Patients with BRAF V600E–Mutant NSCLC Show Improved Overall Survival with Dabrafenib + Trametinib Combination

2020 Year in Review - Non–Small-Cell Lung Cancer - Lung Cancer

Treatment with dabrafenib and trametinib produced similar benefits in pretreated and treatment-naïve patients.

Updated survival and genomic analysis data from a multicenter, open-label phase 2 study (BRF113928) were presented at the 2020 ASCO Virtual Scientific Program. The study evaluated the safety and efficacy of dabrafenib + trametinib in pretreated patients (cohort B) and treatment-naïve patients (cohort C) with BRAF V600E–mutant, metastatic non–small-cell lung cancer (NSCLC); the results of the initial primary analysis were previously reported.

Thirty-six treatment-naïve patients and 57 pretreated patients were given 150 mg dabrafenib twice daily and 2 mg trametinib once daily. The primary end point was overall response rate; secondary end points were progression-free survival (PFS), duration of response, overall survival (OS), safety, tolerability, and pharmacokinetics of dabrafenib and trametinib. The next-generation sequencing Oncomine Dx Target Test was used to sequence tumor samples. To assess the possible associations between patient efficacy end points and genomic landscape, the researchers used Kaplan-Meier curves and Cox regression models.

As of June 22, 2019, the treatment-naïve patients had a median follow-up of 16.3 months and a median OS of 17.3 months (95% confidence interval [CI], 12.3-40.2; 3-year OS, 40%); 14 of 36 patients were still alive. The pretreated patients had a median follow-up of 16.6 months and a median OS of 18.2 months (95% CI, 14.3-28.6; 3-year OS, 33%); 11 of 57 patients were still alive.

Among 62 tumor samples from 93 patients, 57 had confirmed BRAF V600E mutation. Of the 5 nonconfirmed BRAF tumor samples, 2 had JAK3 S493C mutations, 1 had a c-MET T1010I mutation, 1 had a KRAS G12V mutation, and 1 had an ALK fusion, with a median PFS of 13.8 months and an OS that was not estimable because of limited data. There were 11 BRAF V600E–mutant patients with concomitant somatic mutations and/or genetic alterations: 4 patients had mutations in the PI3K pathway, 4 patients had mutations at IDH1 R132X, 1 patient had a BRAF G466V mutation, 1 patient had a KRAS G13C mutation, and 1 patient had a c-MET exon 14 skipping mutation. Patients with these concomitant mutations, especially PI3K pathway mutations, had a trend of decreased PFS and OS. The safety profile showed similar results to the previous report.

The authors concluded that dabrafenib + trametinib treatment improves OS in patients with BRAF V600E–mutant NSCLC, and noted that concomitant genetic mutations can influence clinical outcomes in these patients. Additional analysis of genomic data is ongoing.

  Treatment-naïve Pretreated
N=57
  N = 36  
ORR, n (%)a 23 (63.9) 39 (68.4)
95% CI 46.2-79.2 54.8-80.1
mDOR, monthsa 10.2 9.8
95% CI 8.3-15.2 6.9-18.3
mPFS, monthsa 10.8 10.2
95% CI 7.0-14.5 6.9-16.7
mOS, months 17.3 18.2
95% CI 12.3-40.2 14.3-28.6
OS rates, % (95% CI)
12-month 74 (55-85) 66 (52-77)
24-month 49 (32-65) 41 (28-53)
36-month 40 (24-56) 33 (21-46)
48-month NA (NA) 26 (15-38)
aInvestigator assessment.

CI indicates confidence interval; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; NA, not applicable; ORR, overall response rate; OS, overall survival.

Reference
Planchard D, et al. J Clin Oncol. 2020;38(suppl 15):Abstract 9593.

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