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Baseline factors predict survival benefit from BRAF/MEK inhibitor combination
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Baseline lactic acid dehydrogenase levels, the sum of target lesion diameters and the number of organ sites with metastases predicted survival benefit in patients with BRAF V600–mutant melanoma treated with dabrafenib plus trametinib, according to results of a pooled analysis presented at HemOnc Today Melanoma and Cutaneous Malignancies.
The COMBI-d and COMBI-v phase 3 studies showed a benefit from the frontline use of dabrafenib (Tafinlar, Novartis), a BRAF kinase inhibitor, plus trametinib (Mekinist, Novartis), a MEK inhibitor, in BRAF V600–mutant melanoma.
Updated 2- and 3-year analyses of the studies also showed long-term clinical benefit and tolerability with the combination.
Additional analyses identified baseline lactate dehydrogenase (LDH) level and number of organ sites with metastases to be predictors of clinical outcomes for PFS and OS.
“To confirm which patients treated with dabrafenib plus trametinib can achieve maximum benefit, further analyses with extended follow-up and among patients with defined time points of therapy duration are needed,” Georgina V. Long, BSc, PhD, MBBS, FRACP, chair of melanoma medical oncology and translational research at the Melanoma Institute of Australia, and colleagues wrote. “The continued homogeneity of data from COMBI-d and COMBI-v has provided the opportunity for further exploration of factors associated with long-term outcomes.”
Long and colleagues conducted a retrospective study to determine clinical factors and potential time-dependent predictors associated with 3-year outcomes in the pooled population of patients treated with dabrafenib plus trametinib in both studies.
The analysis included 563 treatment-naive patients assigned to receive 150 mg dabrafenib twice daily in combination with 2 mg trametinib once daily in both the COMBI-d (n = 211) and COMBI-v (n = 352) trials.
Progression or death occurred in 71% of patients in the COMBI-d trial and 54% of patients in the COMBI-v trial.
In total, 373 patients had a median PFS of 6 months or more, with a median follow-up of 36.2 months.
The pooled population demonstrated a median PFS of 11.1 months and median OS of 26.2 months.
Three-year PFS was 23% in the COMBI-d trial and 44% in the COMBI-v trial.
Multivariate analyses showed PFS and OS were associated with:
- age (PFS, HR for 10-year increment = 0.92; 95% CI, 0.86-0.99; OS, HR = 0.91; 95% CI, 0.83-0.99);
- ECOG performance status (PFS, HR for 0 vs. ≥ 1 = 0.58; 95% CI, 0.47-0.72; OS, HR = 0.4; 95% CI, 0.32-0.51);
- sex (PFS, HR for female vs. male = 0.79; 95% CI, 0.65-0.97; OS, HR = 0.69; 95% CI, 0.55-0.87); number of organ sites with metastases (PFS, HR for < 3 vs. ≥ 3 = 0.54; 95% CI, 0.44-0.65; OS, HR = 0.41; 95% CI, 0.32-0.52); and
- LDH level (normal vs. ≥ 2 times upper limit of normal [ULN]: PFS, HR = 0.24; 95% CI, 0.18-0.32; OS, HR = 0.17; 95% CI, 0.12-0.23; ≥ 1 to < 2 times ULN vs. ≥ 2 times ULN: PFS, HR = 0.49; 95% CI, 0.35-0.68; OS, HR = 0.4; 95% CI, 0.28-0.56).
Researchers noted baseline LDH, sum of target lesion diameters and number of organ sites with metastasis most influenced progression. Median PFS was longest in patients with normal LDH, sum of target lesion diameters smaller than 66 mm, and fewer than three organ sites (24 months; 95% CI, 19.8-34.5) and shortest in patients with LDH two or more times greater than the ULN (5.5; 95% CI, 4.3-6.2).
Patients in the best prognostic group demonstrated a 3-year PFS of 42%.
Baseline LDH level was the only predictive factor for OS. A greater proportion of patients with normal LDH achieved OS than patients with elevated LDH at 2 years (66% vs. 27%) and 3 years (55% vs. 22%).
Of the patients who were progression free at 6 months, 71% had normal LDH and 77% had an ECOG performance status of 0. Median target lesion size was 17 mm.
Patients with normal LDH at baseline but elevated LDH at 6 months demonstrated worse outcomes with extended follow-up than patients who maintained normal levels (median PFS, 21.4 months vs. 23.9 months). Patients with elevated LDH levels at baseline had shorter median PFS, regardless of whether their LDH levels returned to normal at 6 months (12.9 months) or remained elevated (11.1 months).
Postbaseline factors included in the analysis did not improve the prediction of progression or survival in patients.
“Additional analyses with longer-term follow-up and/or further defined windows of therapy duration may be needed to confirm which patients treated with dabrafenib plus trametinib can achieve maximum benefit,” Long and colleagues wrote. – by Kristie L. Kahl
Reference:
Long GV, et al. Three-year pooled analysis of baseline and postbaseline factors associated with clinical benefit with combination dabrafenib and trametinib across phase 3 trials. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.
Disclosures: Long reports consultant roles with Amgen, Bristol-Myers Squibb, Merck/Merck Sharp & Dohme, Novartis and Roche; and honoraria from Bristol-Myers Squibb, Merck/Merck Sharp & Dohme and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.