Editor’s Note: With the continuous development and market release of new ADC drugs, the treatment landscape for breast cancer patients has changed. For patients with advanced breast cancer, the feasibility of using another ADC drug after the initial ADC treatment has become a common clinical concern. In the “In-depth Inquiry” segment of the 2024 North-South Meeting, Professor Ting Luo from West China Hospital of Sichuan University delivered a report titled “Rescue Treatment for Advanced Breast Cancer: ADC After ADC?”. This article reviews the content of her lecture.

At the beginning of her report, Professor Ting Luo mentioned that for advanced breast cancer, the use of different drug regimens has always been explored, including endocrine therapy (ET), chemotherapy, monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and CDK4/6 inhibitors. In the current era of emerging ADC drugs, exploring the sequential use of ADC drugs is a direction that requires careful consideration.

Different Mechanisms Provide a Basis for Sequential Use

ADC drug resistance is mainly related to ADC recognition, delivery, and payload. Based on this, ADC sequential schemes can be broadly divided into same-target sequential therapy and different-target sequential therapy.

Same-Target ADC Sequential Therapy

Changing the payload of ADCs targeting the same receptor can effectively overcome resistance. For example, ADCs with topoisomerase inhibitors (such as T-DXd) and ADCs with microtubule inhibitors (such as T-DM1) have different mechanisms of action for their payloads. Therefore, they do not cause cross-resistance, providing a theoretical basis for sequential use. Most patients treated with T-DXd, especially those with HER2-positive tumors, still have detectable levels of HER2. A study showed that T-DXd treatment of HER2-positive breast cancer does not significantly alter the HER2 expression status, maintaining the receptor binding capability for HER2 ADCs. This makes same-target sequential therapy feasible.

Different-Target ADC Sequential Therapy

Trop-2 is a cell surface glycoprotein and a transmembrane calcium signaling protein. It was first discovered in human placental trophoblast cells and is expressed in various normal tissues. In HER2-low tumors, there is co-expression of HER2 and Trop-2, suggesting the coexistence of these two targets. This provides a premise for different-target ADC sequential therapy. Research data indicate that Trop-2 expression is not affected by HER2 receptor status and is comparable in HER2-low populations and other groups.

Different Approaches for Same-Target Sequential Therapy

HER2 ADC Sequential Therapy – Exploring the Root

Currently, there are various types of HER2-targeted ADCs. Due to differences in antibodies, linkers, and payloads, HER2 ADCs have diverse mechanisms of action. The DESTINY-Breast02 study results showed that patients with HER2-positive advanced breast cancer who previously received T-DM1 as a second-line treatment still benefited from T-DXd in terms of overall survival (OS). The DESTINY-Breast03 study, an open-label, randomized, multicenter phase III trial, compared the efficacy and safety of T-DXd and T-DM1 in second-line treatment for HER2-positive advanced breast cancer. The study suggested that for patients previously treated with trastuzumab and taxanes, T-DXd showed clinically and statistically significant benefits in progression-free survival (PFS) and OS compared to T-DM1. At the 2022 SABCS conference, updated results from the DESTINY-Breast03 study showed that the median PFS2 was 40.5 months for the T-DXd group versus 25.7 months for the T-DM1 group (HR=0.47, 95% CI: 0.35-0.62). A portion of patients in both groups received subsequent anti-tumor treatments, with 35.2% of patients in the T-DXd group receiving T-DM1 treatment and 17.3% of patients in the T-DM1 group using T-DXd, partially proving the benefits of the T-DXd sequential T-DM1 mode.

Currently, several studies on sequential HER2 ADC treatment after standard ADC therapy are ongoing, although there is no data yet on Trop-2 ADC sequencing. However, the potential for multiple Trop-2 ADCs provides endless possibilities for sequential treatment.

HER2 ADC Sequential Therapy – In-Depth Inquiry

Professor Luo summarized that the conventional sequential schemes for HER2 ADC therapy are mature, and new sequential modes have potential. The optimal sequential mode can only be determined through practical application. Although there is no direct evidence for sequential treatment with Trop-2 ADCs, the possibilities are endless.

