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Pembrolizumab vs Placebo as Adjuvant Therapy in Completely Resected Stage IIB or IIC Melanoma
TAKE-HOME MESSAGE
- The first and second interim analyses of the phase III KEYNOTE-716 trial assessed recurrence-free survival with pembrolizumab as adjuvant therapy in patients with completely resected, high-risk stage IIB or IIC melanoma. At the first and second interim analyses (median follow-up, 14.4 months and 20.9 months, respectively), pembrolizumab continued to significantly reduce the risk of disease recurrence or death compared with placebo, with a safety profile consistent with the known toxicity profile of the drug in the adjuvant setting.
- Adjuvant pembrolizumab for 1 year has become the standard of care for patients with stage IIB or IIC melanoma following complete resection. Overall survival data are awaited.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival.
METHODS
In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual.
FINDINGS
Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred.
INTERPRETATION
Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile.
Additional Info
Disclosure statements are available on the authors' profiles:
Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial
Lancet 2022 Mar 31;[EPub Ahead of Print], JJ Luke, P Rutkowski, P Queirolo, M Del Vecchio, J Mackiewicz, V Chiarion-Sileni, L de la Cruz Merino, MA Khattak, D Schadendorf, GV Long, PA Ascierto, M Mandala, F De Galitiis, A Haydon, R Dummer, JJ Grob, C Robert, MS Carlino, P Mohr, A Poklepovic, VK Sondak, RA Scolyer, JM Kirkwood, K Chen, SJ Diede, S Ahsan, N Ibrahim, AMM EggermontFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The KEYNOTE-716 trial by Luke et al is a practice-changing trial. Why?
It is the first trial to demonstrate the efficacy of modern drugs in the adjuvant treatment of patients with stage IIB/C melanoma. The authors demonstrated an estimated 18-month relapse-free survival (RFS) benefit of 9% (86% vs 77%; HR, 0.61) after a median follow-up of 20.9 months. This has led to an approval by the FDA and will likely make pembrolizumab a standard-of-care treatment option from now on for patients with stage IIB/C melanoma.
Although the hazard ratio is very similar to what has been previously shown for stage III melanoma, this merely demonstrates the relative risk reduction. Unsurprisingly, the relative risk reduction for pembrolizumab is stable across different stages of disease. The important issue here is the absolute risk reduction, which will differ for stage II compared with stage III. Since the a priori risk was lower in stage II, the absolute benefit will be lower.
A critical review of this data suggests that the number needed to treat is 11 to prevent 1 recurrence (9% RFS benefit), but the number needed to harm is 6.25 to prevent 1 recurrence (16% grade 3/4 treatment-related adverse events [AEs]). Many of these AEs are endocrinopathies, which are most often chronic or permanent, and this is without taking into account the financial toxicity of 1 year of pembrolizumab. Moreover, half of the recurrences are local, satellite/in-transit, and/or nodal recurrences that could be salvaged with a simple surgical procedure. Thus, the number to treat to prevent 1 distant recurrence is 22. In other words, we, as a society and together with payers, will need to thoroughly discuss the risk/benefit ratio of this new standard-of-care treatment and the costs to society. Looking at a hazard ratio and P-value alone is not sufficient, and patients will require adequate consultation to discuss the absolute risk-reduction benefit versus the risks.
Currently, another trial is evaluating adjuvant anti–PD-1 immunotherapy in stage IIB/C melanoma: the CheckMate 76K study, which is assessing the use of nivolumab and is likely to report the first results in 2022 (NCT04099251). Additionally, the phase III COLUMBUS trial has recently started to examine the value of adjuvant targeted therapy with encorafenib and binimetinib versus placebo in BRAF V600E/K–mutant stage IIB/C melanoma (NCT05270044). All of these trials have simply used the American Joint Committee on Cancer (AJCC) staging system as an inclusion criterion for their trials. However, in the future, there is a need to find adequate biomarkers, for example, gene expression profiles, including DecisionDx, MelaGenix, and Merlin to be able to truly select high-risk stage I/II patients who might benefit from adjuvant therapy with a better number needed to treat ratio than simply using AJCC staging.
In conclusion, as is often the case with an excellent phase III clinical trial, it answers a question; however, it creates many new questions. Adjuvant pembrolizumab for treating patients with stage IIB/C melanoma is practice-changing and has started the next era of melanoma treatment.