Editor’s Note: With the continuous advancement of medical research, the field of treatment for advanced triple-negative breast cancer (TNBC) is experiencing unprecedented transformation. During the recently held "Northern Breast Cancer Salon Annual Progress Review" conference, Oncology Frontier invited Dr. Pin Zhang from Cancer Hospital Chinese Academy of Medical Sciences to introduce the advances made in the treatment of advanced TNBC in 2024 and discuss the future development directions for ADC (antibody-drug conjugate) therapies in this field.Oncology Frontier: Could you briefly introduce the key advancements in the treatment of advanced triple-negative breast cancer (TNBC) in 2024? How have these advancements impacted patients’ survival or quality of life?
Dr. Pin Zhang: In 2024, there have been several notable advancements in the treatment of advanced TNBC. With the clinical application of immunotherapy and antibody-drug conjugates (ADCs), patients’ prognosis has improved significantly. The recently approved domestic Trop-2 ADC, sacituzumab govitecan, has brought a new treatment option for patients with advanced TNBC. The OptiTROP-Breast01 study showed that sacituzumab govitecan significantly extended progression-free survival (PFS) compared to single-agent chemotherapy and showed a trend toward improving overall survival (OS). Its approval provides a more affordable and accessible treatment option for TNBC patients in China, offering renewed hope for survival.
BRCA1/2 genes are the most common susceptibility genes in breast cancer, and with the emergence of PARP inhibitors, breast cancer with germline BRCA mutations has entered the era of targeted therapy. For patients with advanced breast cancer carrying germline BRCA1/2 mutations, olaparib, a PARP inhibitor, is an option for treatment, although it has not yet been approved for advanced indications in China. In December 2024, based on the positive results from the FABULOUS study, the domestic PARP inhibitor fluzoparib was approved in China for the treatment of breast cancer. Fluzoparib, either as a monotherapy or in combination with apatinib mesylate, is now approved for treating HER2-negative advanced breast cancer in patients with germline BRCA mutations. As a domestic PARP inhibitor, fluzoparib offers higher accessibility and a more affordable price, meaning more Chinese patients will benefit from it.
There are also several new drugs in the pipeline, including bispecific antibodies and ADCs targeting Nectin-4, which are undergoing clinical research. Two bispecific antibodies (targeting PD-1 and VEGF) are currently in Phase II trials in China for first-line treatment of advanced TNBC. Early results suggest that PM8002/BNT327 or Ivonescimab, when combined with taxane-based chemotherapy, have shown encouraging results in terms of overall response rate (ORR) and PFS. We expect larger Phase III studies to follow, which will further confirm these findings. In the exploration of advanced TNBC treatment, there were also some negative results reported this year, such as the AKT inhibitor capivasertib combined with paclitaxel failing to improve PFS in PAM pathway-mutant patients. Similarly, the Nectin-4-targeting ADC Enfortumab Vedotin (EV) showed suboptimal efficacy in late-line treatment of advanced TNBC, not meeting expectations. However, these studies have provided valuable insights for future treatment strategies.
Oncology Frontier: Antibody-drug conjugates (ADCs) like sacituzumab govitecan have shown significant efficacy in the treatment of advanced TNBC. Can you discuss which other ADCs or combination treatment options you think will be promising in the future of TNBC treatment?
Dr. Pin Zhang: Currently, the ADCs developed for TNBC target two main markers: HER2 and Trop-2. Sacituzumab govitecan, an ADC targeting Trop-2, is the first ADC approved for this marker. In the Phase III ASCENT study, sacituzumab govitecan demonstrated significant benefits in PFS and OS compared to the physician’s choice of chemotherapy (TPC) in advanced TNBC patients who had previously received at least two lines of chemotherapy. The median PFS for the sacituzumab govitecan group was 4.8 months, with a median OS of 11.8 months, while the TPC group had a median PFS of only 1.7 months (HR=0.41) and median OS of 6.9 months (HR=0.51). Although this study showed some survival benefits with sacituzumab govitecan over TPC, we still need more drugs with better efficacy.
The results of the OptiTROP-Breast01 Phase III study showed the treatment efficacy of the domestic Trop-2 ADC, sacituzumab govitecan. With a median follow-up of 10.4 months, sacituzumab govitecan significantly prolonged median PFS by 4.2 months compared to TPC, with median PFS of 6.7 months versus 2.5 months (HR=0.32, 95% CI: 0.22–0.44, P<0.00001). Although the median OS results have not yet matured, sacituzumab govitecan has already shown a 47% reduction in the risk of death (HR=0.53, 95% CI: 0.36–0.78, P=0.0005). Based on these results, sacituzumab govitecan has been approved in China for patients with locally advanced or metastatic TNBC who have previously received at least two lines of systemic treatment, providing Chinese patients with a better treatment option.
In addition, another Trop-2-targeting ADC, Dato-DXd, has shown positive efficacy in previous studies, such as the TROPION-PanTumor01 trial for late-line treatment of advanced TNBC. At the 2023 ESMO conference, data from the BEGONIA Ib/II study, cohort 7, showed that Dato-DXd combined with durvalumab in first-line treatment for advanced TNBC resulted in an ORR of 79% (95% CI: 66.8–88.3) and a median PFS of 13.8 months (95% CI: 11.0–NC), with a median duration of response (DoR) of 15.5 months (95% CI: 9.92–NC). These results are very encouraging and suggest that
there is great potential for ADC drugs combined with immune therapy in first-line treatment for advanced TNBC. Although there were no new results for Dato-DXd in advanced TNBC treatment presented at the 2024 ESMO conference, future data from this drug are still highly anticipated.
Looking ahead, Trop-2-targeted ADCs are advancing toward first-line treatment, with ongoing exploration of combination treatment strategies, such as combining ADCs with immunotherapy or anti-angiogenesis drugs, to further enhance efficacy and extend patient survival.
For HER2-negative breast cancer, the HER2-targeted ADC, trastuzumab deruxtecan (T-DXd), has been approved in China for the HER2-low advanced breast cancer indication and included in national insurance coverage. The DB-04 study also explored the efficacy of T-DXd in late-line treatment for HER2-low advanced TNBC. The results showed that the T-DXd group had a median PFS of 6.3 months and median OS of 17.1 months, significantly outperforming the single-agent chemotherapy group (PFS 2.9 months, OS 8.3 months). Currently, T-DXd remains an important choice for late-line treatment of HER2-low TNBC.
Dr. Pin Zhang
Chief Physician, Department of Medical Oncology, Chinese Academy of Medical Sciences Cancer Hospital Professor, Doctoral Supervisor Vice Chair of the Breast Disease Branch, Beijing Medical Association Vice Chair of the Breast Cancer Committee, Chinese Women Doctors Association Vice Chair of the Breast Disease Prevention and Treatment Committee, Beijing Breast Disease Association Vice Chair of the Breast Cancer Subcommittee, Chinese Geriatrics Society Standing Committee Member, Breast Cancer Committee, Chinese Research Hospital Association Standing Committee Member, Clinical Oncology Committee, Chinese Women Doctors Association Standing Committee Member, Breast Disease Expert Committee, Chinese Medical Association Member, Breast Cancer Committee, Chinese Anti-Cancer Association Member, Oncology Clinical Chemotherapy Committee, Chinese Anti-Cancer Association Member, Breast Disease Expert Committee, Beijing Medical Association
