Editor’s Note:

For neoadjuvant immunotherapy in triple-negative breast cancer (TNBC), do you prefer the "TP-AC" or "TP" regimen? At the 2024 Breast Cancer Summer Forum · Northern Salon's "Raising Questions and Seeking Answers" session, Dr. Qiang Zhang from Liaoning Cancer Hospital and Dr. Li Wang from Xingtai People's Hospital presented their viewpoints. Dr. Qiang Zhang favors the TP-AC regimen, while Dr. Li Wang opts for the TP regimen. After the session, Oncology Frontier invited both experts to elaborate on their perspectives.

Presenting Views and Analyzing Reasons

Dr. Qiang Zhang: Choosing the TP-AC Regimen

Numerous studies have explored neoadjuvant immunotherapy combined with chemotherapy for TNBC, including the NeoTRIP study[1], NeoPACT study[2], and IMpassion031 study[3]. However, the pCR results and EFS benefits varied among these studies. The NeoTRIP study, using carboplatin plus nab-paclitaxel combined with atezolizumab (TP+PD-L1 inhibitor) for neoadjuvant treatment, did not show significant benefits in pCR and EFS. In contrast, the NeoPACT study, using carboplatin plus docetaxel plus pembrolizumab, demonstrated pCR and EFS benefits, although it was a phase II study with a smaller sample size and less robust evidence.

The TP-AC regimen is the classic treatment protocol from the KEYNOTE-522 study[4], which achieved dual endpoints (pCR and EFS) benefits. With a median follow-up of 63.1 months[5], the study confirmed the sustained benefits of neoadjuvant pembrolizumab combined with chemotherapy, increasing the 60-month EFS rate by 9% (81.3% vs. 72.3%) compared to the control group. Regardless of pCR status, neoadjuvant pembrolizumab combined with chemotherapy, followed by sequential pembrolizumab adjuvant treatment, continuously provided EFS benefits for stage II-III TNBC patients.

Neoadjuvant therapy aims to translate pCR benefits into EFS and OS benefits. Achieving pCR in both the tumor and axillary lymph nodes indicates complete response, but patients may still have other subclinical lesions. Only by addressing subclinical lesions along with the primary tumor and lymph node metastases can true survival benefits be achieved. Among all explored neoadjuvant immunotherapy combinations, the KEYNOTE-522 study is the only one that achieved pCR in primary tumors, lymph node metastases, and subclinical metastatic lesions, leading to better EFS outcomes.

Neoadjuvant treatment regimens for TNBC are still being explored, and there are unlimited possibilities for combining chemotherapy and immunotherapy. Based on current evidence, the TP-AC regimen from the KEYNOTE-522 study remains the preferred treatment option for neoadjuvant immunotherapy.

Dr. Li Wang: Choosing the TP Regimen

TNBC is one of the breast cancer subtypes with the poorest prognosis, and neoadjuvant treatment is crucial for managing TNBC. With current chemotherapy combined with immunotherapy, we have been exploring better drug combinations to improve outcomes, which is the focus of today’s debate.

As Professor Zhang shared, the KEYNOTE-522 study’s four-drug combination (TP-AC) clearly benefited TNBC patients in terms of pCR and EFS. However, in the pre-immunotherapy era, multi-drug combinations that enhanced pCR also introduced adverse effects, as demonstrated by the NeoSTOP study. NeoSTOP[6], a multicenter phase II randomized study, assessed the efficacy of platinum-based neoadjuvant chemotherapy with and without anthracyclines in TNBC patients. The results showed significant differences in grade 3/4 adverse events (AEs), with higher rates in the PCb→AC group compared to the DCb group (73% vs. 21%, P<0.0001), particularly in terms of neutropenia, febrile neutropenia, and anemia.

The KEYNOTE-522 study data suggest that immunotherapy can be applied in neoadjuvant treatment for TNBC. Thus, we can explore whether simplifying chemotherapy regimens can reduce adverse effects and improve treatment adherence. Professor Jiang Zefei’s cTRIO study[7] effectively addressed this question. cTRIO, a multicenter, open-label phase II study, included untreated, histologically confirmed stage II-III TNBC patients. Patients received six cycles of neoadjuvant therapy with toripalimab combined with nab-paclitaxel and carboplatin, followed by 12 cycles of adjuvant toripalimab. The primary endpoint was pCR (ypT0/TisypN0). Among 62 evaluable patients, 35 achieved pCR (ypT0/TisypN0), resulting in a pCR rate of 56.5% (95% CI: 43.3-69.0), meeting the primary endpoint.

This study demonstrated that a six-cycle TP combined with immunotherapy regimen could improve the pCR rate in early TNBC patients, with good overall tolerance and safety. We look forward to long-term follow-up data to translate pCR benefits into EFS and OS gains. Additionally, the study included nine N3 patients, with a pCR rate of 33%, further boosting our confidence in the TP neoadjuvant chemotherapy regimen. Thus, regardless of tumor burden, the cTRIO study’s TP combined with immunotherapy can enhance pCR.

