Results and exploratory biomarker analyses of a phase II study CHANGEABLE: Combination of HX008 and niraparib in germ-line-mutated metastatic breast cancer.
Authors: Jin Yizi , Du Yiqun , Meng Yanchun , Shao Xuchen , Liu Xiaojun , Mu Yuxin , Liu Yun , Shao Zhimin , Hu Zhen , Zhang Jian 
Published: June 2024

1084 Background: The combination of poly (ADP-ribose) polymerase inhibitors and immune-checkpoint inhibitors demonstrated synergistic antitumor activity in preclinical studies. Here we report the efficacy, safety, and biomarker analyses of the combination of niraparib and PD-1 inhibitor HX008 in metastatic breast cancer (MBC) patients with germline DDR gene mutations in a phase II trial (CHANGEABLE). Methods: Eligible patients had histologically confirmed MBC with at least one measurable disease and germline pathogenic/suspected pathogenic mutations in DDR genes. Patients were enrolled into two cohorts: the main cohort (HER2-negative MBC patients with gBRCA1/2, gPALB2, gCHEK2) and the exploration cohort (MBC patients with gDDR gene mutations and brain metastases). Simon's Two-Stage design was used for recruiting patients in the main cohort. Patients with HER2-negative MBC received niraparib 200 mg qd combined with HX008 200 mg q3w, while HER2-positive patients received additional anti-HER2 TKI pyrotinib 400mg qd if having brain metastases, until disease progression. The primary endpoint was ORR. NGS of tissue and ctDNA were performed for exploratory biomarker analyses. Results: As of January 12, 2024, 37 patients were enrolled. In the main cohort with gBRCA1/2 mutations (n = 28), ORR was 78.6% (22/28), with 3 patients having complete response. DCR was 96.4% (27/28). Median PFS was 7.3 months (95%CI 4.2 to 10.4). According to Simon's Two-Stage design, since two patients with gCHEK2 mutations in the first stage had only stable disease, the recruitment was terminated. One patient with gPALB2 mutation had stable disease and the remaining one is in the screening process. In the patients having brain metastases (exploration cohort), ORR was 40% (2/5) and DCR was 80% (4/5). The most common treatment-related adverse events of grade 3 or higher were anemia (13 [35.1%]), thrombocytopenia (4 [10.8%]), and neutropenia (3 [8.1%]). No treatment-related deaths were reported. In the biomarker analysis, NGS of 700 genes was performed on 24 patients with gBRCA1/2 mutations in the main cohort. No significant difference was found in ORR or PFS between gBRCA1 and gBRCA2 mutations. Somatic mutations in XPO1 (16 patients (73%), 15/18 PR+CR, 1/4 SD+PD) showed significant correlation with response. Somatic TP53 mutations are significantly correlated with shorter PFS, while ASXL1 mutations are significantly correlated with longer PFS. Four somatic mutations (AR_c.1418_1420del, AR_c.231_239dup, 2 DUSP22 mutations) showed a consistent trend of decreasing in PD samples, while NF1_c.3198-4dup showed a consistent trend of increasing in PD samples. Conclusions: The combination of niraparib and HX008 demonstrated promising clinical benefits with a tolerable safety profile in MBC patients with germline BRCA1/2 mutations, even in patients with brain metastases. Clinical trial information: NCT04508803 .