Long-term follow-up confirms survival benefits with adjuvant pembrolizumab in Stage III melanoma: KEYNOTE-054

Wednesday, 11 Nov 2020

Long-term data from KEYNOTE-054 presented at the recent ESMO 2020 Virtual Congress has confirmed the durability of the relapse-free survival (RFS) benefit of adjuvant pembrolizumab after complete resection of Stage III melanoma. The study also found that adjuvant pembrolizumab resulted in a significant reduction in the risk of distant metastases compared to placebo (HR:0.60; 95% CI 0.49 – 0.73; p<0.001).1 The results from KEYNOTE-054 are timely, given the PBS listing of Keytruda (pembrolizumab) for adjuvant treatment of Stage IIIB, IIIC, and IIID resected melanoma in September of this year.2

The limbic spoke to Associate Professor Matteo Carlino a medical oncologist at Westmead and Blacktown Hospitals and a primary author of the study, about the clinical significance of this data to Australian oncologists.

A/Prof. Matteo Carlino explained that the design of the KEYNOTE-054  trial means its findings are particularly relevant study for Australian oncologists. “The placebo-controlled nature of the trial reflects the historical management of Stage III melanomas after complete resection in Australia, which was largely observation-based,” he said. “Because it’s a placebo-controlled trial it’s simple to communicate the potential value of adjuvant therapy to the patient – what happens when you’re given the drug, and what happens when you’re not given the drug. We didn’t have a trial like this until now,” he explained.

KEYNOTE-054 data confirms sustained RFS benefits

KEYNOTE-054 is a Phase 3, randomised, double-blind study evaluating adjuvant therapy with pembrolizumab compared with placebo in patients with completely resected, high-risk Stage III melanoma.1,3,4 Patients received adjuvant therapy (pembrolizumab 200mg IV every three weeks or placebo for 18 doses – approximately one year) or until disease recurrence or unacceptable toxicity. The co-primary endpoints were relapse-free survival (RFS) for all patients and RFS for patients with PD-L1-positive tumours. The study is continuing in order to evaluate its secondary endpoint of overall survival.

The RFS primary analysis at 15 months median follow-up was reported in 20183 and showed pembrolizumab significantly improved RFS compared to placebo in the overall intention-to-treat (ITT) population (HR 0.57; 98.4% CI 0.43 – 0.74; P<0.001) and in the PD-L1 positive sub-group (HR 0.54; CI 0.42 – 0.69; P<0.001). Grade 3–5 adverse events were reported in 14.7% of patients in the pembrolizumab group compared to 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.

An updated analysis presented earlier this year at ASCO 20203 showed that at three-year median follow-up, the RFS benefit was sustained in both primary populations (Overall ITT: HR 0.56; CI 0.47 – 0.68; P<0.0001. PD-L1-positive: HR 0.57; CI 0.43 – 0.74; P<0.0001).

The three-and-a-half-year follow-up data was presented at the ESMO 2020 Virtual Congress in September,4 and confirmed the sustained RFS benefits of pembrolizumab in the adjuvant setting in Stage III melanoma (HR in the ITT population 0.59; 95% CI 0.49 – 0.70).

Distant metastases-free survival benefits

The data presented at the ESMO Congress also included first-time results for distant-metastases-free survival (DMFS), a secondary endpoint of the study.1 At 3.5-year median follow-up, pembrolizumab compared with placebo significantly prolonged DMFS in the overall population (65.3% versus 49.4%; HR 0.60, 95% CI 0.49–0.73; P<0.0001) and in the PD-L1-positive tumour sub-group (N=853; HR 0.61; 95% CI 0.49–0.76; P<0.0001).1

“Local relapses can be dealt with by surgery, but relapses to distant parts of the body are an issue,” noted A/Prof. Carlino. “The data shows that the benefit of pembrolizumab with respect to distant metastases is as strong as the relapse-free survival benefit,” he said.

Survival benefits across all subgroups

The impact of pembrolizumab on DMFS was similar in patients with PD-L1-negative tumour (N=116; HR 0.49; 99% CI 0.24–0.99) and in other subgroups, including according to AJCC-7 and AJCC-8 staging, and BRAF mutational status.4 “The PDL-1 status, BRAF mutant or wild type status, and the stage of the disease are all significant clinical factors to be considered when treating a patient,” said A/Prof. Carlino.

Long-term data showed no new safety signals

There were no new safety signals with the updated data. Immune-related adverse events (Grade 1 or above) were seen in 37.7% of patients for pembrolizumab (versus 9.0% with placebo).  The majority of these events were categorised as endocrine disorders (23.4% for pembrolizumab versus 5.0% for placebo).1

The occurrence of immune-related adverse events has been found to be significantly associated with a longer RFS in pembrolizumab-treated patients (HR 0.61; 95% CI 0.39 – 0.95; P=0.03).5

A cross-over design to address unanswered questions

A unique feature of the trial design involved unblinding at relapse or after one year of therapy and allowing crossover to pembrolizumab (or rechallenge with pembrolizumab if the patient had relapsed six or more months after the active 12-month arm). This trial design will help address the question of whether an adjuvant anti-PD1 treatment would be beneficial for all patients or could result in a similar benefit if provided only to those who relapse.

“Whether or not we should wait until a patient relapses before giving therapy is still an unanswered question. The important point is that this trial will allow that question to be answered.” explained A/Prof. Carlino. “Not every patient will cross over to pembrolizumab because they could be treated at relapse by other means, but the trial design guarantees that every patient will be offered PD-1-based therapy if they recur,” he said.

“This trial hasn’t yet answered the question of whether having adjuvant therapy early is better than waiting until relapse, but the design ensures that the question can be answered,” A/Prof.  Carlino added. In presenting the data at the ESMO Virtual Congress, Professor Eggermont noted that it remains crucial to answer this question.




  1. Eggermont AM et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Final results regarding distant metastases-free survival from EORTC 1325-MG/Keynote 054 double-blinded phase III trial. ESMO 2020 Congress abstract LBA46.
  2. Pharmaceutical Benefits Scheme Authority Listing: Pembrolizumab
  3. Eggermont AM et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma N Engl J Med 2018; 378:1789-1801
  4. Eggermont AM et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325 MG/Keynote 054 double-blinded phase III trial at three-year median follow up. ASCO 2020 Meeting abstract 10000.
  5. Eggermont AM et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: A secondary analysis of a randomized clinical trial. JAMA Oncol 2020; 6(4):519–527.

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