For clinical practitioners, we strive for the most effective treatment regimen, pursuing the goal of “To safe, To better.” The TP combined with immunotherapy is an effective and low-toxicity treatment option. Despite differing viewpoints in today’s debate, both Professor Zhang and I aim for better pCR rates in TNBC with existing treatment options to achieve improved survival.

In Pursuit of Truth and New Horizons

Dr. Qiang Zhang: Dr. Li Wang, in neoadjuvant treatment, can pCR as a surrogate endpoint always translate into EFS and OS benefits? Is pCR or EFS/OS the true gold standard in clinical research?

Dr. Li Wang: For TNBC or other breast cancer subtypes, although some patients achieve pCR, not all can gain long-term survival, which is a clinical dilemma. Clinically, we focus on treatment regimens that can improve pCR. If a regimen can enhance pCR, it is a viable option in neoadjuvant clinical practice. However, over time, whether pCR benefits can translate into EFS gains remains to be explored. Determining which subtypes can achieve pCR benefits and converting these to EFS benefits is a future research direction.

Breast cancer patients’ overall survival is influenced by multiple factors, making it challenging to determine OS outcomes based on initial neoadjuvant regimens alone. While pCR can be an alternative endpoint for neoadjuvant treatment, it is insufficient as an OS assessment standard. Comprehensive patient data are needed to analyze treatment outcomes.

Dr. Li Wang: In neoadjuvant treatment, if four cycles of TP combined with immunotherapy achieve significant tumor regression or even cCR, would you still add the AC regimen?

Dr. Qiang Zhang: I would add the AC regimen. As Professor Wang mentioned, not all pCRs can convert to EFS benefits. In pCR evaluation, we mainly assess complete remission of the primary tumor and lymph node metastases. Early breast cancer may present with systemic and subclinical metastases. The pCR in primary and lymph node metastases might be superficial, and it is challenging to determine if subclinical lesions have achieved pCR. Clinical trial follow-up data are needed to verify complete remission of primary tumors, lymph node metastases, and subclinical lesions.

The TP-AC regimen remains the preferred neoadjuvant treatment for TNBC for several reasons: first, it has the longest follow-up time; second, it includes the largest number of cases; third, it has the highest level of evidence; and fourth, it significantly improves pCR and EFS. Based on this substantial evidence, the TP-AC regimen is the favored choice for neoadjuvant immunotherapy.

Dr. Li Wang: I fully agree with Professor Zhang’s viewpoint. Similar to how the CSCO BC guidelines incorporate new evidence each year, we look forward to more evidence supporting TP regimens in neoadjuvant immunotherapy for TNBC. We hope for the best treatment choices for patients.

Vote

For neoadjuvant immunotherapy in TNBC, do you prefer the “TP-AC” or “TP” regimen? Single choice:

• TP-AC
• TP
• Abstain

Dr. Qiang Zhang

Director of the Fourth Department of Breast Surgery, Liaoning Cancer Hospital, Chief Physician, MD Graduate Advisor at Dalian University of Technology, China Medical University, and Dalian Medical University Member of the “Hundred, Thousand, and Ten Thousand Talents Project” in Liaoning Province Chair-Elect of the Breast Cancer Individualized Diagnosis and Treatment and MDT Professional Committee, Beijing Cancer Prevention and Treatment Society Member of the Breast Group of the Chinese Medical Association Oncology Branch Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Executive Director of the Chinese Medical Education Association Standing Committee Member of the Breast Disease Professional Committee of the Chinese Medical Education Association Deputy Director of the Breast Cancer MDT Group of the Chinese Medical Education Association Standing Committee Member of the Breast Disease Branch of the Chinese Medical Promotion Association Deputy Director of the Targeted Therapy Professional Committee of the Liaoning Anti-Cancer Association Trained in the Breast Department at MD Anderson Cancer Center and the European Institute of Oncology (IEO)

Dr. Li Wang

MD, Associate Chief Physician, Associate Professor, Graduate Advisor Xingtai People’s Hospital, Leader of General Surgery, Director of Breast Surgery Member of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO BC) Member of the Breast Professional Committee of the Chinese Medical Women’s Association Member of the Young Expert Group of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Member of the Bio-Medicine Committee of the China Youth Science and Technology Workers Association Chairman of the Tumor Science Popularization Professional Committee of the Hebei Tumor Prevention and Treatment Federation Deputy Director of the Breast Cancer Reconstruction Professional Committee of the Hebei Tumor Prevention and Treatment Federation Deputy Leader of the Breast Group of the Hebei Medical Association General Surgery Branch Youth Committee Member of the Breast Cancer Professional Committee of the Hebei Anti-Cancer Association Chairman of the Breast Disease Professional Committee of the Xingtai Rehabilitation Association