Trametinib Research Articles

BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors.

Inhibitors targeting active protein kinases, such as EGFR or ALK, have demonstrated significant efficacy in the treatment of lung cancer. Activating mutations in the MAPK pathway, which includes the enzymes RAS, RAF, MEK, and ERK, result in constitutive signalling, leading to oncogenic cell proliferation and escape from apoptosis; therefore this pathway is a focus of crucial interest for the development of cancer drugs. In melanoma, the most commonly mutated gene is BRAF, with mutations usually occurring in about 50% of all tumours. The BRAF Val600Glu (V600E) mutation constitutes more than 90% of mutations in melanoma. V600E BRAF mutation shows a great dependency on MEK activity, and offers a rational therapeutic strategy for this genetically defined tumour subtype. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. The frequency of V600E BRAF mutation in lung adenocarcinoma is 1.5% to 2.8%. Treatment of V600E BRAF-mutant lung adenocarcinomas with dabrafenib is under evaluation in a phase 2 trial, and could represent another milestone in individualized therapy for lung cancer patients. The next step will be a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib.

Abstract 2344: Modeling 1st- and 2nd-line therapy of BRAF mutant melanoma using a novel BRAF inhibitor with DFG-out binding mode.

Abstract The BRAF inhibitor vemurafenib (VEM) was approved for treatment of patients with BRAFV600E melanoma based on an ORR of 48% and a PFS of 5.3 months. Phase III data reported for the BRAF inhibitor dabrafenib (DAB) as well as the MEK inhibitor trametinib (TRA) in BRAFmut melanoma indicate similar outcomes. Phase I/II data published recently for a combination of DAB and TRA suggest improved efficacy compared with single-agent therapy; nevertheless, the short duration of responses even for the combination points to an urgent need for further improvement. BI 882370, a potent and selective B/CRAF inhibitor, binds to the DFG-out (inactive) conformation of BRAF, whereas VEM as well as DAB occupy the DFG-in (active) conformation. BI 882370 inhibited proliferation of BRAFmut melanoma cell lines with about 100x higher potency (EC50 1 - 10 nM) than VEM; BRAFwt cell lines were not affected at 1 μM. For studies in nude mouse xenograft models, VEM and DAB were dosed to provide exposures achieved in patients; TRA was used at the MTD for mice, resulting in exposures at or above the exposures tolerated by humans. In the G361 melanoma model (BRAFV600E), 1st line treatment with 25 mg/kg BI 882370 administered twice daily (bid) resulted in partial regression of all tumors, superior to results achieved by VEM, DAB as well as their combination. To model clinical resistance, a large cohort of A375 melanoma (BRAFV600E) bearing mice was treated with VEM; without exception, all tumors responded with partial regression and their median volume reached a nadir on day 11. Thereafter, the majority of tumors resumed growth in spite of continued treatment, whereas tumors in a subset of animals regressed further. Progressing tumors were randomized to 2nd line therapy on day 36 (median volume 280 mm3). TRA did not show any efficacy in this resistant population. BI 882370 induced tumor regression, however, resistance developed within 3 weeks. BI 882370 in combination with TRA resulted in more pronounced regressions and resistance was not observed until the end of the experiment, 6 weeks after initiation of 2nd line therapy. Importantly, in multiple in vivo studies performed to date, mice treated with BI 882370 at doses of 25 mg/kg bid for several weeks did not show any body weight loss or clinical signs of intolerability. Mice treated for 2 weeks were euthanized and major organs subjected to histological analysis. No changes were observed in any of the animals; in particular, there was no evidence for epidermal hyperplasia. Further, a pilot study in male rats dosed at 25 mg/kg bid for 2 weeks did not result in any toxicologically relevant findings in terms of clinical chemistry, hematology, pathology and toxicogenomics of liver and skin. Our results suggest that compared to 1st generation BRAF inhibitors, BI 882370 may provide an improved therapeutic window, enabling more pronounced and longer-lasting pathway suppression and thus resulting in improved efficacy. Citation Format: Irene C. Waizenegger, Anke Baum, Heinz Stadtmüller, Steffen Steurer, Gerd Bader, Pilar Garin-Chesa, Norbert Schweifer, Andreas Bernthaler, Christian Haslinger, Otmar Schaaf, Sien Mousa, Florian Colbatzky, Günther R. Adolf. Modeling 1st- and 2nd-line therapy of BRAF mutant melanoma using a novel BRAF inhibitor with DFG-out binding mode. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2344. doi:10.1158/1538-7445.AM2013-2344

Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group

Background Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. Methods In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. Results Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54;95% CI, 0.32 to 0.92; P = 0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. Conclusions Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials .gov number, NCT01245062.)

