Update Shows Long-Term Benefit With Dabrafenib Plus Trametinib in Advanced Melanoma in COMBI Trials

Caroline Robert, MD, PhD

Caroline Robert, MD, PhD

In a recent review of the 5-year outcomes from the COMBI-d and COMBI-v trials published in theNew England Journal of Medicine, investigators saw long-term benefit with the use of dabrafenib (Tafinlar) plus trametinib (Mekinist) as first-line treatment in about one-third of patients with unresectable or metastatic melanoma andBRAFV600E or V600K mutations.

At 5 years, the combined progression-free survival (PFS) rate was 19% (95% CI, 15%-22%) and the overall survival (OS) rate was 34% (95% CI, 30%-38%) for the 2 trials.

"Our analysis demonstrates that first-line therapy with Tafinlar plus Mekinist leads to 5-year disease control in about one-fifth of the patients and 5-year survival in about one-third of those treated," Caroline Robert, MD, PhD, the lead study author, said in a press release. "While metastatic melanoma has historically had a very poor prognosis for patients, there are many reasons to be encouraged today. Our analysis demonstrates a clinically meaningful and positive impact on patient survival. These results show that targeted therapies may provide long-term survival and offer durable outcomes."

In the studies, 563 patients were randomly assigned to receive dabrafenib plus trametinib, including 211 previously untreated patients in COMBI-d and 352 patients in COMBI-v. Each trial had a different primary endpoint, PFS for the COMBI-d trial and OS for the COMBI-v trial.  

Disease progression or death occurred in 417 (74%) of the patients by the data cut-off of October 8, 2018. The median PFS was 11.1 months (95% CI, 9.5-12.8) and median OS duration was 25.9 months (95% CI, 22.6-31.5).

The response rate across the 2 studies was 68%, with 19% achieving a complete response. Among the patients who had a complete response, the 5-year PFS rate was 49% (95% CI, 39-58); it was 16% (95% CI, 12-22) in patients with a partial response, and 1% (95% CI, 0-6) in patients with stable disease. There was a confirmed objective response in 58 of the 59 patients (98%; 95% CI, 91%-100%) who were progression-free 5 years after randomization, and 37 (63%) of them had a complete response.

Five years after randomization, 72 of 161 patients (45%) who were still alive had a complete response, with a median duration of 36.7 months (95% CI, 24.1-not reached), and most had a confirmed objective response (90%; 95% CI, 84%-94%).

Regardless of cause, adverse events (AEs) were reported in 548 of 559 patients (98%) and led to permanent discontinuation in 99 patients (18%). Permanent discontinuation of dabrafenib plus trametinib was most common in patients who experienced pyrexia, in 23 (4%); decreased ejection fraction in 21 (4%); and an increased alanine aminotransferase level in 7 (1%). There were no trial-related deaths observed.

Discontinuation of treatment led to 299 of the 563 patients (53%) taking subsequent anticancer therapy, most commonly immunotherapy. Of the 299 patients, 196 (66%) were administered immunotherapy, including 151 (51%) who received anti—CTLA-4 therapy and 102 (34%) who received anti–PD-1 therapy. There were 161 patients who survived, 72 (45%) of which received subsequent anticancer therapies and 89 (55%) who did not report receiving any post-treatment therapy during the trial.

Baseline Factors Impacting Survival and Further Research

Several baseline factors that significantly prolonged the duration of PFS (P<.05), as well as OS, in the trial were identified by a multivariate analysis. These included female sex,BRAFV600E genotype, better performance status, older age, fewer than 3 disease sites, and normal lactate dehydrogenase (LDH) level. The investigators corroborated these findings by analyzing baseline characteristics in patients who had disease progression after the median duration of PFS, compared to those who had progression before, and in patients who were progression-free 5 years after randomization, compared with the overall population.

Patients taking dabrafenib plus trametinib with normal LDH level at baseline (43%; 95% CI, 38%-49%) had a higher OS rate at the 5-year mark than those with elevated levels (16%; 95% CI, 11%-22%). Their 5-year PFS rate was 25% (95% CI, 20%-30%) compared with 8% (95% CI, 4%-13%) in patients with elevated LDH levels at baseline.

Additionally, 194 (34%) of all the patients had an elevated LDH level. Identified by previous regression-tree analysis, there was a subgroup of 216 (38%) patients who had a prolonged duration of PFS characterized by a normal LDH level and fewer than 3 disease sites at baseline. This subgroup&rsquo;s 5-year PFS rate was 31% (95% CI, 24%-38%) and the 5-year OS rate was 55% (95% CI, 48%-61%).

&ldquo;Across trials evaluating available therapeutic options, including trials of immune checkpoint inhibitors, substantially worse outcomes have been observed in patients who had an elevated [LDH] level at baseline. These patients with more aggressive tumor kinetics need new therapeutic options,&rdquo; the investigators wrote in the published report.&nbsp;

LHD level and other categories of response were evaluated as biomarkers because of their association with long-term outcomes and may constitute a surrogate endpoint for earlier assessment in future studies, according to the trial authors. &ldquo;One potential option under evaluation is the combination of targeted therapy and immune checkpoint inhibitors. Such combination strategies are being evaluated in the ongoing phase III COMBI-i trial (NCT02967692), in which a regimen of spartalizumab (an anti—PD-1 antibody) plus dabrafenib and trametinib is being compared with placebo plus dabrafenib and trametinib.&rdquo;

Beyond this, several studies are ongoing to evaluate the most effective sequencing of treatment because of the uncertainty in the clinical use of targeted therapy and immune checkpoint inhibitors in patients with metastatic melanoma.

Reference:

Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma.N Engl J Med.2019;381(7):626-636. doi: 10.1056/NEJMoa1904059.