In the field of breast cancer treatment, innovative therapies are emerging constantly, yet many issues still urgently need to be addressed. Recently, Academician Binghe Xu and Dr. Fei Ma from the Cancer Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College published an article in Nature Medicine titled "Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial." The study introduces the latest progress in metronomic chemotherapy combined with immunotherapy in breast cancer. This research not only provides a new treatment option for breast cancer patients but also reveals the synergistic potential of metronomic chemotherapy and immunotherapy. At the Seventh Tumor Precision Diagnosis and Treatment Conference and the Tenth Breast Cancer Individualized Treatment Conference (2024 COMB), Oncology Frontier invited Dr. Fei Ma to discuss the current state of breast cancer treatment and his team's related articles.Oncology Frontier: In the field of early TNBC immunotherapy, the results of recent studies such as KEYNOTE-522, IMpassion 031, and A-BRAVE have varied. How do you view the current state and future of immunotherapy for early TNBC?
Dr. Fei Ma: In recent years, immunotherapy has achieved groundbreaking progress in the neoadjuvant treatment of triple-negative breast cancer (TNBC). Through the application of innovative drugs, TNBC has achieved a significant increase in pathological complete response (pCR) rates, and some patients have even been converted to long-term survival benefits. The primary reason for the success of neoadjuvant immunotherapy is that patients are receiving anti-tumor treatment for the first time, their overall immune status is better, and their good physical condition greatly helps enhance the efficacy of immunotherapy.
However, there are still some related issues worth considering in the field of neoadjuvant immunotherapy for TNBC. For example, we currently base neoadjuvant treatment strategies on patients’ PD-L1 expression levels, but we have seen that patients with low or even negative PD-L1 expression can also benefit from neoadjuvant immunotherapy. This makes us question whether PD-L1 is an important companion diagnostic. Which populations can benefit from immunotherapy? In the future, identifying the advantageous populations for immunotherapy will be our direction of exploration.
Additionally, we have found that even patients who did not achieve pCR from neoadjuvant treatment can significantly improve their event-free survival (EFS) with continued postoperative immunotherapy, sometimes to a greater extent than those who achieved pCR. Therefore, it is worth exploring how to conduct subsequent adjuvant therapy for patients who achieve pCR after neoadjuvant treatment.
Oncology Frontier: In the field of late-stage TNBC immunotherapy, domestic and international studies such as KEYNOTE-355 and TORCHLIGHT have reached positive endpoints, but the protocols (including immunotherapy and chemotherapy) and biomarker thresholds differ. Can you introduce late-stage TNBC immunotherapy?
Dr. Fei Ma: Due to the multiple lines of treatment for patients with advanced TNBC, the road to immunotherapy in advanced TNBC is not smooth. Additionally, the low benefits of immunotherapy may also be related to the selection of advantageous populations for companion diagnostics. Currently, there is no ideal companion diagnostic for TNBC immunotherapy. Clinically, several PD-L1 expression statistical standards have been defined, such as TPS, CPS, IC, but these standards cannot completely guarantee the selection of the best-benefit populations at the advanced stage. Therefore, we need to further identify the advantageous populations that benefit from immunotherapy in advanced TNBC.
The combination treatment regimens for immunotherapy in advanced TNBC patients are also worth further exploration. Different drugs combined with immunotherapy may produce different results. Even combining the same drug with a slightly different structure can yield different outcomes. For example, the IMpassion 130 study[1] and the IMpassion 131 study[2] combined albumin-bound paclitaxel and paclitaxel, respectively, producing vastly different results. This indicates that selecting the best partner for immunotherapy is crucial. Furthermore, even the same drug combined with immunotherapy using different strategies can yield different outcomes. Therefore, in the future exploration of immunotherapy for advanced TNBC, selecting the best companion diagnostics and treatment partners is a critical direction.
