On September 19, 2020 Merck & Co., Inc., Kenilworth, N.J., U.S.A., known as MSD outside the United States and Canada, and the European Organisation for Research and Treatment of Cancer (EORTC) reported new and updated findings from the Phase 3 EORTC1325/KEYNOTE-054 trial evaluating KEYTRUDA, MSD’s anti-PD-1 therapy, as adjuvant therapy in resected, high-risk stage III melanoma (Press release, EORTC, SEP 19, 2020, View Source [SID1234565379]). Late-breaking, first-time study results showed that with 3.5 years of follow-up, adjuvant KEYTRUDA met the key secondary endpoint of distant metastasis-free survival (DMFS), reducing the risk of distant metastasis or death by 40% versus placebo (HR=0.60 [95% CI, 0.49-0.73]; p<0.001), with 3.5-year DMFS rates of 65.3% and 49.4%, respectively. In addition, KEYTRUDA demonstrated a sustained recurrence-free survival (RFS) benefit versus placebo across stage IIIA (>1 mm lymph node metastasis), IIIB and IIIC melanoma, with 3.5-year RFS rates of 59.8% for KEYTRUDA versus 41.4% for placebo (HR = 0.59 [95% CI, 0.49-0.70]; p<0.001). The RFS and DMFS benefits were observed across key subgroups, including disease stages (both according to AJCC-7 and AJCC-8), BRAF mutation status and PD-L1 expression.
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"Despite surgical intervention, patients diagnosed with high-risk stage III melanoma can experience disease recurrence, and for those with distant metastasis, they often face a significantly worse prognosis," said Alexander Eggermont, study chair, Chief Scientific Officer Princess Máxima Center, Utrecht, Netherlands. "These new and updated data, including first-time results for distant metastasis-free survival are significant, showing that adjuvant KEYTRUDA not only delayed recurrence but also delayed distant metastasis, further reinforcing the benefits of KEYTRUDA for these patients with stage III melanoma."
"In KEYNOTE-054, adjuvant treatment with KEYTRUDA also continued to demonstrate long-term improvements in the prevention of new disease compared to placebo, with nearly 60% of patients alive and recurrence-free after 3.5 years," said Dr. Scot Ebbinghaus, vice president, clinical research, MSD Research Laboratories. "Taken together with the new distant metastasis-free survival results shown in this trial, these data point to the important role KEYTRUDA plays in melanoma in the adjuvant setting and are encouraging for the evaluation of KEYTRUDA in earlier disease states in other tumor types."
These late-breaking data were presented as a proffered paper at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 on Saturday, Sept. 19 (Abstract #LBA46). As announced, data spanning more than 15 types of cancer will be presented from MSD’s broad oncology portfolio and investigational pipeline at the congress. A compendium of presentations and posters is available here.
KEYTRUDA is currently approved for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection in more than 70 countries based on the results from EORTC1325/KEYNOTE-054. Merck & Co., Inc., Kenilworth, N.J., U.S.A.’s broad clinical development program in melanoma and skin cancers is addressing areas of unmet need by investigating KEYTRUDA in earlier stages of disease and in combination with other anti-cancer therapies across multiple potential registration-enabling studies, including KEYNOTE-716, LEAP-003 and LEAP-004.
EORTC1325/KEYNOTE-054 Trial Design and Additional Subgroup Data (Abstract #LBA8)
EORTC1325/KEYNOTE-054 (ClinicalTrials.gov, NCT02362594) is a Phase 3, randomized, double-blind study sponsored by Merck & Co., Inc., Kenilworth, N.J., U.S.A. and conducted in collaboration with the EORTC designed to evaluate adjuvant therapy with KEYTRUDA compared versus placebo in patients with resected, high-risk melanoma (stage IIIA [>1 mm lymph node metastasis], IIIB and IIIC). The co-primary endpoints are RFS for all patients and RFS in patients whose tumors expressed PD-L1. Secondary endpoints include DMFS and overall survival (OS) in all patients and in patients whose tumors expressed PD-L1. Data from a three-year analysis of RFS were presented in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. In accordance with the trial protocol, the study is continuing in order to evaluate secondary endpoint of OS; however, upon documented recurrence, patients were eligible for crossover/re-challenge with KEYTRUDA.
Key Subgroup Analysis Results From EORTC1325/KEYNOTE-054
3.5-Year DMFS Rate, % DMFS, HR P-Value (Log Rank)*
PD-L1 Positive (n=853) KEYTRUDA 66.7% 0.61 (95% CI, 0.49-0.76) <0.001
Placebo 51.6%
PD-L1 Negative (n=116) KEYTRUDA 58.0% 0.49 (99% CI, 0.24-0.99) 0.008
Placebo 40.2%
With BRAF V600 E/K Mutation (n=440) KEYTRUDA 63.7% 0.53 (99% CI, 0.36-0.77) <0.001
Placebo 43.4%
Without BRAF Mutation (n=449) KEYTRUDA 62.1% 0.73 (99% CI, 0.50-1.07) 0.035
Placebo 51.4%
*Stratified by stage given at randomization
In addition, the DMFS benefit demonstrated with KEYTRUDA was similar in patients with AJCC-7 stage IIIA (HR=0.64), IIIB (HR=0.58) and IIIC (HR=0.61) melanoma. Adjuvant KEYTRUDA decreased the incidence of distant metastasis as a first recurrence by 43% (at 3.5 years: 24.9% versus 39.5%, HR= 0.57 [95% CI, 0.46-0.72]; p<0.001).
No new safety data were identified as part of the 42-month analysis. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with advanced melanoma. Grade 3-5 immune-related adverse events occurred in 7.7% of patients who received KEYTRUDA and 0.6% of patients who received placebo.