Abstract P021: Genomic biomarkers for response to 9-ING-41, a small molecule selective glycogen synthase kinase-3 (GSK-3) inhibitor, in pancreas cancer: Preliminary results
Authors: Borden Brittany A. , De Souza Andre , Mahalingam Devalingam , Powell Steven , Munster Pamela N. , Huntington Kelsey , Mazar Andrew , Calvacante Ludmila , Giles Francis J. , El-Deiry Wafik S. , Safran Howard P. , Carneiro Benedito A. 
Published: December 2021

Abstract
Background: 9-ING-41, a small molecule specific GSK-3 inhibitor, demonstrated favorable efficacy and safety in a Phase I clinical trial evaluating 9-ING-41 monotherapy and 8 chemotherapy combinations in 236 patients (pts) that has since been expanded to a Phase II multicenter study (NCT03678883). Interim results documented encouraging clinical activity, especially in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and durable responses in melanoma and ATLL. Potential genomic biomarkers for 9-ING-41 response have not yet been evaluated. Methods: Next-generation sequencing (NGS) of tumor samples was obtained, whenever possible, for those receiving 9-ING-41 alone or in combination with chemotherapy across all sites. Genomic sequencing reports were reviewed for somatic alterations deemed potentially actionable or biologically relevant. For those with PDAC, best response was determined using RECIST 1.1 for those who completed at least two cycles of treatment. Chi-square frequency statistics were used to show the observed versus expected rate of pathogenic variants between patients with disease control (complete response [CR], partial response [PR] or stable disease [SD]) and progressive disease (PD). Results: NGS results were available for 135 pts across 11 sites. Most common histologies were PDAC (n=32), colorectal (n=17), and melanoma (n=9). Among pts with PDAC, NGS results were available for 32 pts (23 tumor samples, 9 ctDNA). Four patients received 9-ING-41 monotherapy; 28 received 9-ING-41 combined with gemcitabine/nab-paclitaxel (n=18), gemcitabine (n=7), or irinotecan (n=3). The most frequently mutated genes among PDAC included KRAS (n=22 pts), TP53 (n=21), CDKN2A (n=12), SMAD4 (n=4), CDKN2B (n=4), MTAP (n=3), ATM (n=3), AKT2 (n=2), and ARID1A (n=2). Of these 32 pts, 25 pts were evaluable for response: 2 pts had CR, 2 PR, 9 SD, and 12 PD. Among the pts with CR, one had tumor without pathogenic variants, the other displayed TP53 and KRAS mutations. Pts with PR: one tumor had no pathogenic mutations, the other tumor harbored mutations in ARID1A, TP53, FGF14, and ROS1. Of the nine patients with SD, 8 had KRAS mutations, 5 had CDKN2A loss of function, and 4 inactivating mutations in SMAD4. Eight out of 12 pts with PD had KRAS mutations. There were no significant differences between pts who had disease control and those with PD in the frequency of KRAS (χ2= 0.0189, P=0.89), TP53 (χ 2= 0.0712, P=0.78), or SMAD4 (χ 2= 1.9631, P= 0.1611). Conclusions: 9-ING-41 has shown clinical benefit in patients with PDAC independent of tumor somatic mutational profile. Preliminary analysis does not reveal pathogenic mutations that are associated with clinical benefit. Additional biomarker studies are ongoing.
Citation Format: Brittany A. Borden, Andre De Souza, Devalingam Mahalingam, Steven Powell, Pamela N. Munster, Kelsey Huntington, Andrew Mazar, Ludmila Calvacante, Francis J. Giles, Wafik S. El-Deiry, Howard P. Safran, Benedito A. Carneiro. Genomic biomarkers for response to 9-ING-41, a small molecule selective glycogen synthase kinase-3 (GSK-3) inhibitor, in pancreas cancer: Preliminary results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P021.