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A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma

Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor.

Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling.

Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression.

Conclusions: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

 

Comments:

The study aimed to evaluate the efficacy and safety of combining GSK2256098, an oral focal adhesion kinase (FAK) inhibitor, with trametinib, an oral MEK1/2 inhibitor, in patients with advanced pancreatic ductal adenocarcinoma (PDAC) whose disease had progressed after first-line palliative chemotherapy. The primary endpoint of the study was clinical benefit, defined as a complete response, partial response, or stable disease lasting for at least 24 weeks.

A total of 16 patients were enrolled in the study, and 11 of them were included in the response evaluation. Among the 11 response-evaluable patients, 10 experienced progressive disease as the best tumor response, indicating disease worsening, while one patient achieved stable disease for 4 months. No treatment-related grade ≥3 adverse events (AEs) were observed during the study, suggesting that the combination therapy was well tolerated.

The median progression-free survival (PFS) was 1.6 months, with a 95% confidence interval (CI) ranging from 1.5 to 1.8 months. The median overall survival (OS) was 3.6 months, with a 95% CI ranging from 2.7 months to not reached, indicating that the study did not follow patients long enough to determine the upper limit of OS.

Serial blood samples were collected to analyze circulating tumor DNA (ctDNA) for mutation profiling. In one patient who was not evaluable for response, clinical stability was achieved for 5 months, accompanied by a reduction in CA19-9 (a tumor marker) and ctDNA levels. However, at clinical progression, a treatment resistance mutation in the MAP2K1 gene was detected in the ctDNA sample.

In conclusion, the combination of GSK2256098 and trametinib was well tolerated but did not demonstrate significant activity in the unselected population of advanced PDAC patients enrolled in the study. The median PFS and OS were relatively short, suggesting limited effectiveness of the combination therapy in this patient population.

Related Products

Cat.No. Product Name Information
S8523 GSK2256098 GSK2256098 is a potent, selective, reversible, and ATP competitive FAK kinase inhibitor with apparent Ki of 0.4 nM. GSK2256098 inhibits cancer cell growth and induces apoptosis.

Related Targets

Apoptosis related FAK