Updated analysis of the phase II NeoCombi study shows low rates of recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at 5 years with neoadjuvant dabrafenib plus trametinib in clinical stage III melanoma. These survival outcomes are similar to those achieved with adjuvant targeted therapy alone. There was a trend toward improved RFS and overall survival (OS) in patients with a pathological complete response (pCR), but those with pCR still had an approximate 50% risk of recurrence, in contrast to those treated with neoadjuvant immunotherapy who seldom recur.
It is unlikely that neoadjuvant targeted therapy will play a role in the routine care of patients with melanoma according to Assoc. Prof. Alexander M Menzies of the Melanoma Institute Australia and colleagues who published the findings on 14 May 2024 in the Annals of Oncology.
Stage III cutaneous melanoma carries a high risk of post-surgical recurrence, with recurrence rates of up to 70% depending on sub-stage. Adjuvant targeted therapies for approximately 40% of patients with melanoma and BRAF mutations and immune checkpoint inhibitors reduce the risk of recurrence by 40–55% compared with surgery alone and have become standard of care.
Neoadjuvant therapy is another approach to improve outcomes. Neoadjuvant administration of pembrolizumab is superior to adjuvant administration of the same drug, with a 47% reduction in event-free survival at 2 years (absolute risk difference of 23%). Responses to neoadjuvant immunotherapy are typically of high quality, with a low risk of recurrence, particularly in patients with a major pathological response (MPR).
The authors wrote in the background that neoadjuvant targeted therapy has been examined in 2 small phase II studies, CombiNeo and NeoCombi. In both studies, targeted therapy was associated with excellent initial activity, so one trial was terminated early due to an overwhelming statistical benefit in the neoadjuvant arm. However, early analysis suggested the risk of recurrence may be high, even in patients with a MPR. In the latest article published in the Annals of Oncology, they report 5-year outcomes of neoadjuvant dabrafenib plus trametinib from the NeoCombi, which represents the longest follow-up of a neoadjuvant targeted therapy to date.
NeoCombi was a single-arm, open-label, single-centre, phase II study. Eligible patients were adults (aged ≥18) with histologically-confirmed, resectable, RECIST-measurable AJCC 7th edition clinical stage IIIB–C BRAF V600E/K-mutated melanoma and Eastern Co-operative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with 150 mg dabrafenib orally twice per day plus 2 mg trametinib orally once per day, with complete resection of the pre-therapy tumour bed at week 12.
Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off on 17 August 2021, the median follow-up was 60 months (95% confidence interval [CI] 56–72). Overall, 21 of 35 patients (60%) recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years.
At 5 years, RFS was 40% (95% CI 27–60), DMFS was 57% (95% CI 42–76%), and OS was 80% (95% CI 67–94); 5-year survival outcomes were stratified by pathological response: RFS was 53% with pCR versus 28% with non-pCR (p = 0.087), DMFS was 59% versus 55% (p = 0.647), and OS was 88% versus 71% (p = 0.205).
The authors commented that of the 17 patients with pCR, 8 (47%) recurred, with 7 developing distant metastases. This is in contrast to immune checkpoint inhibitors, where patients with a MPR (defined as pCR or near-pCR) seldom recur, and pathological non-response can identify patients requiring further treatment.
Recurrences in this study included a mix of locoregional and distant disease. Half of the patients with local recurrence had distant recurrence soon after, indicating the unmet need for patients with resectable local recurrence for further effective neo/adjuvant systemic therapy. Interestingly, of the 4 patients receiving neo/adjuvant immunotherapy in this setting, 3 remain recurrence-free, despite evidence in the metastatic setting that prior treatment with targeted therapy has been associated with poorer response to subsequent immunotherapy.
While circulating tumour DNA was detectable in almost half of all patients at baseline, it did not significantly associate with survival, and it was not able to identify recurrence earlier than via routine clinical assessments.
The authors concluded that neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.
Reference
Menzies AM, Lo SN, Saw RPM, et al. Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma. Annals of Oncology; Published online 14 May 2024. DOI: https://doi.org/10.1016/j.annonc.2024.05.002