Concurrent dabrafenib, trametinib, and pembrolizumab produces higher response rates than sequential treatment with these drugs or pembrolizumab alone in patients with stage III melanoma, according to a phase 2 trial.

However, the improvement in response rates did not translate to improvements in survival outcomes, and concurrent therapy was associated with greater toxicity.

These findings, from the NeoTrio trial, were presented at the 2022 ASCO Annual Meeting.


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NeoTrio (ClinicalTrials.gov Identifier: NCT02858921) enrolled 60 patients with resectable, measurable stage III melanoma. The median age was 53 years (range, 42-63), and 42% were women. The BRAF V600E mutation was present in 82% of patients, and clinical stage N1b was documented in 63% of patients. 

Patients were randomly assigned to 3 types of neoadjuvant therapy:

  • Pembrolizumab alone (200 mg every 3 weeks for 2 cycles)
  • A sequence of dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) for 1 week, followed by pembrolizumab (200 mg on days 8 and 22) for 2 cycles
  • Concurrent treatment with all 3 drugs at the same doses as in the sequence arm.

Each treatment arm contained 20 patients, and baseline characteristics were similar across the arms. In all arms, neoadjuvant treatment was followed by complete lymph node dissection (CLND). Post-CLND, patients received 11 cycles of adjuvant pembrolizumab. The median follow-up was 20.3 months. 

Response rates were highest in the concurrent arm. The pathologic response rate was 80% in the concurrent arm, 55% with pembrolizumab alone, and 50% in the sequential arm. The pathologic complete response rate was 50%, 30%, and 15%, respectively. 

The 12-month event-free survival rate was 80% in all 3 arms. The 12-month recurrence-free survival rate was 89% with pembrolizumab alone, 84% with concurrent therapy, and 80% with sequential therapy. 

The 12-month overall survival rate was 100% with sequential therapy, 95% with pembrolizumab alone, and 90% with concurrent therapy. 

The rate of treatment-related adverse events (TRAEs) was 100% with concurrent therapy, 95% with sequential therapy, and 85% with pembrolizumab alone. 

The most common TRAEs (in the pembrolizumab, sequential, and concurrent arms, respectively) were fatigue (65%, 70%, and 70%), pyrexia (0%, 20%, and 85%), and rash (45%, 35%, and 35%). 

Grade 3/4 AEs occurred in 5% of patients in the pembrolizumab arm, 25% of those in the sequential arm, and 55% of patients in the concurrent arm. Neoadjuvant treatment interruptions occurred in 0%, 15%, and 95% of patients, respectively. Permanent discontinuation occurred in 5%, 0%, and 40%, respectively. 

Disclosures: This research was sponsored by Melanoma Institute Australia in collaboration with Merck Sharp & Dohme LLC and Novartis. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.  

Reference

Long GV, Carlino MS, Au-Yeung G, 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. Presented at ASCO 2022; June 3-7, 2022. Abstract 9503.