Abstract
Co-mutation of ATM and ASXL1 and relationship to durable response of a novel PARP1/2 inhibitor, venadaparib, in patients with pancreatic cancer.
Author
person
Keun Seok Lee
Department of Internal Medicine, National Cancer Center, Goyang, South Korea
info_outline
Keun Seok Lee, Woo Jin Lee, Heejung Chae, Keun-Wook Lee, Jin Won Kim, Hee Kyung Ahn, Inkeun Park, Jin Hyoung Kang, Se Jun Park, Seock-Ah Im, Do-Youn Oh, Jeesun Yoon, Won Sik Lee, Chan-Young Ock, Aili Wang, Eunyoung Heo, Jeongsook Bang, Min Ju Hong, Eun-Jihn Roh, KYOUNG SOO HA
Full text
Authors
person
Keun Seok Lee
Department of Internal Medicine, National Cancer Center, Goyang, South Korea
info_outline
Keun Seok Lee, Woo Jin Lee, Heejung Chae, Keun-Wook Lee, Jin Won Kim, Hee Kyung Ahn, Inkeun Park, Jin Hyoung Kang, Se Jun Park, Seock-Ah Im, Do-Youn Oh, Jeesun Yoon, Won Sik Lee, Chan-Young Ock, Aili Wang, Eunyoung Heo, Jeongsook Bang, Min Ju Hong, Eun-Jihn Roh, KYOUNG SOO HA
Organizations
Department of Internal Medicine, National Cancer Center, Goyang, South Korea, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea, Republic of (South), Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea, Division of Medical Oncology, Gachon University Gil Medical Center, Incheon, South Korea, Medical Oncology, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea, Medical Oncology, Seoul National University Hospital, Seoul, South Korea, Medical Oncology, Seoul National University Hospital, Seoul, Korea, Republic of (South), Idience Co., Ltd., Seoul, South Korea, Idience Co., Ltd., Seoul, Korea, Republic of (South), Idience Inc., South San Francisco, CA
Abstract Disclosures
Research Funding
Pharmaceutical/Biotech Company
Idience Co., Ltd.
Background:
Homologous recombination repair (HRR) alterations such as
BRCA
mutation (BRCAm) and
ATM
mutation (ATMm) are established predictive biomarkers for poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor in pancreatic cancer (PC). Mutations in the
ASXL1
gene (ASXL1m) have been associated with hematologic malignancies. In solid cancers, however, associations between HRR and non-HRR mutation such as ASXL1m as well as treatment response in patients with those are not well known. The aim of this analysis was to explore genetic alterations co-existing with HRR mutation to better predict efficacy from a monotherapy of venadaparib, a PARP inhibitor under development, in patients with metastatic PC.
Methods:
Patients with HRR mutation and no standard treatment or prior treatment failure were enrolled in a phase Ib basket trial (NCT04174716) to receive venadaparib monotherapy. Tumor response to treatment was evaluated according to RECIST 1.1. Exploratory blood samples were collected to analyze genetic alterations using ctDNA next-generation sequencing (NGS) (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Prevalence of co-occurring mutations was estimated and mutual exclusivity between HRR and non-HRR mutations were statistically tested by Fisher’s exact test using the cBioPortal for Cancer Genomics (http://cbioportal.org) in The Cancer Genome Atlas (TCGA) Pan-cancer and AACR Project Genie v13.0 registries. Efficacy between patients with co-mutations and single mutation only were presented.
Results:
In public dataset, the prevalence of ATMm and ASXL1m was 3.0% and 0.9% in TCGA pan-cancer study (n = 10,967), 3.0% and 1.7% in Genie v13.0 (n = 131,996), respectively. In both datasets, co-mutation of ATM and ASXL1 was tested significant (Log2 Odds Ratio 2.663 and 1.176 respectively; q-value 0.001 and 0.006 respectively). In the basket trial, 8 patients were enrolled, with 50% male, and a median age 66 (range 47-72). 6 patients had 2 prior palliative chemotherapy. 6 patients had ATMm and 2 had BRCA2m confirmed by enrolling institution at baseline. All patients had responded to prior platinum containing regimen. ctDNA NGS samples were available in 6 patients. Patients with ATMmASXL1m (n = 3) had a 33% overall response rate (1 partial response, 2 stable disease, range of progression-free survival (PFS), 23-113 weeks), while those with ATMmASXL1wt (n = 1) had a 0% (1 progressive disease (PD), PFS 9 weeks) and others (ATMwtASXL1wt, n = 2, 1 PD; ctDNA not available, n = 2, 2 PD) had a 0% response rate (range PFS 3-16 weeks). Two patients with BRCA2m only had PD on weeks 3 and 8.
Conclusions:
In this exploratory analysis, patients with co-occurring ATMm and ASXL1m showed higher tumor response. This signals potential value from ATM and ASXL1 co-mutation predicting efficacy of Venadaparib in PC and warrants further validation. Clinical trial information: NCT04174716.
Clinical status
Clinical
1 clinical trial
2 organizations
1 drug
3 targets
Clinical trial
An Open-label, Multi-center, Phase 1b/2a Basket Trial of IDX-1197 in Patients With Homologous Recombination Repair Mutated Solid TumorsStatus: Active (not recruiting), Estimated PCD: 2023-12-31
Organization
IdienceOrganization
Idience Inc.Drug
venadaparibTarget
ASXL1Target
ATMTarget
BRCA1