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Distinct Features Associated With Benefit for BRAF/MEK Inhibition

Sigrid Eckardt
Published Online: May 23,2016
According to Robert, patients with “low LDH respond extremely well to targeted treatment. Patients with high LDH, whatever treatment we use, remain a big medical need. They derive a small benefit each time we evaluate a new, effective therapy. The benefit is always less in this population.” 

Tumor Burden and Timing of BRAF MEK Inhibitor Therapy

Consistent features associated with better outcomes with combined BRAF/MEK inhibitor in long-term analyses also included earlier-stage melanoma and fewer metastatic sites. Furthermore, according to Long and co-authors, “good prognostic features at progression seemed to prolong survival from the time of progression but were also associated with receiving subsequent systemic therapy.”2

The presence of less than 3 organ disease sites was a baseline feature that met stringent criteria for association with longer OS (Cox proportional hazard regression analysis).2 The median OS in patients with less than 3 metastatic sites was 45.5 versus 17.5 months in patients with ≥3 metastatic sites (HR, 0.36; 95% CI, 0.18-0.69).2 The corresponding OS rates were 92% versus 68% at 1 year, 73% versus 30% at 2 years, and 58% versus 19% at 3 years.2 In patients with earlier stage disease (IIIC/M1a/M1b vs M1c), the median OS had not been reached and was 21.9 months in patients with M1c stage disease (HR, 0.36; 95% CI, 0.18-0.72). Other baseline features evaluated, including age, sex, ECOG performance status, and prior immunotherapy, did not correlate with added benefit from combination therapy (TABLE 1).2 

TABLE 1. Survival by Baseline Characteristics With Dabrafenib/Trametinib

  Median OS, months
LDH > ULN 16.6
LDH ≤ ULN 45.5
≥3 disease sites 17.5
<3 disease sites 45.5
Male 23.8
Female 25.5
IIIC/M1a/M1b not reached
M1c 21.9
≥65 years 21.3
<65 years 28.4
Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal.

Several indicators of a good prognosis, including the presence of fewer than three metastatic organ sites, lower median sum of diameters, lower melanoma stage, lower ECOG performance status, and no history of brain metastases were baseline factors that were also more frequent among patients who had a continued long-term response without progression.2 Consistent with these observations, patients who progressed and did not receive further systemic chemotherapy had higher ECOG performance status, higher LDH, larger sum of diameters of RECIST target lesions at progression, greater absolute change in the RECIST sum of diameters from nadir, progression in the brain, and female sex (TABLE 2).2

TABLE 2. Survival Comparison by Baseline Characteristics With Dabrafenib/Trametinib

LDH ≤ ULN vs > ULN HR, 0.21 (95% CI, 0.10-0.44)
Disease sites <3 vs ≥3 HR, 0.34 (95% CI, 0.17-0.70)

Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal.

Findings that low tumor burden predicts superior long-term outcomes imply that BRAF/MEK inhibitor therapy should also be considered earlier in the disease course, in healthier patients with lower disease burden, in whom immunotherapy is often preferred. Long and co-authors noted that, “on the basis of longer-term survival data from the current study and other studies, it would not be possible to use baseline features to select one therapy over another. Specifically, this study showed that long-term survival and durable responses with dabrafenib plus trametinib are associated with good prognostic features at baseline, including factors associated with low-volume disease—classically considered a hallmark for frontline immunotherapy.” 

Observations from a phase Ib trial have also identified tumor burden as a predictor of clinical outcome with BRAF/MEK inhibition with vemurafenib and cobimetinib.6

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