Editor's Note: In recent years, the rapid development of immunotherapy and targeted therapy has continuously updated the treatment strategies for metastatic breast cancer (MBC) patients. PARP inhibitors and immune checkpoint inhibitors, developed based on the concept of synthetic lethality, have become important treatment options for HER2- MBC patients, yet there remains a significant unmet need for treatment. Recently, at the ASCO 2024 conference, a collaborative team led by Professors Zhen Hu , Jian Zhang, and Yun Liu from Fudan University Shanghai Cancer Center shared the results of the Phase II CHANGEABLE study. This study revealed new hope for the combination of the PARP inhibitor niraparib and the PD-1 monoclonal antibody HX008 in MBC patients with germline DDR gene mutations. At ASCO 2024, Oncology Frontier interviewed Professor Jian Zhang to discuss the background, results, and significance of this study. The key insights are summarized below:Study Overview
Study Title: CHANGEABLE Phase II Study: Results and Exploratory Biomarker Analysis of HX008 Combined with Niraparib in Germline Mutated Metastatic Breast Cancer
The combination of poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors has shown synergistic antitumor activity in preclinical studies. At ASCO 2024, a team from Fudan University Shanghai Cancer Center reported the efficacy, safety, and biomarker analysis of niraparib combined with the PD-1 inhibitor HX008 in a Phase II trial (CHANGEABLE) in metastatic breast cancer (MBC) patients with germline DDR gene mutations.
Patients included in the study had histologically confirmed MBC with at least one measurable disease site and pathogenic or likely pathogenic germline DDR gene mutations. Patients were divided into four cohorts: one primary cohort (HER2- MBC patients with gBRCA1/2, gPALB2, or gCHEK2 mutations) and three exploratory cohorts (HER2- MBC with other gDDR mutations; HER2+ MBC with gDDR mutations; MBC with gDDR mutations and brain metastases without or without progressing brain radiotherapy). The primary cohort was recruited using a Simon two-stage design. HER2- MBC patients received niraparib 200 mg daily combined with HX008 200 mg every three weeks, while HER2+ patients with brain metastases additionally received the anti-HER2 TKI pyrotinib 400 mg daily until disease progression. The primary endpoint was ORR (objective response rate). Tissue and ctDNA were analyzed using NGS (next-generation sequencing) for exploratory biomarker analysis.
Results showed that as of January 12, 2024, a total of 37 patients were enrolled. In the primary cohort with gBRCA1/2 mutations (n = 28), the ORR was 78.6% (22/28), with 3 patients achieving complete response (CR). The DCR (disease control rate) was 96.4% (27/28). The median PFS (progression-free survival) was 7.3 months (95% CI: 4.2~10.4). The most common treatment-related grade 3 or higher adverse events were anemia (13 patients [35.1%]), thrombocytopenia (4 patients [10.8%]), and neutropenia (3 patients [8.1%]). No treatment-related deaths were reported.
In the biomarker analysis, 24 gBRCA1/2-mutated patients in the primary cohort underwent NGS of 700 genes. There was no significant difference in ORR or PFS between gBRCA1 and gBRCA2 mutations. XPO1 mutations (16 patients [73%], 15/18 PR+CR, 1/4 SD+PD) were significantly associated with treatment response. TP53 mutations were significantly associated with shorter PFS, while ASXL1 mutations were significantly associated with longer PFS. Four specific mutations (AR_c.1418_1420del, AR_c.231_239dup, and 2 DUSP22 mutations) showed consistent downward trends in PD samples, while NF1_c.3198-4dup showed a consistent upward trend in PD samples. These results suggest that the combination of niraparib and HX008 has promising clinical benefits in MBC patients with germline BRCA1/2 mutations and is well-tolerated, even in patients with brain metastases.
Researcher Insights
1. Oncology Frontier: In the CHANGEABLE study, your team used a combination of niraparib and HX008. Can you share the main efficacy and safety data of this combination therapy in treating MBC patients?
Professor Jian Zhang: Our clinical study is named CHANGEABLE, which reflects both the initials of the drugs involved and our hope to bring change to clinical practice. While PARP inhibitors have proven feasible for patients with germline BRCA1/2 mutations, we noted that these patients often respond well to immunotherapy. Thus, we explored the effects of combining PARP inhibitors with immunotherapy, a strategy already examined in several studies abroad. In our study, patients were divided into multiple cohorts, including HER2-negative, HER2-positive, and brain metastasis cohorts. Detailed analysis revealed that for patients with germline BRCA1/2 mutations, the combination of niraparib and HX008 was highly effective. The ORR reached about 78%, the DCR nearly 100%, and three patients achieved complete remission (CR). The median PFS was around 7.5 months. These results suggest that this treatment approach is worth further exploration and research.
2. Oncology Frontier: In the exploratory biomarker analysis, what gene mutations did your team find to be significantly associated with treatment outcomes? What is the significance of these findings for future individualized treatment strategies?
Professor Jian Zhang: We conducted a broad gene panel analysis covering 700 genes, screening all patients comprehensively. The results showed a significant association between specific XPO1 mutations and treatment efficacy, indicating better treatment outcomes. Additionally, TP53 mutations were associated with shorter PFS. However, these biomarkers need further validation and confirmation. Overall, we hope to identify biomarkers that indicate sensitivity and resistance to the combination of PARP inhibitors and immunotherapy, providing valuable references for future clinical strategies and research.
3. Oncology Frontier: What challenges did your team encounter during the CHANGEABLE study? What are your future research plans or prospects in the field of MBC treatment?
Professor Jian Zhang: The CHANGEABLE study was a collaborative effort by Professor Hu Zhen from our hospital, myself, and Professor Liu Yun from Shanghai Jiao Tong University. The study aimed to provide a reference for future research. One major challenge we faced was finding suitable study participants, especially those with germline mutations, which is relatively difficult. To differentiate our study from others, we also included some patients with brain metastases and found that this approach was about 40% effective in this subgroup. This finding suggests that further exploration of this method in treating brain metastases is warranted. Additionally, we faced challenges in gene testing, as there is relatively little previous research on resistance genes for PARP inhibitors combined with immunotherapy. Despite these difficulties, we made corresponding efforts and analyses. Overall, conducting each clinical trial is challenging, but our research was successfully completed thanks to the joint efforts and contributions of all participants, including Professor Hu Zhen and Professor Liu Yun. We look forward to conducting further validation clinical research to confirm our findings.
