Higher response rates for concurrent triple therapy versus sequential therapy in melanoma

Induction therapy with dabrafenib plus trametinib did not increase the response to subsequent pembrolizumab in patients with BRAF-mutated stage III melanoma in the phase 2 NeoTrio trial. Concurrent therapy with dabrafenib, trametinib, and pembrolizumab resulted in the highest pathological response rates, but at a cost of increased toxicity in this population.

The phase 2 NeoTrio trial (NCT02858921) aimed to identify the optimal treatment regimen for patients with BRAF-mutated stage III melanoma (n=60). Previous studies have suggested that overall response rates are higher if patients are treated with BRAF plus MEK inhibitors, whereas anti-PD1 therapies demonstrate longer progression-free survival and overall survival rates [1,2]. The participants of the NeoTrio trial were randomised 1:1:1 to pembrolizumab alone, dabrafenib plus trametinib induction therapy followed by pembrolizumab (sequential arm), or simultaneous dabrafenib, trametinib, and pembrolizumab (concurrent arm) [3]. After 6 weeks, all patients could receive surgery for lymph node dissection and adjuvant pembrolizumab. The pathological response at week 6 was the primary outcome. Prof. Georgina Long (The University of Sydney, Australia) presented the results.

The highest pathological response rates were observed in the concurrent arm (80%), whereas participants in the pembrolizumab alone arm (55%) and the sequential arm (50%) displayed lower response rates. The pathological complete response rates were 50%, 30%, and 15% in the concurrent, monotherapy, and sequential arm, respectively. In contrast, the 12-month event-free survival rates (80% in all groups), recurrence-free survival rates (80–89%), and overall survival rates (90–100%) appeared not to differ between treatment groups. Prof. Long added that the pathological responses must be interpreted in the context of received therapy type: “Patients with a pathological complete response or near-pathological complete response with regimens containing BRAF-targeted therapy may recur.”

Grade 3/4 treatment-related adverse events were more common in the concurrent arm (55%) than in the pembrolizumab alone (5%) or sequential arm (25%). Correspondingly, treatment discontinuations were more prevalent in the concurrent arm (40%) than in the pembrolizumab arm (5%), or the sequential arm (0%). Pyrexia (15%) and elevated alanine aminotransferase/aspartate transaminase levels (10%) were the most frequently reported grade 3/4 adverse events in the concurrent arm.

Although the first results of the NeoTrio trial indicate that BRAF plus MEK inhibitors do not enhance the response to PD-1 inhibitors in patients with BRAF-mutated stage III melanoma, trial follow-up and translational studies are ongoing to gain further insights in the applicability of triple therapies in this population.

1. Robert C, et al. N Engl J Med. 2019;381:626–636.
2. Larkin J, et al. N Engl J Med. 2019;381:1535–1546.
3. Long GV, et al. NeoTrio: Randomized trial of neoadjuvant (NAT) pembrolizumab (Pembro) alone, in sequence (SEQ) with, or concurrent (CON) with dabrafenib plus trametinib (D+T) in resectable BRAF-mutant stage III melanoma to determine optimal combination of therapy. Abstract 9503, ASCO 2022 Annual Meeting, 3-7 June.

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Posted on 5 August 202222 February 2024