Niraparib plus PD-1 inhibitor for patients previously treated with immune checkpoint inhibitor for solid tumors with homologous recombination repair gene mutation (IMAGENE): A phase II basket study.

Abstract

2613 Background: Prior clinical trials have established the effectiveness of poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) or immune checkpoint inhibitor (ICI) monotherapy in patients with cancer characterized by mutations in homologous recombination repair (HRR) genes. This trial aims to evaluate the efficacy and safety of PARPi and PD-1 inhibitor in patients with HRR gene-mutated solid tumors previously treated with ICIs. Methods: IMAGENE is an open-label phase II basket study evaluating the efficacy and safety of niraparib and PD-1 inhibitor in patients with HRR gene-mutated cancers that have shown resistance to one or more standard therapy including ICIs. HRR mutation status was evaluated by circulating tumor DNA (ctDNA) or tumor tissue DNA. The primary endpoint was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with niraparib (200 mg orally daily) and nivolumab/pembrolizumab (240 mg/body intravenously every 2 weeks or 3 mg/kg every 3 weeks, respectively). Results: Of 47 enrolled patients, 22 were enrolled based on HRR gene alteration detected in ctDNA. The most common tumor type was gastric cancer (36.2%), followed by bladder cancer (BC, 25.5%), and renal cell carcinoma (RCC, 12.8%). As of data cutoff (September 30, 2024), the median duration of follow-up was 31.7 weeks. The median number of prior treatment line was 6.5 (1 to 20). In total, the cORR was 4.4% (90% CI, 0.8 to 13.3), with a disease control rate (DCR) of 55.6% (90% CI, 42.3 to 68.3). Notable DCRs were observed in patients with RCC (83.3%) and BC (80.0%). The median duration of response and progression-free survival (PFS) were 35.0 weeks (90% CI, 20.0 to 50.0) and 11.6 weeks (90% CI, 7.0 to 13.6), respectively. At data cutoff, 28 patients (62.2%) had died, with 12-month overall survival (OS) rate of 41.7% (90% CI, 29.1 to 53.8). Interestingly, BRCA1/2 -mutated patients had significantly shorter OS compared to those with other HRR gene mutations (p = 0.0096). The three most common treatment-emergent adverse events (TEAEs) were nausea (31.1%), vomiting (31.1%), and anaemia (26.7%). Grade ≥3 TEAEs were reported in 18 patients (40.0%), with the most common being anaemia (17.8%). TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs. Conclusions: Niraparib combined with PD-1 inhibitor showed modest activity even in heavily pretreated patients with HRR gene-mutated cancers who progressed on ICI therapy. Furthermore, patients with specific cancer type had promising benefit from this combination therapy, warranting further investigation in specific populations. Clinical trial information: jRCT2051210120 .