Editor’s Note:
ADC drugs, also known as Antibody-Drug Conjugates, combine targeted antibodies with cytotoxic drugs to accurately attack tumor cells and minimize damage to normal cells. In recent years, ADC drugs have made significant breakthroughs in the field of cancer treatment and have become a focus of attention. At this year’s ESMO conference, several studies on ADC drugs garnered significant attention. In this report, Professor Jian Zhang from Fudan University-affiliated Cancer Hospital introduces the progress in the treatment of breast cancer using ADC drugs.
1
LBA11 – TROPION-Breast01: Efficacy of Dato-DXd vs. Chemotherapy in Inoperable or Metastatic HR+/HER2- Breast Cancer
Research Overview
TROPION-Breast01 is a global, randomized, multicenter, open-label Phase III clinical trial designed to evaluate the efficacy and safety of Dato-DXd (6.0 mg/kg, q3w) compared to investigator’s choice of single-agent chemotherapy (ICC) in patients with inoperable or metastatic HR-positive, HER2-low-expressing, or HER2-negative (IHC 0, 1+, or IHC 2+/ISH-) advanced breast cancer who have progressed on or are unsuitable for endocrine therapy (must have received at least 1-2 lines of chemotherapy). The study also employed a dual primary endpoint design, including BICR-assessed PFS and OS. Key secondary endpoints included ORR, investigator-assessed PFS, and safety.
A total of 732 patients were enrolled (365 in the Dato-DXd group and 367 in the ICC group). Baseline characteristics were balanced between the two groups, with 82% and 18% of patients in the Dato-DXd group having received 1st/2nd-line treatment, compared to 61% and 38% in the ICC group. The proportion of patients who had received CDK4/6i treatment was 82% and 18% in the Dato-DXd group and 78% and 22% in the ICC group, respectively.
As of the data cutoff date (July 17, 2023), 93 patients in the Dato-DXd group and 39 patients in the ICC group were still receiving treatment. The median PFS for patients in the Dato-DXd group and ICC group was 6.9 months and 4.9 months, respectively. Patients in the Dato-DXd group had a significantly reduced risk of disease progression or death compared to the ICC group, with a 37% lower risk (HR 0.63, 95% CI: 0.52–0.76; P < 0.0001). Subgroup analysis showed consistent PFS benefits across different subgroups.
The ORR in the Dato-DXd group and ICC group was 36.4% and 22.9%, respectively. OS data are not yet mature, but there is a trend of benefit observed in the Dato-DXd group (HR 0.84, 95% CI: 0.62–1.14).
In comparison to the ICC group, the Dato-DXd group had lower rates of ≥3-grade treatment-related adverse events (TRAEs) (21% vs. 45%) and TRAEs leading to dose reduction (21% vs. 30%). In the Dato-DXd group, 9 patients (3%) experienced different grades of ILD, with only 1 case being Grade 3 ILD.
Expert Commentary
The TROPION-Breast01 study primarily focuses on patients with HR-positive/HER2-low-expressing breast cancer and treats them with the drug Dato-DXd, which targets Trop-2. A total of 732 patients were randomized into two groups, with 365 patients in the Dato-DXd treatment group and 367 patients in the investigator’s choice of chemotherapy (ICC) group, which included drugs like eribulin, capecitabine, vinorelbine, or gemcitabine. This study has dual primary endpoints, including BICR-assessed PFS and OS. Overall, the data showed that patients in the Dato-DXd group had a significantly improved median PFS compared to the ICC group, with a 37% reduction in the risk of disease progression or death. The PFS benefit was consistent across different patient subgroups. In terms of safety, the Dato-DXd group had lower rates of ≥3-grade TRAEs and TRAEs leading to dose reduction compared to the ICC group.
The TROPION-Breast01 study corroborates the TROPiCS-02 study, but it appears to include patients who had received earlier-line treatments. Patients in the study had previously progressed on or were unsuitable for endocrine therapy and had received at least 1-2 lines of chemotherapy. With the publication of data from these two clinical studies, there is hope that more HR+/HER2- patients can benefit from ADCs targeting Trop-2.