And the Hits Keep Coming

This month, a third agent joined vemurafenib and trametinib as a highly effective treatment for BRAF -mutated melanomas. In a prospective, randomized phase III study, the selective BRAF inhibitor dabrafenib was found to improve the survival of stage IV melanoma patients. The investigators …

Abstract B155: A phase I study of the MEK inhibitor GSK1120212 (GSK212) in combination with PI3K/mTOR inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors.

Abstract Background: This is a Phase I, open-label, dose escalation, pharmacokinetic (PK), pharmacodynamic (PD) and safety study in patients (pts) with advanced solid tumors exploring the combination of the investigational drugs GSK458 and GSK212. GSK212 is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinases 1 and 2 (MEK1 and MEK2). GSK458 is a potent, reversible, ATP-competitive, pan-phosphoinositide-3 kinase (PI3K) inhibitor, which also inhibits the mammalian target of rapamycin (mTOR), and the common activating mutations of catalytic isoform p110α. The MTD for daily, continuous dosing of monotherapy GSK458 is 2.5mg and GSK212 is 2.0mg. Methods: The study consists of two parts: dose escalation in Part 1 (ongoing) uses a zone design (3+3 rules) to study safety, tolerability, PK, PD and clinical activity, and to establish the maximum tolerated doses (MTDs) and schedules for the combination. Adult pts with relapsed or refractory solid tumors are receiving oral doses of GSK458+GSK 212 once daily until disease progression or toxicity. Efficacy is assessed using RECIST 1.1. Part 2 will examine safe dose combinations from Part 1 in patients with tumors likely to respond to MEK/PI3K pathway inhibition. Genetic and protein profiles collected from blood and tumor samples will be used to explore relationships between predictive biomarkers of response and efficacy. Results: 34 pts(45% female) with a mean age of 58y (range 37–82y) have enrolled. Safety data includes31 subjects who have received ≥1 dose of GSK458+GSK212. Most commonly reported drug-related AEs &amp;gt;10%, n=31) include rash (68%; G3/4, 3%), diarrhea (42%; G3/4, 6%), nausea (29%; G3/4, 0%), vomiting (23%; G3/4, 3%), decreased appetite (19%; G3/4, 0%), stomatitis (13%; G3/4, 3%) and fatigue (13%; G3/4; 3%). Of 21 serious adverse events (SAEs) reported in 14 pts, 3 were considered related to study drug. Stable disease has been observed in several patients with the longest being at 6 months (renal cell carcinoma and colorectal cancer). The combination of GSK458 0.5 mg + GSK212 2.0 mg exceeded the MTD. However, once daily and continuous combination dosing of GSK458 (0.5, 1.0 or 1.5mg) + GSK212 ≤ 2.0 mg were well tolerated. Conclusions: The preliminary safety profile and anti-tumor activity of this combination warrants further investigation in continued dose escalation and planned expansion cohorts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B155.

Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436).

CRA8503 Background: In preclinical models, the BRAF/MEK inhibitor (i) combination GSK436/GSK212 has demonstrated enhanced activity against BRAF-mutant cancer cells compared to either drug alone, delayed emergence of GSK436 resistance, and prevented proliferative skin lesions attributable to BRAFi exposure. Methods: Eligible patients (pts) had BRAF V600 mutation positive solid tumors. Part 1: pharmacokinetic (PK) drug-drug interaction (DDI) study. Part 2: Dose escalation of continuous daily dosing of the combination followed by expansion cohorts; Part 3: Randomized phase II trial in untreated stage IV melanoma. Results: 45 pts have received ≥ 1 dose of GSK212 + GSK436, including 43 melanoma (all BRAFi naïve), 1 NSCLC and 1 salivary duct carcinoma. PK results of 7 pts in Part 1 showed no effect of GSK212 on single dose of GSK436. There was no clinically meaningful DDI between GSK436 and GSK212 after repeat dosing of the combination (Part 2). GSK436 was dosed 75-150 mg BID in combination with GSK212 1.0, 1.5, 2.0 mg QD. The recommended dose was 2 mg QD GSK212 in combination with 150 mg BID GSK436. At 1.5 mg GSK212, there was one DLT, a recurrent grade (G) 2 neutrophilic panniculitis. The only G4 adverse event (AE) was a sepsis-like syndrome with fever/hypotension. G3 AEs included generalized rash (n=2, 4%) and neutropenia (n=2, 4%). Skin toxicity ≥ G2 occurred in 9 (20%) pts; of these, G2 rash (n=4, 8%) and G2 macular rash (n=1, 2%). No cutaneous squamous cell carcinoma (SCC) or hyperproliferative skin lesions have occurred at any dose level. Other common G2 toxicities were pyrexia (n=5, 11%), vomiting (n=2, 4%) and fatigue (n=2, 4%). Of 16 evaluable pts in Part 2, 13 pts had PR and 3 SD for an ORR of 81% (95% CI 54.4%-96.0%) and all but 2 pts remain on study. In 10 evaluable pts who received 150 mg BID GSK436 + ≥1 mg QD GSK212, 9 pts had PR and 1 SD. Conclusions: GSK212 at 2 mg QD combines safely with GSK436 150 mg BID, no SCC thus far and decreased frequency of rash compared to previous trials of single agent GSK436 and GSK212, respectively. The preliminary anti-tumor activity warrants further investigation; the randomized phase II trial (Part 3) is accruing.