Oncology Frontier: Metronomic chemotherapy can avoid the high toxicity and short-lasting effects of traditional chemotherapy. Recently, your clinical study on metronomic chemotherapy combined with immunotherapy for breast cancer was published in “Nature Medicine.” Can you introduce the main content of this study and share your views on the application prospects of metronomic chemotherapy combined with immunotherapy?
Dr. Fei Ma: Metronomic chemotherapy is not a new treatment concept; we started applying it clinically 20 years ago. Compared with high-dose chemotherapy, its short-term efficacy is relatively poor, but it has the advantage of low toxicity. Therefore, metronomic chemotherapy has been widely used in elderly patients, frail individuals, and maintenance therapy. In the era of combined immunotherapy, metronomic chemotherapy and immunotherapy can have synergistic effects, including anti-tumor, anti-angiogenesis, and immune microenvironment modulation.
Against this background, we applied the concept of metronomic chemotherapy combined with immunotherapy to clinical research. We conducted a small-sample phase II randomized controlled trial[3]. This study used Bayesian posterior probability randomization and efficacy monitoring methods, allowing us to quickly focus on subgroup populations with limited samples, saving sample sizes, reducing research costs, and increasing the likelihood of finding the best combination therapy.
The study included 97 patients, randomly divided into five cohorts: (1) Metronomic chemotherapy with vinorelbine (NVB) monotherapy (n=11); (2) Metronomic chemotherapy with vinorelbine combined with a PD-1 inhibitor (α-PD1+NVB group, n=7); (3) Metronomic chemotherapy with vinorelbine combined with conventional cisplatin chemotherapy and a PD-1 inhibitor (DDP group, n=26); (4) Metronomic chemotherapy with vinorelbine combined with bevacizumab and a PD-1 inhibitor (BEV group, n=27); (5) Metronomic chemotherapy with vinorelbine, capecitabine, and cyclophosphamide combined with a PD-1 inhibitor (VEX group, n=26). The primary endpoint was the disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety.
Through studying the five cohorts, we reached different conclusions. Metronomic chemotherapy combined with immunotherapy can produce various outcomes: 1+1<1, 1+1>1, or 1+1>2. In the VEX treatment group, the combination of three chemotherapeutic agents and immunotherapy significantly improved DCR, PFS, and OS (DCR was 69.7%, PFS was 6.6 months, and OS was 42.6 months).
This is the world’s first prospective clinical study of metronomic chemotherapy combined with immunotherapy, showing good therapeutic effects. It suggests that immunotherapy-induced immune remodeling may be related to the drugs used. Whether metronomic chemotherapy can change clinical practice in the future needs to be verified by larger phase III clinical studies.
Dr. Fei Ma
Chief Physician, Professor, Doctoral Supervisor, Yangtze River Scholar Distinguished Professor Director of the Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences Secretary-General of the National Anticancer Drug Clinical Application Monitoring Committee Vice Chairman of the Breast Cancer Committee of the National Tumor Quality Control Center Secretary-General of the Breast Cancer Screening and Early Diagnosis and Treatment Standard Committee of the National Cancer Center Expert of the Health China Action Promotion Committee Vice Chairman of the Oncology Pharmacist Branch of the China Pharmacists Association Vice Chairman of the Integrated Oncology Cardiology Branch of the China Anti-Cancer Association Vice Chairman of the Committee for Multiple Primary and Unknown Primary Tumors of the China Anti-Cancer Association Secretary-General of the Clinical Research Committee on Tumor Drugs of the China Anti-Cancer Association Vice Chairman of the National Committee for Ovarian Protection and Anti-Aging Promotion in Women Director-General of the Geriatric Oncology Branch of the Chinese Geriatrics and Gerontology Society Vice Chairman of the Beijing Breast Disease Prevention and Treatment Society Chairman of the Tumor Chemotherapy Quality Control Committee of the Beijing Tumor Treatment Quality Control and Improvement Center Editor-in-Chief of Cancer Innovation Recipient of the National Science and Technology Progress Award Second Prize, “Top Ten Outstanding Young Doctors in the Capital,” “China Young Scientist in Oncology Award,” and other honors