379MO – Datopotamab Deruxtecan (Dato-DXd) + Durvalumab (D) as First-Line Treatment for Unresectable Locally Advanced/Metastatic Triple-Negative Breast Cancer (a/mTNBC): Latest Results from the BEGONIA Study
Research Overview
The BEGONIA study (NCT03742102) is an ongoing open-label, multi-arm, two-part, multicenter Phase Ib/II clinical trial evaluating the safety, tolerability, and preliminary efficacy of novel ADCs, including Dato-DXd, in combination with durvalumab as first-line treatment for patients with unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC). Early results from Cohort 7 of this study demonstrated encouraging anti-tumor activity of Dato-DXd in TNBC. This conference presents updated results from the study.
As of February 2, 2023, a total of 62 patients received treatment with Dato-DXd in combination with durvalumab (29 patients are still ongoing). The median follow-up time was 11.7 months (range 2-20). The confirmed overall response rate (cORR) was 79% (49/62, 95% CI: 66.8-88.3), with 10% of patients achieving complete response (CR) and 69% achieving partial response (PR). Response did not correlate with PD-L1 expression levels.
The median progression-free survival (PFS) was 13.8 months (95% CI: 11.0-NC), and the median duration of response (DoR) was 15.5 months (95% CI: 9.92-NC). Nausea and oral mucositis were the most common adverse events, occurring at rates of 65%. Three patients (5%) experienced treatment-related interstitial lung disease/pneumonia, with 2 cases being Grade 2 and 1 case being Grade 1. There were no treatment-related deaths, and 16% of patients discontinued any study drug due to adverse events, with no new safety signals reported.
Expert Commentary
The second clinical study presents the latest data from Cohort 7 of the BEGONIA study, which assesses the treatment effects, safety, and more of Dato-DXd in combination with durvalumab as first-line therapy for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC). The data is highly anticipated, and Cohort 7 included 62 patients. The presented data showed a cORR of 79%, with 10% of patients achieving CR and 69% achieving PR. This high response rate for TNBC patients, combined with manageable overall toxicity, is promising and suggests that this combination therapy is worth further exploration.
Historically, immunotherapy combined with chemotherapy has shown that patients with TNBC who have a PD-L1 CPS≥10 benefit, but this study suggests that immunotherapy combined with ADC treatment may not require such a criterion. During the live presentation at this year’s ESMO conference, a question was raised to the presenter, Peter Schmid, regarding this issue. Peter Schmid’s response was that immunotherapy combined with ADC treatment may not depend on PD-L1 expression and can potentially offer treatment benefits to other patients. Therefore, more data on this approach is eagerly awaited.
3
376O – T-DXd vs. Physician’s Choice Therapy (TPC) in HER2-Low-Expressing Unresectable and/or Metastatic Breast Cancer (mBC) Patients: Survival Results Update from the Randomized Phase III DESTINY-Breast 04 Study
Research Overview
The DESTINY-Breast04 (DB-04) study compared the efficacy of T-DXd with TPC in patients with HER2-low-expressing (IHC 1+ or 2+, ISH-) metastatic breast cancer. As of the preliminary analysis data cutoff date (DCO, January 11, 2022), the median overall survival (OS) for the full analysis set (FAS, HR+ and HR-) patients showed that patients in the T-DXd group had a median OS of 23.4 months compared to 16.8 months in the TPC group (HR 0.64; P=0.001). This conference presents further follow-up analysis results from the DESTINY-Breast 04 study (cutoff date March 1, 2023), including investigator-assessed OS (HR+ patients and FAS patients), progression-free survival (PFS), and safety data.
As of March 1, 2023, the median follow-up time for patients was 32 months. The median treatment duration for patients in the T-DXd group and TPC group was 8.2 months (range: 0.2 to 39.1 months) and 3.5 months (range: 0.3 to 19.7 months), respectively. Total survival data indicated that in HR-positive patients, the T-DXd vs. TPC group had a median OS of 23.9 months (95% CI: 21.7-25.2) vs. 17.6 months (95% CI: 15.1-20.2) (HR 0.69, 95% CI: 0.55-0.87). In the overall patient population, the T-DXd vs. TPC group had a median OS of 22.9 months (95% CI: 21.2-24.5) vs. 16.8 months (95% CI: 14.1-19.5) (HR 0.69, 95% CI: 0.55-0.86), with a 31% reduced risk of death.