Different Targets for the Same Population

Different-Target ADC Sequential Therapy – Exploring the Root

Professor Luo introduced that current clinical Trop-2 ADC payloads are primarily one type of drug—TOP1 inhibitors, which may lead to cross-resistance. For ADC resistance with similar payloads, changing to a different-target ADC for sequential treatment might be a good choice. At the 2023 ASCO conference, a study explored different-target ADC sequential modes. Among 35 patients treated with more than one ADC between August 2014 and February 2023, 15 had HR+/HER2- mBC, 20 had TNBC, and 24 had HER2-low mBC. Before starting the second ADC treatment, patients received a median of four lines (range 2-12) of therapy. The results showed that PFS for ADC 1 seemed better than ADC 2, but due to the small sample size, the findings should be interpreted cautiously.

For different-target ADC sequential therapy, several studies discussed HER2-low advanced breast cancer at the 2023 SABCS conference. Raghavendra’s real-world study found that using T-DXd followed by SG was more effective, with ADC1 PFS/ADC2 PFS of 7.6 and 5.5 months superior to 4.6 and 2.4 months. Other retrospective cohort studies indicated that in HER2-low patients, regardless of HR status, using SG followed by T-DXd was more effective. PFS values for initial SG use ranged from 4.9 to 8.3 months, while initial T-DXd use ranged from 1.4 to 5.5 months. Although it appeared that SG sequential T-DXd was superior, some studies showed different conclusions, and various influencing factors were involved.

Different-Target ADC Sequential Therapy – In-Depth Inquiry

Professor Luo concluded that these studies have significant limitations, such as sample size, patient heterogeneity, patient selection, treatment bias, and interspersed treatments. Therefore, results may be biased. Moreover, comparisons were not adjusted for baseline patient receptor status or prior treatment lines, so they cannot be considered absolute evidence. Currently, it is unclear which ADC should be the initial treatment, and precise identification is the ultimate solution. When ADCs enter early treatment stages, sequential ADC therapy in later stages becomes inevitable. To address this issue, prospective large-sample studies are needed to determine the best sequential therapy.

Summary

Currently, the sequential use of same-target or different-target ADC drugs requires individualized differentiation, and it is unclear which ADC1 or ADC2 should be preferred. Based on current evidence-based medicine, practice will ultimately test the truth. The future is here, and early layout for ADC sequential therapy is needed. Professor Luo concluded her lecture with “It is the trend of the times, time waits for no one, strive forward, and love while moving on,” summarizing the content. She mentioned that the ADC era is no longer about choosing A or B exclusively; the sequential modes between ADCs will continue to test clinical practice, eventually leading to a flourishing scene of “one sings after another, and flowers bloom in succession.”

Professor Ting Luo:

• Deputy Director of the Breast Disease Center, West China Hospital, Sichuan University
• Chief Physician, Doctor of Medicine, Master Supervisor
• Standing Member of the Young Experts Committee of the Chinese Society of Clinical Oncology (CSCO)
• Member of the Breast Cancer Committee of CSCO
• Young Expert of the Breast Cancer Committee of the Chinese Anti-Cancer Association
• Youth Committee Member of the Breast Cancer Group, Oncology Branch, Chinese Medical Association
• Standing Member of the Breast Disease Professional Committee, China Health Promotion Foundation
• Deputy Director of the Yangtze River Academic Breast Alliance
• Chairman of the Breast Cancer Committee, Sichuan International Medical Exchange Promotion Association
• Deputy Chairman of the Breast Cancer Committee, Sichuan Anti-Cancer Association
• Vice President of the Breast Professional Branch, Sichuan Medical Doctor Association
• Standing Member and Youth Chairman of the Breast Disease Prevention and Control Branch, Sichuan Preventive Medicine Association
• Deputy Chairman of the Breast Cancer Committee, Sichuan Oncology Society
• Recipient of the “Outstanding Contribution Award in the Field of Breast Cancer” at the 3rd “People’s Good Doctor · Golden Camellia Plan”