2018-12-21| Trials & Approvals

European approval of Pembrolizumab for resected Stage III melanoma – KN-54 excerpts

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By Ajay V. Patil, PhD

Melanoma – Europe and Worldwide

Following the trend of last four years this year is expected to see over 287,000 new melanoma cases and over 60,000 deaths from the disease worldwide. In Europe, the five-year survival rate for advanced or metastatic melanoma is estimated to be about 5-22 percent. Complete resection surgery is the dependable treatment for malignant melanoma patients but recurrence of melanoma in patients with complete tumor resection is a common trend and reliable therapies for this section of patient are in development.

Merck & Co.’s anti-PD-1 therapy Pembrolizumab have been approved by European Commission for the adjuvant treatment of adults with stage III melanoma and lymph node involvement who have undergone complete resection. This approval was based on Phase III study EORTC1325 / KEYNOTE-054.


In a double blind, multicenter, randomized trial, completely resected stage III melanoma patients were recruited. Through randomization 514 patients received 200 mg of pembrolizumab and 505 patients received placebo; intravenously every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxic effects occurred. Primary endpoints of the study were ‘recurrence free survival in intention to treat population and in subgroup of patients that was positive for PD-L1 expression.

First Evaluation

In the intention-to-treat analysis, recurrence-free survival was 75.4% at 1 year for pembrolizumab vs 61% for placebo. At 18 months, recurrence-free survival was 71.4% for pembrolizumab compared to 53.2%, for placebo — a 43% reduction in recurrence favoring pembrolizumab.

In PD-L1–positive patients, the 1-year recurrence-free survival rate was 77.1% vs 62.6%, respectively; At 18 months, 46% improvement was observed in pembrolizumab group.

In PD-L1–negative patients, the 1-year rate of recurrence-free survival was 72.2% vs 52.2%, respectively, and at 18 months, 53% improvement was observed with pembrolizumab.

These results imply that, to get the benefit of pembrolizumab, it doesn’t matter whether you are PD-L1–positive or –negative.

Updated data analysis in December 2018

Updated analysis of recurrence-free survival (RFS) data, with an additional 7 months of follow-up in comparison to the initial data cut off analysis, carried out at the request of the European Medicines Agency, demonstrated that Pembrolizumab significantly prolonged RFS, reducing the risk of disease recurrence or death by 44 percent compared to placebo in the overall population of patients with resected, high-risk stage III melanoma (HR=0.56; 98% CI, 0.44-0.72; p<0.0001).

The most common adverse reactions with pembrolizumab were fatigue (34.1%), rash (22.7%), nausea (21.7%) and diarrhea (21.5%) and pruritus (20.2%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity.

Importance of the trial in the competitive scenario

In his presentation during AACR, 2018, past chair of the EORTC Melanoma Group and ESMO executive board member (2015-2017) – Dr. Alexander M.M. Eggermont said, “KEYNOTE-054 is the only adjuvant trial to offer crossover therapy at recurrence”. He said, “In 2.5 years, we will have the answer to a crucial question: Do you get a bigger benefit if you start with adjuvant pembrolizumab or wait until recurrence.”




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