (Abstract LBA3_PR). At a median follow-up of 14.4 months, pembrolizumab significantly reduced the risk of recurrence by 35% (P = .00658).

The current standard of care for completely resected stage II melanoma is observation (not adjuvant therapy). Patients with stage IIB and IIC melanoma have a deep or ulcerated primary tumor and are at the same risk of disease recurrence and death as those with stage IIIA and IIIB melanoma. These interim results of KEYNOTE-716 are poised to upend the current approach and suggest that adjuvant immunotherapy should be a new standard of care for high-risk stage II melanoma (if approved for that indication).

Jason J. Luke, MD

Jason J. Luke, MD

Omid Hamid, MD

Omid Hamid, MD

“The U.S. Food and Drug Administration is currently examining pembrolizumab for the adjuvant treatment of stage IIB and IIC melanoma, which, if approved, means we would be introducing immunotherapy earlier in the patient journey. This has the potential to spare patients recurrence and metastases. It is important to note that the trial included not just adults but also children and adolescents aged 12 years and older,” commented invited discussant Omid Hamid, MD, Chair of the ESMO Congress’ melanoma and other skin cancers track and Chief of Research/Immuno-Oncology at The Angeles Clinic & Research Institute, a Cedars-Sinai affiliate. Dr. Hamid was not involved in KEYNOTE-716.

“These results are set to substantially change the population of patients with melanoma who get treated in the adjuvant setting. Historically, we have defined high-risk patients after surgery as those with lymph node–positive disease. This trial suggests that the depth of the primary tumor and the ulceration status provide substantial information about the risk of recurrence and metastases and whether or not we might pursue adjuvant therapy. In the future, we will need to reconsider how we incorporate sentinel lymph node biopsy into our risk stratification,” stated lead author Dr. Luke, Director of the Cancer Immunotherapeutics Center at the University of Pittsburgh Hillman Cancer Center.

Study Details

KEYNOTE-716 is the first randomized phase III trial of an anti–PD-1 therapy in resected stage II melanoma, Dr. Luke said. The study randomly assigned 976 patients with completely resected cutaneous stage IIB or IIC melanoma and no lymph node involvement to receive immunotherapy with pembrolizumab vs placebo, and treatment was continued for up to 1 year. Part 2 of the two-part study has an open-label design and includes patients who experienced disease recurrence on pembrolizumab or placebo and are slated to receive up to 35 additional cycles of pembrolizumab. Part 2 data are not yet mature.

At the interim analysis of part 1, 54 (11.1%) of patients on pembrolizumab experienced a disease recurrence vs 82 (16.8%) of those receiving placebo. Distant recurrences were numerically lower with immunotherapy as well: 23 events (4.7%) vs 38 events (7.8%), respectively.

The 12-month recurrence-free survival rate was 90.5% for pembrolizumab vs 83.1% for placebo. Median recurrence-free survival was not reached in either group at this relatively early time point.

“There has been a belief that early-stage melanoma doesn’t recur very fast and that these patients don’t develop metastatic disease. These data clearly disprove that and show that patients with high-risk stage II melanoma recur quickly and distantly, just the same as patients with stage IIIA and IIIB. Treatment with pembrolizumab reduced recurrence in a meaningful and statistically significant way, indicating that stage II patients should be offered adjuvant therapy,” Dr. Luke stated.

Dr. Luke also noted that other drugs used for adjuvant therapy of melanoma (ie, high-dose interferon and ipilimumab) lead to severe adverse events in more than 50% of patients and have been withheld for early-stage patients due to tolerability issues.

“Anti–PD-1 therapy is more attractive from a risk/benefit point of view, and given results of this trial, I think we should be offering this to our patients [with high-risk stage II disease],” he said.


  • The 12-month recurrence-free survival rate was 90.5% for pembrolizumab vs 83.1% for placebo.
  • At the interim analysis of part 1, 54 (11.1%) of patients on pembrolizumab experienced a disease recurrence vs 82 (16.8%) of those receiving placebo.

Grade 3 or 4 any-cause events occurred in 125 (25.9%) patients in the pembrolizumab group vs 83 (17.1%) in the placebo group. Grade 3 or 4 treatment-related adverse events were reported in 78 (16.1%) of patients receiving pembrolizumab and 83 (17.1%) patients receiving placebo. Discontinuations due to drug-related adverse events were reported in 74 (15.3%) pembrolizumab-treated patients vs 12 (2.5%) placebo-treated patients.

No deaths due to any cause or treatment-related causes were attributed to pembrolizumab, whereas four deaths due to any cause occurred with placebo. Immune-mediated events attributable to pembrolizumab were mostly grades 1 and 2. The most common immune-mediated adverse events were hypothyroidism (15.7% vs 3.5%, respectively) and hyperthyroidism (10.4% vs 0.6%).

The study authors concluded, “Adjuvant pembrolizumab 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 recurrence-free survival and a favorable benefit-risk profile.”

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