A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

Adjei, Alex A.; Richards, Donald A.; El-Khoueiry, Anthony B.; Braiteh, Fadi; Becerra, Carlos; Stephenson, Joe; Hezel, Aram F.; Sherman, Morris; Garbo, Lawrence; Leffingwell, Diane P.; Iverson, Cory; Miner, Jeffrey N.; Shen, Zancong; Yeh, Li‐Tain; Gunawan, Sonny; Wilson, David M.; Manhard, Kimberly J.; Rajagopalan, Prabhu; Krissel, Heiko; Clendeninn, Neil J.

doi:10.1158/1078-0432.ccr-15-1681

Cited by 18 publications

(11 citation statements)

References 25 publications

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“…RAS-MAPK signaling has been implicated in tumor progression and dissemination in HCC (2). A phase I study of the combination of refametinib with sorafenib in patients with advanced malignancies including HCC demonstrated a favorable safety profile and pharmacokinetic profile at a maximum tolerated dose of refametinib 50 mg twice daily in combination with sorafenib 400 mg twice daily (12).…”

Section: Introductionmentioning

confidence: 99%

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma

Lim

Merle

Weiss

et al. 2018

Clinical Cancer Research

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Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with -mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with-mutant unresectable or metastatic HCC. Eligible patients with mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Of 1,318 patients screened, 59 (4.4%) had a mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in (63.0%), (48.1%), and β-catenin (; 37.0%). Prospective testing for family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of-mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. .

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Section: Introductionmentioning

confidence: 99%

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma

Lim

Merle

Weiss

et al. 2018

Clinical Cancer Research

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“…It has been shown to inhibit MAPK signalling downstream from MEK in vitro . Refametinib has been previously tested both alone [ 35 ] and in combination with both the mutli-target tyrosine kinase inhibitor sorafenib [ 36 ] and the PI3K inhibitor copanlisib [ 37 ] in Phase I and Phase II studies. It was well tolerated in all trials, with manageable drug-related adverse effects, either used alone or in combination with targeted therapies and demonstrated benefit in some patients with advanced cancer [ 35 - 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacodynamics analysis of patients recruited to the Phase I trial of refametinib [ 36 ] identified that refametinib can achieve a peak plasma conc of 700μg/ml (1.223μM). We classified HCC1954 cells which have an IC 50 of <500nM as sensitive to refametinib, whilst BT474 cells which have an IC 50 of 1.2μM are classified as slightly sensitive.…”

Section: Discussionmentioning

confidence: 99%

A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib

et al. 2017

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PurposeThe MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance to trastuzumab or lapatinib.MethodsA panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib. Reverse phase protein array (RPPA) was used to determine the effect of refametinib alone and in combination with PI3Ki and HER2-inhibitors on expression and phosphorylation of proteins in the PI3K/AKT and MEK/MAPK pathways. We validated our proteomic in vitro findings by utilising RPPA analysis of patients who received either trastuzumab, lapatinib or the combination of both drugs in the NCT00524303/LPT109096 clinical trial.ResultsRefametinib has anti-proliferative effects when used alone in 2/3 parental HER2-positive breast cancer cell lines (HCC1954, BT474), along with 3 models of these 2 cell lines with acquired trastuzumab or lapatinib resistance (6 cell lines tested). Refametinib treatment led to complete inhibition of MAPK signalling. In HCC1954, the most refametinib-sensitive cell line (IC50 = 397 nM), lapatinib treatment inhibits phosphorylation of MEK and MAPK but activates AKT phosphorylation, in contrast to the other 2 parental cell lines tested (BT474-P, SKBR3-P), suggesting that HER2 may directly activate MEK/MAPK and not PI3K/AKT in HCC1954 cells but not in the other 2 cell lines, perhaps explaining the refametinib-sensitivity of this cell line. Using RPPA data from patients who received either trastuzumab, lapatinib or the combination of both drugs together with chemotherapy in the NCT00524303 clinical trial, we found that 18% (n=38) of tumours had decreased MAPK and increased AKT phosphorylation 14 days after treatment with HER2-targeted therapies. The combination of MEK inhibition (MEKi) with refametinib and copanlisib led to synergistic inhibition of growth in 4/6 cell lines tested (CI @ED75 = 0.39-0.75), whilst the combinations of lapatinib and refametinib led to synergistic inhibition of growth in 3/6 cell lines (CI @ED75 = 0.39-0.80).ConclusionRefametinib alone or in combination with copanlisib or lapatinib could represent an improved treatment strategy for some patients with HER2-positive breast cancer, and should be considered for clinical trial evaluation. The direct down-regulation of MEK/MAPK but not AKT signalling by HER2 inhibition (e.g. by lapatinib or trastuzumab), which we demonstrate occurs in 18% of HER2-positive breast cancers may serve as a potential biomarker of responsiveness to the MEK inhibitor refametinib.

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“…No results appear to have been posted as of December 2019. A phase I safety study was performed on combining refametinib and sorafenib and demonstrated acceptable safety profiles [90]. Therefore, a phase II clinical trial (NCT01204177) to examine the effects of combining the drugs refametinib and sorafenib was performed with HCC patients [91].…”

Section: Background and Strategies Based On Targeting Ras/raf/mek/erkmentioning

confidence: 99%

New landscapes and horizons in hepatocellular carcinoma therapy

Cervello

Emma

Augello

et al. 2020

Aging

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Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and welltolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.

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A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

Cited by 18 publications

References 25 publications

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma

A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib

New landscapes and horizons in hepatocellular carcinoma therapy

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