Phase I/II trial of the MEK1/2 inhibitor GSK1120212 (GSK212) in patients (pts) with relapsed/refractory myeloid malignancies: Evidence of activity in pts with RAS mutation.

6506 Background: Signaling through the RAS/RAF/MEK pathway is activated in many human cancers. GSK212 is a potent, selective allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A phase I/II study of a single, daily, oral dosing regimen was conducted to define the recommended phase II dose (RP2D) and evaluate pharmacokinetics, toxicity and preliminary activity in pts with previously treated hematologic malignancies. Results reported are from the RP2D; 2mg/day. Methods: Pts with relapsed/refractory AML, MDS, ALL or CMML with WBC <30,000/µL and adequate hepatic, renal and cardiac function were eligible for this study. Pts were prospectively screened for KRAS mutations at amino acids 12 and 13 using a PCR-based kit and for NRAS mutations at amino acids12, 13, and 61 using sequence analysis. Clinical response was assessed using International Working Group (2003 and 2006) criteria for AML and MDS. Results: 45 pts (30 AML, 12 MDS transformed to AML) received 2mg GSK212 daily. 73% were male; median age 62 (range 21–87) and 93% had received prior therapy. GSK212 exhibited long effective half-life with small peak/trough ratios and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Drug-related adverse events (AEs; >10%) were diarrhea 29% (n=13; 24% Grade 1/2, 4% Grade 3), and rash 22% (n=10; 20% Grade 1/2, 2% Grade 3), myelosuppression was not noted. AEs possibly related to inhibition of MEK signaling were blurred vision (n=3; 4% Grade 1, 2% grade 3) and decreased cardiac ejection fraction (n=1; Grade 3). Conclusions: GSK212 demonstrates encouraging signs of clinical activity with manageable AEs in pts with previously treated AML characterized by somatic RAS mutations. Recruitment of pts with N or KRAS mutant AML/MDS and CMML is ongoing. Best response n=39* N or KRAS mutated n=13 RAS wt or unk n=26 CR/CRp 3 (23%) 0 MLFS 1 (8%) 0 PR 0 2 (8%) HI/HI-N/HI-P 1 (8%) 4 (15%) SD# 7 (54%) 9 (35%) PD 1 (8%) 11 (42%) ORR 31% (95% CI 9%, 61%) 8% (95% CI 1%, 25%) * 6 pts not evaluable were RAS wt/unk; 5 had screen assessments only; 1 lacked follow-up. #Investigator assessed. Abbreviation: MLFS, morphologic leukemia-free state.

Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795).

3085 Background: The RAS/RAF/MEK and PI3K/AKT pathways are activated in many human cancers. GSK212 is a potent and selective allosteric inhibitor of MEK1/2 and GSK795 is a potent ATP-competitive in...

Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436).

CRA8503 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20, 2011, issue of Journal of Clinical Oncology.

Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study

4502 Background: GSK089 is an oral, small-molecule inhibitor of cMET and VEGFR2/KDR, and has potent antitumor activity in cMET-amplified cell lines and xenografts. cMET is reportedly amplified, overexpressed and/or activated in GC, making it an attractive therapeutic target. This phase II study examines the safety and efficacy of 2 dosing schedules of GSK089 as a single agent in patients (pts) with metastatic GC. Methods: Pts with distal esophagus, GE junction or stomach adenocarcinoma, 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG PS 0–2 are sequentially enrolled in 2 cohorts: 1) Intermittent 5 days on/9 off - GSK089 240 mg/d on D1–5 repeated every 14 days, and 2) Daily - 80 mg/d. Primary study endpoint (response) is assessed every 8 weeks. cMET amplification by FISH (≥2 copies of cMET per copy of chromosome 7) is not an entry criterion, but is determined on archival tissue for all pts. Pre- and on-treatment tumor biopsies in select pts and plasma samples in all pts are analyzed for GSK089 effects on direct and downstream drug targets. GSK089 pharmacokinetics (PK) are also evaluated. Results: As of 12/19/08, enrollment to the 5 on/9 off cohort is complete with 41 evaluable pts, and 14 evaluable pts have enrolled on the daily cohort. cMET amplification was seen in 3/43 (7%) pts tested; all 3 were in 5 on/9 off cohort. Best response of stable disease (SD), was noted in 6/41 (15%) pts in the 5 on/9 off cohort (none were cMET-amplified), with 2 pts SD &gt;6 months, 1 ongoing; and in 3/14 (21%) pts in the daily cohort. Among all-enrolled pts (48 pts in 5 on/9 off, 16 pts in daily cohort), LFT abnormalities (9%), fatigue (5%), and venous thromboembolism (3%) were the most common GSK089 related grade 3- 4 adverse events (AE). Only 1 possibly related grade 5 AE, death due to unknown cause, was noted. Conclusions: GSK089 is well tolerated on both dosing schedules. cMET amplification in metastatic GC is rare. Single agent GSK089 demonstrates minimal antitumor activity in a cMET-unselected gastric population on the 5 on/9 off schedule. Enrollment on the daily dosing schedule continues, now with mandatory pre- and on-treatment biopsies to better define cMET pathway and target inhibition with GSK089. No significant financial relationships to disclose.

A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC)

5103 Background: GSK089 is a potent, orally available small molecule inhibitor of MET and VEGFR2. Activating mutations and/or amplifications in MET have been described in pts with PRC. Two of 4 PRC pts treated with intermittent dosing of GSK089 on a Phase I study sustained partial responses (PR) for 1 and &gt; 3 years respectively. The aim of the current study is to evaluate the efficacy, safety and tolerability of 2 dosing regimens of GSK089 as a single agent in pts with advanced sporadic PRC (SPRC) or hereditary PRC (HPRC). Methods: Adults with advanced PRC are enrolled in 2 cohorts with different dosing schedules of GSK089: cohort 1) 240 mg/day on days 1–5 of every 14 days (5-on/9-off); cohort 2) 80 mg daily. Pts are stratified based on status of MET-pathway activation (activating MET mutation, MET [7q31] amplification, or trisomy 7). The primary endpoint is RECIST response rate, assessed every 8 weeks. Plasma markers reflecting potential effects of MET inhibition and anti-VEGF therapy are analyzed. Results: As of December 15, 2008, 37 pts were enrolled in the 5-on/9-off cohort (19 with MET activation including 5 HPRC, 18 SPRC without MET activation or unknown MET status), and 16 pts in the daily dosing cohort (2 with HPRC, 14 SPRC with unknown MET status). Enrollment is ongoing in cohort 2. In cohort 1, of the 35 evaluable pts, 4 pts (2 HPRC and 2 SPRC) had confirmed PRs and 27 had stable disease (SD) as best response with 6 ≥12mo, 3 ≥ 9mo and 3 ≥ 6mo. Four of 5 HPRC pts (1 not evaluated) had shrinkage (15–53%) in all measurable tumors. Twenty-three SPRC pts had shrinkage (2–58%) in the sum of measurable tumors. In cohort 2, of the 9 evaluable pts, 2 (both SPRC) had confirmed PRs, and 7 had SD. The most frequent adverse events (AEs) associated with GSK089 were fatigue, hypertension, nausea, vomiting, diarrhea, and increased ALT/AST, primarily grades 1 and 2. Preliminary results from cohort 1 indicated that plasma shed Met (sMET) and VEGF increased and sVEGFR2 decreased after 2 cycles with changes maintained after 4 cycles. Conclusions: GSK089 is well tolerated and demonstrates anti-tumor activity in pts with PRC with both 5-on/9-off and daily dosing. VEGF, sVEGFR2, and sMET are promising pharmacodynamic markers for biological activity of GSK089. [Table: see text]