Trametinib Misses the Mark in BRAF Non-V600-Mutant Solid Tumors and Lymphomas

Apr 29, 2020

"Single-agent trametinib had low rates of clinical activity in patients with heavily pretreated, metastatic cancers harboring non-V600 mutations in BRAF. This contrasts with a number of case reports, largely in melanoma, showing responses in patients with these mutations."

Trametinib failed to demonstrate clinical activity in patients with solid tumors and lymphomas who harbored a BRAF non-V600 mutation or fusion, according to results from the NCI-MATCH study published in Clinical Cancer Research.

“Single-agent trametinib had low rates of clinical activity in patients with heavily pretreated, metastatic cancers harboring non-V600 mutations in BRAF. This contrasts with a number of case reports, largely in melanoma, showing responses in patients with these mutations. Further study might help distinguish subpopulations that benefit from trametinib. In the interim, however, trametinib cannot be recommended as a single agent in patients harboring these mutations,” wrote the study authors led by Douglas B. Johnson, MD, of Vanderbilt Health in Nashville, Tennessee.

The NCI-MATCH study tested trametinib in Subprotocol R, based on preclinical evidence and case reports that suggested that MEK inhibition is a beneficial treatment strategy in tumors positive for BRAF mutations outside the V600 locus and BRAF fusions.

Fifty patients were assigned to Subprotocol R, and of those patients, 45 were enrolled and 15 were deemed ineligible for the study due to performance status (n = 3), other interventional treatment (n =1), monoclonal antibody treatment within 8 weeks of starting the study (n = 1), poor cardiac function/left ventricular ejection fraction (n = 2), prior treatment for or newly diagnosed brain metastases (n = 1), new second primary (n = 1), other medical reason (n = 2), and unknown reasons (n = 3). Following enrollment, an additional 3 patients were found to be ineligible for the study based on out-of-date laboratory tests, creatinine >2x upper limit normal (ULN) and creatinine clearance < 45 ml/min, and evidence of a baseline adverse event (AE), namely, grade 2 anemia.

Overall 32 patients were evaluable for efficacy, but none of the patients achieved a complete response (CR) with trametinib. There was 1 patient with a partial response (PR) and 10 patients with stable disease (SD). Fifteen patients who were evaluated for efficacy had progressive disease (PD). The response calculated from these results was 3% (90% CI, 0.2%-14%), and the potential clinical benefit rate was 34% (90% CI, 21%-50%).

Certain characteristics were notable in terms of efficacy. One relevant characteristic was the BRAF G469E mutation, which was observed in the female patient who had a PR. Additionally, in the 4 patients with SD defined as progression-free survival (PFS) longer than 6 months, 1 patient had lung adenocarcinoma with a BRAF G469A mutation, and another had prostate cancer with a BRAF K601E mutation.

In the overall study population, the median PFS was 1.8 months (90% CI, 1.7–3.4 months). The estimated 6-month PFS rate in the study was 17% (90% CI, 18%-30%). The median overall survival (OS) observed in patients was 5.7 months (90% CI, 4.1-8.1 months), and the estimated 6-month OS rate was 46% (90% CI, 30%-59%).

A total of 29 patients died by the time of the last follow-up. Three patients were alive at 2.2 months, 20.4 months, and 20.8 months.

Histology, co-occurring mutation, BRAF allele fraction, and BRAF mutation type were assessed in an exploratory analysis to determine their impact on trametinib efficacy. Trends found in this analysis included improved OS in patients with exon 11 BRAF compared with other mutation (HR, 3.22; 95% CI, 1.29-8.02), as well as with patients who lacked concurrent PI3K pathway gene mutations compared with those who had these mutations (HR, 0.50; 95% CI, 0.21-1.20). Improvement in PFS was observed in tumors with lower than median BRAF allele frequencies versus median frequencies (HR, 0.76; 95% CI, 0.36-1.61). A trend toward better OS was also seen in low BRAF allele frequencies compared with median BRAF allele frequencies (HR, 0.67; 95% CI, 0.32-1.43). In terms of mutation class, an improvement in PFS and OS were seen in class 2 mutations (HR, 0.50; 95% CI, 0.22-1.14) versus class 3 mutations (HR, 0.62; 95% CI, 0.29-1.31).

Thirty-four patients were evaluated for toxicity in the study. The toxicities observed with trametinib were consistent with known toxicities for MEK inhibitors. Overall 47% of patients experienced a grade 1 or 2 AE, and 35% of patients had a grade 3 AE. The most common AEs were anemia (32%), nausea (35%), peripheral edema (32%), and acneiform rash (32%).

Patients received a median of 2 cycles (range, 1-22) of trametinib in the study. A total of 6 patients (19%) discontinued treatment due to toxicity, while 15 discontinued due to PD and 4 patients died during the study, 2 of which were drug-related deaths.

Although a small number of patients did derive benefit from trametinib, the drug showed low activity overall in patients with solid tumors and lymphomas harboring BRAF non-V600 mutations. Also, the study authors note that the low number of patients with BRAF fusions in the study made it impossible to characterize the population. No explanation for the lack of clinical benefit could be provided. Thus, Johnson et al. do not recommend the use of trametinib as monotherapy in patients with BRAF non-v600 mutations.

Reference:

Johnson DB, Zhao F, Noel M, et al. Trametinib activity in patients with solid tumors and lymphomas harboring braf non-v600 mutations or fusions: results from NCI-MATCH (EAY131). Clin Cancer Res. 2020; 26 (8). doi: 10.1158/1078-0432.CCR-19-3443.

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