Currently, the combination of docetaxel, trastuzumab, and pertuzumab is the standard first-line treatment for HER2-positive metastatic breast cancer (MBC), but still, 60% of patients experience disease progression after 2 years of treatment. The second-line treatment standards include DS-8201, T-DM1, TKIs, etc., but these options still have their limitations and do not fully meet clinical treatment needs. Therefore, the team led by Professor Jian Liu from Fujian Provincial Tumor Hospital explored a second-line treatment regimen combining pyrotinib with inetetamab(the “Chinese Dual Target”) + vinorelbine. The research results were included in the 2023 SABCS conference (Abstract number: PO1-04-05). Tumor Outlook invited Professor Jian Liu to introduce this study.
Abstract Number: PO1-04-05
Effectiveness and safety of inetetamab + pyrotinib + vinorelbine in ≥second-line treatment of HER2-positive metastatic breast cancer
Research Background:
Overexpression of HER2 is one of the independent factors for poor prognosis in breast cancer and a predictor of the efficacy of anti-HER2 targeted therapy, affecting 20%-25% of breast cancer patients. Currently, the combination of docetaxel, trastuzumab, and pertuzumab remains the standard first-line treatment for HER2-positive MBC, but 60% of patients experience disease progression after 2 years of treatment. The current second-line treatments include DS-8201, T-DM1, TKIs, etc. In the EMILIA study, T-DM1 extended the median PFS and median OS compared to lapatinib + capecitabine (mPFS: 9.6 months vs. 6.4 months, HR=0.650; mOS: 30.9 months vs. 25.1 months, HR=0.682). The DESTINY-Breast03 study showed a significant advantage of DS-8201 over T-DM1, with a mPFS of 28.8 months compared to 6.8 months for the T-DM1 group (HR 0.28). DS-8201 is now recommended as a second-line treatment option in both domestic and international guidelines. The PHOEBE study demonstrated that pyrotinib + capecitabine significantly extended mPFS (12.5 months vs. 6.8 months) and OS (NA vs. 26.9 months, P=0.02) compared to lapatinib + capecitabine, leading the National Medical Products Administration (NMPA) to approve pyrotinib as a standard second-line therapy for HER2-positive advanced breast cancer.
In China’s Real-world data, only a small portion of patients use DS-8201 as a second-line treatment; T-DM1 has been included in the medical insurance, but its high rate of grade 3-4 thrombocytopenia (about 40%) limits its clinical use; with pyrotinib approved and included in the medical insurance, there is a significant increase in clinical demand, necessitating the exploration of combined pyrotinib regimens to meet patient needs.
Previous studies have found that combining HER2 monoclonal antibodies with TKIs offers advantages over using HER2 monoclonal antibodies or TKIs alone, as demonstrated by the EGF104900, HER2CLIMB, neoALTTO, CALGB-40601, PHEDRA studies, all showing the benefits of HER2 monoclonal antibody + TKI combinations.Inetetamab is a humanized HER2 monoclonal antibody with a modified Fc segment, sharing the same binding site and mechanism of action with trastuzumab but with stronger ADCC effects. The HOPES study indicated that in patients with HER2-positive MBC who had not previously received trastuzumab treatment, inetetamab combined with vinorelbine extended the median PFS compared to vinorelbine alone (39.1 weeks vs. 14.0 weeks, HR=0.24, P<0.0001), suggesting that the Fc-modified inetetamab could further benefit patients. The “Chinese Dual Target,” namely the combination of pyrotinib and inetetamab, theoretically has the advantage of simultaneously blocking the HER2 signaling pathway from both inside and outside the cell.
Research Conclusion:
The study results suggest that the combination of pyrotinib + inetetamab + vinorelbine can further extend the median PFS to 17 months in second-line MBC patients, numerically superior to the 9.6 months mPFS with T-DM1 in second-line treatment, and also better than the 12.5 months mPFS in the PHOEBE study’s second-line subgroup with pyrotinib + capecitabine. With an ORR of 60% in second-line treatment, this regimen also surpasses the ORR of 44% with T-DM1 in second-line treatment. This regimen is a viable alternative for patients unable to use anti-HER2-ADC drugs in second-line treatment, with a prospective Phase II study currently underway.
Researcher’s Comments:
In the CLEOPATRA study, only about 10% of patients had previously received trastuzumab treatment. A subgroup analysis of the CLEOPATRA study showed no statistically significant difference in extending PFS and OS between the subgroup using THP and the TH regimen among patients who had previously received trastuzumab as adjuvant or neoadjuvant treatment. Approximately 80% of patients in China have already received adjuvant or neoadjuvant treatment with trastuzumab, with some having received dual-target treatment with trastuzumab and pertuzumab. Therefore, the efficacy of pyrotinib combined with inetetamab as first-line treatment also needs further exploration among the patient group that has already used trastuzumab/pertuzumab in clinical practice.
Jian Liu
Director of the Breast Tumor Department, Fujian Provincial Tumor Hospital
#Voice of China#Interview#Commentary#SABCS 2023#Breast Cancer