Long Shares Insight on Pivotal Data in BRAF-Mutant Melanoma

Georgina V. Long, BSc, PhD, MBBS

As the longest follow-up of treatment-naïve patients with BRAF V600E-mutant, unresectable or metastatic melanoma treated with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), the pooled analysis of the phase III COMBI-v and COMBI-d trials provides evidence to support that that the doublet can result in lasting benefit for this patient population, explained Georgina V. Long, BSc, PhD, MBBS, FRACP.¹

Specifically, the pooled analysis demonstrated that 34% of patients with unresectable or metastatic BRAF V600E-mutant melanoma who received the combination as frontline therapy were alive at 5 years; 19% of these patients remained free from progression.

As the longest follow-up of treatment-naïve patients with unresectable or metastatic BRAF V600E-mutant melanoma treated with the combination, these findings provide evidence to support that that the combination can be offered to a sizeable proportion of patients and result in lasting benefit, Long explained.

Among the 563 evaluable patients who remained alive at 5 years, those who achieved a complete response (CR; 19%) were more likely to sustain a long-term OS and progression-free survival benefit (PFS). Specifically, the 5-year OS and PFS rates in these patients were 71% and 49%, respectively. Conversely, patients who experienced a partial response (PR) or stable disease (SD) had a 5-year PFS rate of 16% and 1%, respectively. Similar findings were noted in terms of the 5-year OS rates, with 32% observed after PR and 16% in those who had SD.

Positive prognostic factors for PFS and OS, including favorable baseline lactate dehydrogenase and fewer sites of metastatic disease, contributed to improved 5-year PFS and OS rates of 31% and 55%, respectively.

In the COMBI-v and COMBI-d trials, adult patients who harbored a BRAF V600E/K mutation who had not received prior systemic therapy or been exposed to a BRAF or MEK inhibitor were randomized to either the dabrafenib/trametinib combination, or vemurafenib (Zelboraf) or dabrafenib, respectively. The median age of patients in the pooled analysis was 55 years, and half of patients had ≥3 sites of metastatic disease.

“Patients are doing very well at this early juncture,” said Long, co-medical director of Melanoma Institute Australia (MIA). “We’re seeing high response rates, as expected. However, it seems that we are also improving the durability above what we expect with either dabrafenib and trametinib alone or a PD-1 inhibitor alone.”

In addition to the doublet, clinicians should also keep an eye out for the triplet of the PD-1 inhibitor spartalizumab, dabrafenib, and trametinib, which induced a CR of 40%, a median PFS of 23.7 months, and an OS that was not reached in a pooled analysis of 36 patients in parts 1 and 2 of the 3-part COMBI-i trial.²

In an interview with OncLive, Long, who is also chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discussed the activity of the doublet alone as well as in combination with spartalizumab in patients with advanced BRAF V600E-mutant melanoma.

OncLive: What does the 5-year analysis of the combination of dabrafenib and trametinib show?

Long: We presented the pooled data of the COMBI-v and COMBI-d trials at the 2019 ASCO Annual Meeting; these are phase III trials of dabrafenib and trametinib versus a BRAF inhibitor alone. The COMBI-d trial looked at dabrafenib alone, and the COMBI-v trial looked at vemurafenib alone. This is a pooled analysis of just the patients who received dabrafenib and trametinib, over 500 patients. We’re seeing a very high 5-year OS rate. However, interestingly, in certain populations, we're pushing that survival rate to above 50% at 5 years.

The PFS rate is very high. For example, the majority of patients who have a CR do not progress—only half of patients progress by 5 years. We're seeing a PFS rate of just under 50% for patients who have a CR. When we look at patients with a normal baseline lactate dehydrogenase level and a low level of metastases, defined as less than 3 sites of metastases, they do very well. They also show PFS landmarks well above the 30% and 40% mark. These patients do very well long-term.

With these data, we think that targeted therapy does cure, or at least induces, good long-term control in a proportion of patients. If we look in the total population, just under 20% of patients are progression-free at 5 years. These are good results for targeted therapy.

Could you discuss the results of the pooled analysis of parts 1 and 2 of the COMBI-i study?

The COMBI-i trial is exploring how to combine targeted therapy with immunotherapy; specifically, dabrafenib and trametinib combined with a new anti—PD-1 drug called spartalizumab. The trial has three parts to it. Parts 1 and 2 were presented at the 2019 ASCO Annual Meeting. Here, we looked at 36 patients who were given a full dose of all 3 drugs together. By doing that, we see a very high response rate of 78%, as is expected with targeted therapy. Only one patient progressed. More interestingly is the PFS, the median of which is above 20 months. That compares very well with [what has been seen with] either a PD-1 inhibitor alone or the combination of dabrafenib and trametinib alone. Also, the duration of response and OS have not been met yet.

In terms of adverse events, pyrexia seems a bit more severe and prolonged than what we see with dabrafenib and trametinib alone; however, this is being explored further in part 3 of the trial, the results of which were not presented the 2019 ASCO Annual Meeting. Part 3 is a randomized study of all 3 drugs together versus dabrafenib and trametinib alone. In that trial, we're seeing that the toxicity is very manageable with very good patient and physician education. These are exciting results to watch for in this space.

References

1. Nathan P, Robert C, Grob JJ, et al. Five-year analysis on the long-term effects of dabrafenib plus trametinib (D + T) in patients with BRAF V600-mutant unresectable or metastatic melanoma. J Clin Oncol. 2019;37(suppl 15; abstr 9507). doi: 10.1200/JCO.2019.37.15_suppl.9507.
2. Long GV, Lebbe C, Atkinson V, et al. The anti—PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i. J Clin Oncol. 2019;37(suppl 15; abstr 9531). doi: 10.1200/JCO.2019.37.15_suppl.9531.