Adjuvant therapies provide ‘incredible’ outcomes in melanoma

[Editor’s note: the original version of this story referred only to adjuvant immunotherapy rather than the use of immunotherapy and targeted therapy as adjuvant treatment for high-risk melanoma. We apologise for the inaccuracy. The article has also been edited to clarify a statement relating to improvement across tumour and stage subgroups in Keynote 054.]

Adjuvant therapies have shown significant and durable benefit in relapse-free survival for patients with resected stage III melanoma, according to updated, longer-term findings from KEYNOTE 054 and COMBI-AD presented during the ASCO2020 Virtual Scientific Program.

Speaking to the limbic Professor Georgina Long of the Melanoma Institute Australia, and an investigator on both trials, says it’s a ‘very exciting time’ for melanoma with adjuvant therapies having the potential to give patients a near 50% reduction in risk of disease recurrence.

“At one time melanoma was a certain death sentence even for high risk stage 3 melanoma – it was a very scary disease to have. As these trials are showing, it’s not that orphan tumour anymore – its something for which we have a lot of treatment options and patients are doing well. Rather than having to deal with people dying from their melanoma we’re now dealing with survivorship issues, which is a much nicer problem to have.”

The phase 3 KEYNOTE 054 trial, investigating the adjuvant use of pembrolizumab compared to placebo in high risk stage 3 melanoma patients, reported on new recurrence-free survival (RFS) results at three-year median follow-up.

RFS among the intent-to-treat population and among patients with PD-L1-positive tumours served as the study’s co-primary endpoints.

A previous update of the study at median follow-up of 1.25 years showed treatment with the immune checkpoint inhibitor led to a 43% reduction of their risk of melanoma recurrence or death compared to placebo treatment, prolonging recurrence-free survival. The findings led to FDA and European Medicines Agency approval of the anti-PD-1 agent as adjuvant treatment for this patient population.

The trial included 1,019 adults with stage IIIA (15%), stage IIIB (46%) or stage IIIC (39%) resected melanoma metastatic to lymph nodes, based on AJCC 8th edition classifications.

Investigators randomly assigned patients to adjuvant pembrolizumab dosed at 200 mg every three weeks for up to one year (n = 514) or placebo (n = 505) for a total of 18 doses or until disease recurrence or unacceptable toxicity.

Three year data

Presenting updated findings at ASCO last week, Professor Alexander Eggermont, study chair and Professor of Surgical Oncology at Princess Máxima Center, Utrecht, Netherlands, said adjuvant administration of pembrolizumab provided a sustained prolongation of recurrence free survival compared to placebo.

In the overall population, the 3-year recurrence-free survival (RFS) rate was 64% in the pembrolizumab group versus 44% in the placebo group, resulting in a hazard ratio of 0.56. Professor Eggermont noted: “if you make the subgrouping by AJCC 8 classification, that each group – 3A, B, C, and D – benefit relatively equally from the adjuvant therapy with pembrolizumab.”

And in BRAF-mutated patients the RFS rate difference was 25% (62% vs 37%) and in BRAF-wild type patients it was 16% (62%-46%), demonstrating a significant benefit irrespective of mutational status. In the overall population, the 3-year cumulative incidence of distant metastasis as the first recurrence was 22% (pembrolizumab group) vs 37% (placebo group).

According to Professor Eggermont the BRAF-mutated patients drew a very significant benefit out of adjuvant therapy with pembrolizumab.

“The absolute difference being 25% at three years. For the BRAF wild-type patients that difference is 15% but the hazard ratios and p values are highly significant for both observations.”

Meanwhile he said the immune-related adverse events with the anti-PD-1 were ‘relatively insignificant’.

While the percentage for all immune-related adverse events in the pembrolizumab arm was 37.7%, only 7.7% reflected grade three or higher events.

“The adverse events are largely dominated by the 25% of endocrine events, which are almost exclusively dominated by thyroid events like hyperthyroidism initially, and then mostly hypothyroidism later,” he said.

Talking to the limbic about the significance of the three-year data Professor Georgina Long said it showed ‘a strong effect’.

“In the pembrolizumab arm 36% of people had recurred disease but in the placebo arm 56% of people had recurred at three years, a marked difference giving a hazard ratio of 0.56 essentially 44% reduction in risk of recurrence with pembrolizumab compared with placebo.

Every subgroup seems to benefit – all stages, whether you had the BRAF mutation or whether you didn’t, whether you were BRAF wild type, whether your tumour was PD-L1 or PD-L negative both benefit. It is hard when the subgroups are small to say whether there is a bigger or lesser benefit [between sub groups] but it’s a pretty strong effect when all the known prognostic features in terms of the natural history of melanoma show that this drug has benefited.”

Other adjuvant immunotherapies

However, the findings do need to be placed in context of trials like COMBI-AD and CHECKMATE 238 investigating other adjuvant immunotherapies in the advanced melanoma setting, she added.

CheckMate 238 compared patients with high-risk stage III or IV melanoma who received adjuvant nivolumab, a PD-1 blocking antibody, against those who received the anti CTLA-4 antibody ipilimumab (the control arm).

The three-year outcome data presented last year reported superior RFS benefit with nivolumab (HR = 0.68; 95% [CI] = 0.56–0.82, P < .0001). Like KEYNOTE 054, adjuvant treatment with nivolumab was consistent across all disease stages, PD-L1 expression levels, and BRAF mutation status, Professor Long explained.

On the basis of that data, nivolumab received approval from the FDA for patients with stage three resected melanoma.

Meanwhile the five-year RFS data for COMBI-AD were presented this year.

The phase three trial looks at the combination of two agents: dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, for adjuvant treatment of metastatic V600K or V600E mutant melanoma in patients with resected stage IIIA, IIIB, and IIIC disease by the AJCC 7th edition criteria

“That trial was very similar to KEYNOTE 054 in design. It included the same type of patients, however all were BRAF mutated and all had to have more than a millimetre of melanoma in the lymph node. It’s a much more mature trial with five years of data, which shows a very sustained relapse free benefit long term,” notes Professor Long.

The findings, which were also presented as part of the ASCO 2020 program, showed that at five years, the rate of RFS was 52% (95% CI, 48%-58%) with the combination therapy versus 36% (95% CI, 32%-41%) with placebo.

Again, the RFS benefit was observed across all sub groups.

“Whether patients had v600k versus v600e; whether they were men or women young or old, whether they had micro metastasis or macro, whether they were received treatment in Europe, Australia, the US, whether they had one node involved or more than four nodes – all of them benefited from the combination of dabrafenib and trametinib in terms of the relapse free survival,” said Professor Long.

“All three of these trials are absolutely incredible. I mean when you see hazard ratios of 0.5, which is what we see near across all three trials, compared to placebo it’s huge – this is a near 50% reduction in risk of recurrence. These are massive improvements for patient outcomes.”

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