Yet Dr Chapman questioned the significance of the findings by pointing out that although dabrafenib and trametinib improve progression-free survival, the trial has yet to report their effects on overall survival. That’s because too few deaths have occurred to date. “It may be that treatment options in the case of relapse are sufficiently effective that there is little overall survival benefit to adjuvant therapy,” he said. The question remains whether it’s worth the risk of toxicities for patients.
The news of the long-term benefit of adjuvant dabrafenib and trametinib was a bright spot for the melanoma field — in light of disappointing results of another phase 3 trial of 532 patients with advanced BRAF V600 mutation-positive cutaneous melanoma. Investigators of the randomized, double-blind COMBI-i trial looked at how they responded to the triple therapy of dabrafenib and trametinib and the anti–programmed cell death 1 (PD-1) therapy spartalizumab. The results that were announced during a presentation at the European Society of Medical Oncology (ESMO) Virtual Congress 2020 found that although 68.5% of patients responded to the triple therapy, compared to 64.2 who responded to dabrafenib and trametinib, the trial did not meet its primary endpoint of investigator-assessed progression-free survival for patients who received the triple therapy.3
In addition, serious adverse effects occurred for 23% of patients in the triple-therapy arm, compared with 11% in the dabrafenib and trametinib arm. “It tells us that combining the checkpoint inhibitor anti–PD-1 with BRAF targeted therapy improves outcomes but not to the extent we hoped,” said investigator Georgina Long, MD, chair of melanoma medical oncology and translational research at the University of Sydney in Australia. “It is not of large clinical value, so will not change practice.”
Dr Dummer would like to investigate in a future clinical trial whether the triple therapy was superior to the dabrafenib and trametinib combination in an adjuvant setting for high-risk patients who were selected for high mutational burden.
But Dr Chapman said he was cautious about prescribing immunotherapies in that context because their side effects might not be reversible. In the meantime, he was eager to see the overall survival results of these adjuvant trials in the future, including another placebo-controlled adjuvant trial in melanoma called KEYNOTE-054 (ClinicalTrials.gov Identifier: NCT02362594) that compares pembrolizumab to placebo and is estimated to be completed in 2026.“If they do not show an overall survival benefit, then the field will have some soul-searching to do,” he said.
- Dummer R, Brase JC, Garrett J, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. 2020;21(3):P358-372. doi:10.1016/S1470-2045(20)30062-0
- Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020;383:1139-1148. doi:10.1056/NEJMoa2005493
- Nathan P, Dummer R, Long GV, et al. LBA43 Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAFV600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. Ann Oncol. 2020;31(4):S1172. doi:10.1016/j.annonc.2020.08.2273