<div>The combination of the MEK inhibitor refametinib and sorafenib improved overall survival and overall response rate compared with refametinib alone in patients with <em>RAS</em>-mutated hepatocellular carcinoma, according to an analysis of a pair of phase II proof-of-concept studies.</div>
The combination of the MEK inhibitor refametinib and sorafenib (Nexavar) improved overall survival (OS) and overall response rate (ORR) compared with refametinib alone in patients withRAS-mutated hepatocellular carcinoma (HCC), according to an analysis of a pair of phase II proof-of-concept studies.1
Fifty-nine (4.4%) of 1318 total patients screened had aRASmutation. Among patients with the mutation, 16 received 50 mg of refametinib twice daily and 16 received refametinib plus 400 mg of sorafenib. OS was 5.8 months for monotherapy compared with 12.7 months for the combination. ORR (6.3% vs 0%) favored the sorafenib group, but progression-free survival (1.9 vs 1.5 months) and disease control rate (56.3% vs 43.8%) both favored the monotherapy arm.
According to mRECIST, no patient in the monotherapy study had confirmed complete or partial response (PR). There was 1 confirmed and 2 unconfirmed PRs in the combination study.
“Despite the poor ORR in patients withRASmutations, a median overall survival of 13 months in the small population included in the refametinib plus sorafenib study may indicate a synergistic effect between refametinib and sorafenib that should be further explored in a larger patient population that is not stratified byRASmutational status, taking into account other prognostic factors based on patient heterogeneity and intratumor heterogeneity,” first investigator Ho Yeong Lim, MD, PhD, Samsung Medical Center, Sungkyunkwan University School of Medicine, and colleagues wrote.
Patients were prospectively screened forRASmutations based on evaluation of mutational status in ctDNA, which investigators concluded to be a feasible and non-invasive approach for large-scale mutational testing.
Refametinib is a MEK1/2 inhibitor that binds in an allosteric site adjacent to the ATP pocket, and is selective for MEK1/2 versus 205 other kinases.
From September 2013 to June 2014, 498 patients enrolled in the refametinib monotherapy study across 17 countries. A total of 493 patients underwent mutational testing and 32 (6.5%) were positive for aRASmutation.
The median time since initial diagnosis was 72.1 weeks and 9 patients had received sorafenib in first-line. The median patient age was 69 years.
In the refametinib/sorafenib study, 820 patients enrolled at centers across 21 countries from September 2013 to April 2015. Investigators performed mutational testing on 815 patients and 27 (3.3%) had aRASmutation.
The median time since initial diagnosis was 32.2 weeks and the median patient age was 67 years. Regardless ofRASmutation status, baseline characteristics and demographics were similar between the 2 studies.
According to central assessment using mRECIST criteria, 1 (6.3%) patient had an unconfirmed PR and 8 (50%) had stable disease in the monotherapy study. As assessed by RECIST v1.1, no patients had complete or partial response, 10 patients (62.5%) had stable disease and 2 (12.5%) had progression. Four patients were not evaluable.
Four (25.0%) patients in the combination study had stable disease according to mRECIST. As assessed by RECIST version 1.1, 1 had a confirmed PR and 1 had unconfirmed PR. Six (37.5%) patients had stable disease and 5 (31.3%) experienced progression. Data was missing for 4 patients.
Duration of response was 1.4 months for the 1 patient in the combination study who had a confirmed PR according to central assessment. For the 1 patient who had a confirmed response according to investigator assessment, duration of response was 2.7 months. The former patient had aKRASG35Apoint mutation and the latter had aKRASG38Amutation.
Time to progression was 2.8 months in both studies.
The investigators’ target for the first stage of the trials (≥5/15 patients with a CR or PR) was not met, and thus the planned evaluation of refametinib monotherapy or combination therapy in a larger population of patients was not started.
Previous findings from the phase II BASIL trial in patients with HCC demonstrated that the majority of patients who responded to the combination of refametinib and sorafenib hadRASmutations, with an ORR of 75% inRAS-mutant patients and 1.5% in patients not harboring aRASmutation.
Despite these previous findings, investigators found that “these results suggest that the use of RAS mutational status as a prognostic biomarker for treatment response to refametinib monotherapy or in combination with sorafenib was unsuccessful, and targeting MEK with refametinib in this RAS-mutant patient population did not lead to a significant proportion of objective responses.”
However, investigators noted that the low number of patients treated should be taken into account, and the low proportion of responses observed may reflect random error.
Investigators prospectively assessed mutation status using the beads, emulsion, amplification, and magnetics technology (BEAMing; Sysmex Inostics GmbH) to analyze samples collected from 27 patients during pretreatment. They then analyzed peripheral whole-blood samples for detection of genomic alterations in patients with mutatedRASusing FoundationACT, a next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) hybrid-capture-based assay. FoundationACT examines 62 genes for all classes of alterations including base substitutions, insertions and deletions, copy-number variations, and rearrangements/fusions.
NGS confirmed mutational status in 12 (44.4%) patients. Concordance between the 2 assays for detection ofRASsomatic aberration was 91.7%.
“The analysis of mutational status using ctDNA isolated from plasma as a liquid biopsy was a feasible, noninvasive technique in patients with unresectable or metastatic HCC, although RAS mutational frequency was low,” Lim et al wrote. “Further analysis of this technique is warranted for discovery of predictive biomarkers in HCC and other cancers.”
In March of this year, a joint panel from ASCO and the College of American Pathologists concluded ctDNA testing should be used only to screen for participation in, or during, a clinical trial for the time being. After reviewing data from a decade of clinical research, the panel found that it is not possible to know whether the use of most liquid biopsies in advanced cancer is justified outside the context of a clinical trial.2
However, the panel added that liquid biopsies could earn a place in clinical practice as better data becomes available.
All 16 patients in both studies experienced at least 1 treatment-emergent adverse event (TEAE). In the monotherapy arm, 11 (68.8%) patients experienced grade 3 TEAEs and 0 experienced grade 4, compared with 11 and 3 (18.8%), respectively, in the combination study. One patient in the monotherapy study died of progression, 2 died of AEs related to progression, and 2 died of AEs unrelated to progression. Two (12.5%) patients died in the combination study, 1 due to progression and 1 due to progression-related AEs.