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

• Published in: Journal of gastrointestinal oncology Vol. 13; no. 6; pp. 3216 - 3226
• Main Authors: Aung, Kyaw L, McWhirter, Elaine, Welch, Stephen, Wang, Lisa, Lovell, Sophia, Stayner, Lee-Anne, Ali, Saara, Malpage, Anne, Makepeace, Barbara, Ramachandran, Makilpriya, Jang, Gun Ho, Gallinger, Steven, Zhang, Tong, Stockley, Tracy L, Fischer, Sandra E, Dhani, Neesha, Hedley, David, Knox, Jennifer J, Siu, Lillian L, Goodwin, Rachel, Bedard, Philippe L
• Format: Journal Article
• Language: English
• Published: China AME Publishing Company 01.12.2022
• Subjects: Original; trametinib; GSK2256098; FAK inhibition; MEK inhibition; Pancreatic adenocarcinoma (PDAC)
• ISSN: 2078-6891; 2219-679X
• DOI: 10.21037/jgo-22-86

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. 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 (P =0.15, P =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. 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. The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.