New results for adjuvant pembrolizumab in resected stage IIB and IIC melanoma suggest it will be become the standard treatment for high-risk early stage melanoma patients, according to Australian oncologists.
Findings from the KEYNOTE-716 trial presented at ESMO 2021 showed that it decreased the risk of disease recurrence or death by 35% compared with placebo and was associated with significantly prolonged recurrence-free survival and a favourable benefit-risk profile.
In the study, 976 patients with complete resection of cutaneous stage IIB or IIC melanoma and no lymph node involvement were randomly allocated to treatment with the PD-1 inhibitor pembrolizumab or placebo for up to one year.
At a median follow-up of 14.4 months, pembrolizumab significantly prolonged recurrence-free survival compared to placebo, with a hazard ratio of 0.65. Rates of recurrent were 11.1% for pembrolizumab vs 16.8% for plascebo, with almost halving of distant recurrence events in the pembrolizumab group (23) vs placebo (38) group.
The 12-month recurrence-free survival rate was 90.5% vs 83.1%.
Drug-related serious adverse events (Grade ≥3) occurred in 16.1% vs 4.3% patients respectively, and 15.3% vs 2.5% discontinued due to a drug-related adverse event.
Study investigator Dr Jason Luke, Director, Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, Pittsburgh, told the Congress that the results are likely to substantially change the population of melanoma patients 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 tumour and the ulceration status provide substantial information about the risk of recurrence and metastases and whether or not we might pursue adjuvant therapy. In future we will need to reconsider how we incorporate sentinel lymph node biopsy into our risk stratification.”
Dr Luke said 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 that in a meaningful and statistically significant way, indicating that these stage II patients should be offered adjuvant therapy.
Study co-investigator Professor Georgina Long, Co-Medical Director of Melanoma Institute Australia and of The University of Sydney, noted that there are currently no immunotherapy drugs approved for use in Stage II melanoma patients in Australia.
‘These exciting clinical trial results are strong evidence to support approval for this immunotherapy to become standard treatment for high-risk Stage II patients in Australia,” she said.
The US Food and Drug Administration (FDA) is currently evaluating pembrolizumab for the adjuvant treatment of stage IIB and IIC melanoma, according to Dr Omid Hamid, Chief of Research/Immuno-Oncology, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles.
“If approved [this] 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,” he told the Congress.
Dr Hamid suggested that the dose frequency and duration of adjuvant therapy in stage II B/C melanoma should be evaluated in other trials.
“Studies of adjuvant therapy in other stage II solid tumours have suggested that a shorter time course of therapy can provide the best risk/benefit ratio – although these were not immunotherapies. Patients in KEYNOTE-716 were treated for one year and while the incidence of grade 3 or 4 toxicity was minimal, side-effects could potentially have a significant impact on the lifestyle of these patients,” he said.
He added that longer follow-up was required to find out if there is an overall survival benefit with anti-PD-1 therapy in these patients.
“We also need to determine what giving adjuvant anti-PD-1 therapy in stage II B/C means for stage III patients who recur and would currently receive this treatment … I foresee that some of the regimens we now use in the metastatic setting may move up earlier in stage III disease. Ongoing clinical trials are examining novel combinations in the stage III setting – for example, VEGF targeted therapies or pegylated IL-2 or anti-LAG-3 antibody plus anti-PD-1 therapy – versus standard single agent anti-PD-1 therapy.”