PMID- 36636049 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230115 IS - 2078-6891 (Print) IS - 2219-679X (Electronic) IS - 2078-6891 (Linking) VI - 13 IP - 6 DP - 2022 Dec TI - A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma. PG - 3216-3226 LID - 10.21037/jgo-22-86 [doi] AB - 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 (P(0)=0.15, P(1)=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. CI - 2022 Journal of Gastrointestinal Oncology. All rights reserved. FAU - Aung, Kyaw L AU - Aung KL AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - McWhirter, Elaine AU - McWhirter E AD - Juravanski Cancer Centre, Hamilton, ON, Canada. FAU - Welch, Stephen AU - Welch S AD - London Health Science Centre, London, ON, Canada. FAU - Wang, Lisa AU - Wang L AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. FAU - Lovell, Sophia AU - Lovell S AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. FAU - Stayner, Lee-Anne AU - Stayner LA AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. FAU - Ali, Saara AU - Ali S AD - Ottawa Hospital Cancer Centre, Ottawa, ON, Canada. FAU - Malpage, Anne AU - Malpage A AD - London Health Science Centre, London, ON, Canada. FAU - Makepeace, Barbara AU - Makepeace B AD - Juravanski Cancer Centre, Hamilton, ON, Canada. FAU - Ramachandran, Makilpriya AU - Ramachandran M AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. FAU - Jang, Gun Ho AU - Jang GH AD - Ontario Institute for Cancer Research, Toronto, ON, Canada. FAU - Gallinger, Steven AU - Gallinger S AD - Ontario Institute for Cancer Research, Toronto, ON, Canada. FAU - Zhang, Tong AU - Zhang T AD - Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. FAU - Stockley, Tracy L AU - Stockley TL AD - Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Divison of Laboratory Genetics, Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto, ON, Canada. AD - Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada. FAU - Fischer, Sandra E AU - Fischer SE AD - Department of Pathology, University Health Network, Toronto, ON, Canada. FAU - Dhani, Neesha AU - Dhani N AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Hedley, David AU - Hedley D AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Knox, Jennifer J AU - Knox JJ AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Siu, Lillian L AU - Siu LL AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Goodwin, Rachel AU - Goodwin R AD - Ottawa Hospital Cancer Centre, Ottawa, ON, Canada. FAU - Bedard, Philippe L AU - Bedard PL AD - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. LA - eng PT - Journal Article PL - China TA - J Gastrointest Oncol JT - Journal of gastrointestinal oncology JID - 101557751 PMC - PMC9830369 OTO - NOTNLM OT - FAK inhibition OT - GSK2256098 OT - MEK inhibition OT - Pancreatic adenocarcinoma (PDAC) OT - trametinib COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-86/coif). EM received honoraria from Novartis for advisory board and educational activities in melanoma. SW received consulting fees from Amgen and Seattle Genetics and honoraria from GSK, Merk, Eisai, and Pfizer for speaking engagements and participation in advisory boards (these engagements did not relate to pancreatic cancer, nor did they involve the agents studied in this clinical trial). LLS has consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko; stock ownership of Agios (spouse); leadership position in Treadwell Therapeutics (spouse); and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, Avid; data safety monitor board participation with Mirati Therpeutics. PLB has uncompensated consulting/advisory arrangements with Merck, Lilly, BMS, SeaGen, Gilead, Amgen, Genentech/Roche; institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Amgen, Sanofi, Nektar Therapeutics, Bicara Therapeutics, Sanofi, Lilly; data safety monitor board participation with Lilly. The other authors have no conflicts of interest to declare. EDAT- 2023/01/14 06:00 MHDA- 2023/01/14 06:01 PMCR- 2022/12/01 CRDT- 2023/01/13 01:54 PHST- 2022/01/25 00:00 [received] PHST- 2022/08/12 00:00 [accepted] PHST- 2023/01/13 01:54 [entrez] PHST- 2023/01/14 06:00 [pubmed] PHST- 2023/01/14 06:01 [medline] PHST- 2022/12/01 00:00 [pmc-release] AID - jgo-13-06-3216 [pii] AID - 10.21037/jgo-22-86 [doi] PST - ppublish SO - J Gastrointest Oncol. 2022 Dec;13(6):3216-3226. doi: 10.21037/jgo-22-86.