Patients with BRAF-mutated melanoma have the option of receiving either immunotherapy or a targeted therapy in the form of BRAF/MEK inhibitors. But although both therapeutic avenues have shown excellent survival benefit, questions regarding which should be given in the first line remain. Data presented at the American Society of Clinical Oncology Monthly Plenary Series on the results of the DREAMseq trial shed light on this issue.
DREAMseq randomised BRAF-positive, treatment-naïve patients to receive either Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab) and Yervoy (ipilimumab) followed by Opdivo maintenance, or Novartis’ BRAF/MEK inhibitor combination of Tafinlar (dabrafenib) and Mekinist (trametinib). At disease progression, patients were then crossed over to the opposite therapy. At a median follow up of 27.7 months, overall survival (OS) at two years was 72% for patients in the Opdivo/Yervoy-first arm compared with 52% in the Tafinlar/Mekinist-first arm. This finding was enough to prompt the data safety monitoring committee to recommend the study be closed to accrual and patients receiving Tafinlar/Mekinist given the option of switching onto the Opdivo/Yervoy arm. Progression-free survival (PFS) and median duration of response were also longer in the Opdivo/Yervoy arm, but grade three toxicity was greater in the Opdivo/Yervoy arm at 60% versus 52% in the Tafinlar/Mekinist group.
These findings are significant as there has been, until now, a lack of data comparing the efficacy of immunotherapy with that of targeted therapy in BRAF-mutated patients. According to GlobalData’s Melanoma – Global Drug Forecast and Market Analysis to 2029 report, there is a clear preference for the use of targeted therapy in the first line in EU markets. The results of this study may, therefore, have a substantial impact on prescribing patterns, particularly in these markets. Despite this, there will still be subsets of patients for whom Opdivo/Yervoy are not appropriate. Yervoy is relatively toxic and cannot be given to all patients. In addition, in patients with rapidly progressing disease, BRAF/MEK inhibitors may be more appropriate as these elicit faster responses than immunotherapy. Ultimately, additional data on the efficacy of PD-1 inhibitor monotherapy (Opdivo, or Merck’s Keytruda (pembrolizumab)) compared with BRAF/MEK inhibitors are also needed.
A similar trial, SECOMBIT, is also investigating the sequencing of immunotherapy and targeted therapy, with data yet to be published. This trial also has a third arm trialing a ‘sandwich’ approach, whereby patients receive targeted therapy (Pfizer’s Braftovi (encorafenib) and Mektovi (binimetinib)) for eight weeks, followed by Opdivo/Yervoy until disease progression, at which point they are switched back to Braftovi/Mektovi. It will be important to see, firstly, if the results of this trial corroborate those of DREAMseq and, secondly, if the data support the use of a sandwich approach. Sequencing therapy in this way could be of particular use in patients with more rapidly progressing disease.
In indications such as melanoma, where multiple effective therapies are now available, trials such as DREAMseq and SECOMBIT are vital to uncovering exactly how best to utilise these therapeutic options for maximum benefit. It is expected that these data will have profound impacts on clinical practice, prescribing patterns and potentially reimbursement, altogether leading to big changes in market dynamics.