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. 2022 Dec;13(6):3216-3226.
doi: 10.21037/jgo-22-86.

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

Kyaw L Aung  1   2 , Elaine McWhirter  3 , Stephen Welch  4 , Lisa Wang  1 , Sophia Lovell  1 , Lee-Anne Stayner  1 , Saara Ali  5 , Anne Malpage  4 , Barbara Makepeace  3 , Makilpriya Ramachandran  1 , Gun Ho Jang  6 , Steven Gallinger  6 , Tong Zhang  7 , Tracy L Stockley  7   8   9 , Sandra E Fischer  10 , Neesha Dhani  1   2 , David Hedley  1   2 , Jennifer J Knox  1   2 , Lillian L Siu  1   2 , Rachel Goodwin  5 , Philippe L Bedard  1   2
Affiliations

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

Kyaw L Aung et al. J Gastrointest Oncol. 2022 Dec.

Abstract

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.

Keywords: FAK inhibition; GSK2256098; MEK inhibition; Pancreatic adenocarcinoma (PDAC); trametinib.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Duration on study treatment for all patients who are treated with at least one dose of study treatment. The cases highlighted in green are response evaluable patients by RECIST v1.1 and those in red were non-evaluable patients. MOB2-009 highlighted with * was the only evaluable patient who achieved stable disease as the best tumor response and all other evaluable patients had progressive disease. MOB2-004 highlighted with # was on study treatment for 147 days with a CA-19-9 response and clinical stability, however, the patient was inevaluable for radiological response evaluation due to severe contrast allergy.
Figure 2
Figure 2
Percent change in CA19-9 during study treatment in nine response evaluable patients. Of 11 response evaluable patients, one was CA19-9 non-secretor and another did not have complete CA19-9 results. EOT, end of treatment.
Figure 3
Figure 3
Changes in KRAS mutation allelic fraction in plasma during study treatment from 10 evaluable patients who had serial plasma samples available for ctDNA analysis. The red lines represent nine patients who had progressive disease after 2 cycles of study treatment and a marked rise in mutant KRAS allelic fraction was observed in all but one. The green line represents the only patient who had stable disease as the best tumor response and it is noteworthy that mutant KRAS allelic fraction is very low in this patient with no significant change during study treatment. EOT, end of treatment.
See this image and copyright information in PMC

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