Median PFS data showed that in HR-positive patients, the T-DXd vs. TPC group had a median PFS of 9.6 months (95% CI: 8.4-10.0) vs. 4.2 months (95% CI: 3.4-4.9), representing a 63% reduction in the risk of disease progression or death. In the overall patient population, the T-DXd vs. TPC group had a median PFS of 8.8 months (95% CI: 8.3-9.8) vs. 4.2 months (95% CI: 3.0-4.5), with a 64% reduction in the risk of disease progression or death.
Safety data showed that the T-DXd group had a lower rate of ≥3-grade treatment-related adverse events (TEAEs) compared to the TPC group (54.4% vs. 67.4%). The exposure-adjusted incidence rates (EAIRs) of any-grade TEAEs were 1.2 for the T-DXd group and 2.6 for the TPC group. With extended follow-up, no new drug-related interstitial lung disease/pneumonia events were reported [initial DCO: T-DXd: 45 cases (12.1%); TPC: 1 case (0.6%)].
Expert Commentary
The third update is from the DB-04 study. Previously, data from an 18.4-month follow-up had been disclosed, and the presented data at this ESMO conference are from a median follow-up of 32 months. The results continue to show a survival difference and HR values between the two groups, with no change. In this update, the median OS remains favorable for patients in the T-DXd group compared to the TPC group, with a 31% reduced risk of death. PFS data also support this, with a 63% and 64% reduction in the risk of disease progression or death in HR-positive and overall patient populations, respectively. The safety data indicate a lower rate of ≥3-grade TEAEs in the T-DXd group compared to the TPC group (54.4% vs. 67.4%).
These updated data further strengthen the idea that HER2-low-expressing breast cancer patients can benefit from ADC drugs, particularly T-DXd. The data is reliable with long-term follow-up, and it is hoped that more patients in China and worldwide will benefit. Additionally, there is anticipation for data from DB-06 in patients with HER2-very-low-expressing breast cancer to provide further insights.
Chief Physician, Doctor of Medicine
Director of Phase I Clinical Research Ward, Fudan University-affiliated Cancer Hospital
Chief Physician, Department of Oncology
Shanghai “Medical Talent Star” Young Talent Awardee
Deputy Chairperson-elect of the Shanghai Anti-Cancer Association’s Oncology Drug Clinical Research Professional Committee
Standing Committee Member of the Chinese Anti-Cancer Association’s Breast Cancer Professional Committee
Deputy Convener of the Chinese Anti-Cancer Association’s Breast Cancer Professional Committee Youth Committee
Chairman of the Yangtze River Academic Breast Cancer Alliance (YBCSG)
Deputy Chairman of the Chinese Research Hospital Association’s Breast Professional Committee Youth Committee
Deputy Chairman of the National Anti-Tumor Drug Clinical Application Monitoring Youth Committee
Deputy Chairman of the Shanghai Anti-Cancer Association’s Oncology Cardiology Professional Committee
Standing Committee Member of the CSCO Oncology Support and Rehabilitation Treatment Expert Committee
Standing Committee Member of the Chinese Rehabilitation Medicine Society’s Oncology Rehabilitation Professional Committee
Committee Member of the CSCO Breast Cancer Expert Committee
Committee Member of the Chinese Anti-Cancer Association’s Oncology Clinical Research Management Professional Committee
Part-time Reviewer of the first batch of Clinical Pharmacists at the Center for Drug Evaluation of the National Medical Products Administration
Recipient of the 2023 Top Ten Medical Pioneer Experts and the 2023 “People’s Good Doctor” Outstanding Contribution Award
Associate Editor of “Diseases & Research”
First/Co-first/Corresponding Author of 70 SCI Papers (Published in Journals such as Lancet Oncology, Annals of Oncology, Nature Communications, Clinical Cancer Research, Journal of Hematology & Oncology, etc.)
