KEY TAKEAWAYS
- The phase 1 trial aimed to investigate the association between HRD status and the efficacy of combined irinotecan and venadaparib in patients with metastatic GC.
- Researchers noticed promising synergistic effects of venadaparib and irinotecan, particularly in HRD-positive refractory GC patients; further investigation is ongoing.
Tumors with homologous recombination deficiency (HRD), inclusive of BRCA and ATM mutations, have demonstrated predictive value for the response to poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors.
However, the correlation between PARP inhibitor efficacy and BRCA (BRCAm) or ATM gene (ATMm) mutations remains unclear in advanced gastric cancer (GC) patients who have undergone prior treatments. Combining PARP inhibitors with irinotecan has been recognized to enhance cytotoxicity.
Do-Youn Oh and the team aimed to assess the association between HRD status and the effectiveness of the combination therapy involving irinotecan and venadaparib in patients with metastatic GC who have experienced failure with at least two lines of therapy.
Researchers performed an inclusive analysis, conducting MTT assays in vitro to verify and characterize the synergism between venadaparib and SN-38. Data were analyzed using GraphPad Prism (version 9.5.1) and CompuSyn (version 1.0) software. Patients with at least 2 prior palliative treatments were enrolled in a multi-national phase Ib trial (NCT04725994).
Tumor response was evaluated according to RECIST 1.1 criteria. Exploratory genomic analysis was included to assess the correlation between efficacy and HRD, utilizing ctDNA (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose.
The MTT assays, the combination of SN-38 and venadaparib showed a synergistic effect with combination indices (CI) ranging from 0.013 to 0.991 in SNU-638 (BRCA2m), SNU-668 (BRCA1m), AGS (low ATM), and SNU-484 (HR proficient) cells. The synergistic effect between SN-38 and venadaparib remained consistent even at low concentrations of venadaparib (SN-38 IC50; without venadaparib → with 10 nM of venadaparib; SNU-638(1.72→0.28), SNU-668(10.7→1.5), AGS (0.62→0.049), SNU-484(2.25->0.38)).
In the dose-finding part of the clinical study involving 26 enrolled patients (13 with 2 prior treatments and 13 with 3 prior treatments), with a median duration of follow-up of 4.4 (range 1.3 – 23.7) months.
Of the 26 patients enrolled, 5 (1 BRCA2m and 4 ATMm) had HRD (19.2%) and were treated with varying doses of irinotecan and venadaparib. Among these 5 patients, the objective response rate (ORR) was 60%, and the median progression-free survival (mPFS) (95% CI) was not reached (1.2–21.5) months.
Additionally, among the 26 enrolled patients, 11 received varying doses of venadaparib plus 100 mg/m2 of irinotecan, showing an ORR of 36.4% and an mPFS (95% CI) of 5.6 (3.5–not reached) months.
The study concluded that venadaparib, in combination with irinotecan, demonstrated synergistic effects in vitro and promising clinical efficacy in the systemic treatment of refractory gastric cancer, especially in patients with homologous recombination deficiency (HRD).
The ongoing dose expansion phase aims to explore the optimal biological dose and patient selection strategies in a randomized design. The trial was sponsored by Idience Co. Ltd.
Source: https://meetings.asco.org/abstracts-presentations/229249
Clinical Trial: https://clinicaltrials.gov/study/NCT04725994
Oh D Y, Ryu M H, Lee K W, et al. (2024). “Predictive role of homologous recombination deficiency (HRD) for irinotecan in combination with venadaparib, a novel PARP1/2 inhibitor, as third- or fourth-line treatment in patients with advanced gastric cancer.” Presented At ASCO- GI 2024 (Abstract 380).
