A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours

Our plain-English summary of A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours, by G. Mak, J.C. Soria, S.P. Blagden, et al (British Journal of Cancer, 2019).

The study

• Authors: G. Mak, J.C. Soria, S.P. Blagden, R. Plummer, R.A. Fleming, N. Nebot, J. Zhang, J. Mazumdar, D. Rogan, A. Gazzah, I. Rizzuto, A. Greystoke, L. Yan, J. Tolson, K.R. Auger, H.T. Arkenau
• Journal: British Journal of Cancer
• Published: 2019;120(10):975-981
• Cited by: 80 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy.

Methods: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed.

Results: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks).

Conclusions: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

In plain English

This was an early-stage (phase Ib) drug trial, not an asbestos exposure study. It tested two oral cancer drugs together, the focal adhesion kinase inhibitor GSK2256098 and the MEK inhibitor trametinib. The trial included 34 patients with advanced solid tumours at four centres in the UK and France between 2013 and 2016; 21 had mesothelioma. The maximum tolerated dose pairs were GSK2256098 500 mg twice daily with trametinib 0.375 mg once daily, and 250 mg twice daily with 0.5 mg once daily. The commonest adverse events were nausea (59%) and diarrhoea (53%); none were grade 4. After adjusting for dose, trametinib exposure was 2- to 4-fold higher than in earlier trametinib-alone data, while GSK2256098 exposure was unchanged. No patient had an objective response; 13 (38%) had stable disease. In an exploratory analysis of mesothelioma patients, median progression-free survival was 11.8 weeks (95% CI 6.1 to 24.1). It was 15.0 weeks (95% CI 4.4 to 24.1) in 14 patients with absent or low tumour Merlin staining, and 7.3 weeks in 3 Merlin-positive patients (CI not calculable). The authors concluded that support for the combination's efficacy was limited.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multipart phase I (phase Ib) dose-finding study using an adaptive 3 + 3 design, with pharmacokinetic and pharmacodynamic analyses; no formal statistical hypotheses were tested
• Who was studied: 34 adults with mesothelioma or other advanced solid tumours with a high likelihood of MAPK pathway activation, who had received at least one prior course of chemotherapy; 21 (62%) had mesothelioma; treated at three UK centres and one French centre, November 2013 to June 2016
• Exposure: No asbestos exposure was studied. Patients received the oral drugs GSK2256098 (250 or 500 mg twice daily) and trametinib (0.25 to 1 mg once daily) in combination, across five dose cohorts
• Main results:
  • Maximum tolerated doses: GSK2256098 500 mg twice daily with trametinib 0.375 mg once daily (high/low), and GSK2256098 250 mg twice daily with trametinib 0.5 mg once daily (low/high)
  • All 34 subjects: adverse events in at least 20% included nausea (59%), diarrhoea (53%) and decreased appetite (38%)
  • No grade 4 adverse events occurred; 20 subjects (59%) had at least one grade 3 adverse event
  • After dose normalization, trametinib geometric mean peak concentration and AUC were 2- to 4-fold higher when given with GSK2256098 than in trametinib monotherapy data from an earlier study; GSK2256098 exposure was not altered by trametinib
  • All subjects: no objective responses; best response was stable disease in 13 subjects (38%)
  • Mesothelioma subjects: median progression-free survival 11.8 weeks (95% CI 6.1 to 24.1)
  • Mesothelioma subjects by Merlin status: median PFS 15.0 weeks (95% CI 4.4 to 24.1) in 14 Merlin-negative subjects (absent or low staining) versus 7.3 weeks in 3 Merlin-positive subjects (CI not calculable)
  • Of 6 subjects with evaluable paired tumour biopsies, 3 showed more than 70% decrease and 2 more than 45% reduction in pFAK/FAK from baseline; 1 showed an increase
• The authors' conclusion: The authors concluded that they identified maximum tolerated doses for the combination for future studies, but that there was limited support for its efficacy in these patients
• Limitations the authors state:
  • No formal statistical hypotheses were tested; the PFS analysis in mesothelioma was exploratory
  • pERK data were obtained in only three of the eight subjects with paired biopsies

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Disease Progression, Progression-Free Survival, Merlin.

Related studies

• A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors — J.C. Soria, H.K. Gan, et al. (2016)
• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)
• A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours — D. Jamieson, M.J. Griffin, et al. (2016)
• Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma — H. Cho, S. Matsumoto, et al. (2017)
• Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors — R. Bahleda, M.C. Le Deley, et al. (2018)
• Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer — K. Fizazi, M. Ducreux, et al. (2000)

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