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From May 15 to 17, 2024, the high-profile 2024 European Society for Medical Oncology Annual Meeting on Breast Cancer (2024 ESMO BC) will be held in Berlin, Germany. As an international event for breast cancer held in Europe, ESMO BC is a platform to showcase the latest scientific research achievements and clinical treatment progress, and an important place to promote in-depth exchanges and cooperation between global experts. More than 800 professionals are expected to participate in the conference to discuss innovative treatments and patient care strategies for breast cancer, advance translational research and practice in oncology, and open up new prospects for breast cancer treatment and management worldwide. Recently, the 2024 ESMO BC abstract announced that in the field of triple-negative breast cancer (TNBC), antibody-drug conjugates (ADCs) continued to make efforts, continuing their excellent performance in the past few years. The relevant content is now organized as follows for the benefit of readers.
181O - MORPHEUS-PAN BC Study: Phase Ib/II Study of Multiple Treatment (tx) Regimens in Patients With Locally Advanced/Metastatic BC (LA/mBC), Interim Analysis (IA) Results of Atezolizumab + Gosatuzumab (SG) in Patients With TNBC
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Background:
Immunotherapy has changed the treatment landscape for TNBC, but new combinations are needed to further improve patient outcomes. Atezolizumab + nab-paclitaxel (nab-P) was approved for the first-line treatment of PD-L1-positive, inoperable LA/mTNBC. SG is approved for second-line treatment of mTNBC. The investigators present the 18-week IA results of the atezolizumab + SG arm in MORPHEUS-panBC (NCT03424005).
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Research Methods:
Patients with PD-L1-positive, inoperable LA/mTNBC who had not received prior systemic therapy were enrolled and randomly assigned to receive controls (day 1 [D] and day 15 [D] 840 mg IV + nab-P 100 mg/m2 IV) or atezolizumab (1200 mg IV D1) + SG (10 mg/kg IV, D1 and 8) 21-D cycles until unacceptable toxicity/failure of clinical benefit. The primary endpoints are objective response rate (ORR) and safety. To assess the correlation of TROP-2 and PD-L1 IC expression in baseline tumors with treatment remission.
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Findings:
Up to the data cut-off date (March 9, 2023), 11 patients were included in the control group and 31 patients in the atezolizumab + SG group. Younger patients (< 65 years) accounted for 84% in the atezolizumab + SG group and 64% in the control group; The distribution of liver and brain metastases sites was similar between the two groups. The ORR was 76.7% in the atezolizumab + SG arm (n=23; 5 complete responses [CR]) and 66.7% in the control group (n=6; all partial responses [PR]); The clinical benefit rate (CBR) was 83.3% and 66.7%, respectively. Median progression-free survival (mPFS) data are immature, but atezolizumab + SG showed a trend of benefit compared to controls (12.2 versus 5.9 months; Median follow-up was 10.6 months vs. 11.7 months). No new safety signals were observed.
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Conclusions of the study
Atezolizumab + SG regimen observed encouraging activity in first-line treatment in patients with PD-L1-positive LA/mTNBC. PFS data are immature but show a trend of benefit with atezolizumab + SG. The safety profile of atezolizumab + SG was consistent with the characteristics of the individual drugs, and no new safety signals were observed.
Results of Phase I of the Phase II Study of 187P - Dato-DXd in Patients With Active Brain Metastases TNBC (TUXEDO-2)
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Background:
Brain metastases (BM) are common metastases in TNBC, which can improve morbidity and mortality. There is an urgent need to provide strategies for intracranial and extracranial disease control. Dato-DXd is a Trop2-targeting ADC with anti-TNBC activity. The investigators report results from Phase I of a prospective, single-arm phase II TUXEDO-2 trial to investigate the efficacy and safety of Dato-DXd in TNBC patients with active BM.
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Research Methods:
The TUXEDO-2 study primarily included newly diagnosed patients with TNBC who were untreated or BM and did not have an immediate need for topical therapy. The administration of DATO-DXd is 6.0mg/kg, q3w. The primary endpoint is intracranial response rate (RR) as assessed centrally by the Neuro-Oncology Response Assessment (RANO) BM criteria. Secondary endpoints included extracranial RR, PFS, overall survival (OS), safety, quality of life, and cognitive function. Based on Simon's two-stage design (RR > 35% under alternative hypothesis; RR was ≤11%) under the null hypothesis, with a total of 8 patients in the first phase. If ≥2 responses are observed, an additional 12 patients will be added to the trial.
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Findings:
As of February 7, 2022, 8 patients have been enrolled, 75% of whom have newly diagnosed BM and 25% have progressive BM. Two patients had been previously treated with SG and one patient had been treated with trastuzumab (T-DXd). At data cut-off, a total of 5 evaluable responses were observed, and 3 objective intracranial responses were observed, corresponding to an RR of 37.5%. One patient died of intestinal perforation (not related to treatment) and one patient died of extracranial disease progression, both prior to the first reassessment; One remission is not yet available. All responses were observed in patients who had not received prior ADC therapy. Major AEs included grade 1/2 fatigue, grade 2 stomatitis in 1 case, and grade 3 interstitial lung disease in 1 case.
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Conclusions of the study
Three intracranial responses were observed in the TUXEDO-2 trial, with positive results in Phase I, and the trial has progressed to Phase II. The treatment was generally well tolerated, and no new safety signals were observed. Therefore, Dato-DXd may provide an opportunity for systemic treatment of active BM in TNBC.
Effect of height body mass index (BMI) in the 189P - ASCENT study on the safety and efficacy of SG in patients with metastatic triple-negative breast cancer (mTNBC).
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Background:
SG is a Trop-2-targeted ADC that has been approved in several countries for the treatment of relapsed or refractory mTNBC. In the phase III ASCENT study (n=529), with a median follow-up of 17.7 months as of March 11, 2020, SG observed a significant increase in PFS (HR, 0.43; 95% CI, 0.35-0.54) and OS (HR, 0.51; 95% CI, 0.41-0.62) compared with physician's choice chemotherapy (TPC). The incidence of obesity has grown to the point of an epidemic in recent decades, and it is unclear what impact this may have on treatment outcomes, especially for ADCs like SG that have weight-based doses. Here, the investigators investigated the safety and efficacy of SG versus TPC in the BMI subgroup.
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Research Methods:
This ad hoc subgroup analysis included the ITT population from the ASCENT study, where patients received SG or TPC at a dose of 10 mg/kg. BMI was assessed at baseline and classified as follows: leanish/normal (<25 kg/m2), overweight (25-30 kg/m2), and obese (≥30 kg/m2).
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Findings:
As of February 25, 2021, in patients in all BMI subgroups, longer PFS and OS, as well as higher ORR, were observed in the SG group compared to the TPC group. In the lean/normal, overweight, and obese subgroups, adverse events (TEAEs) ≥ grade 3 were observed in 68%, 78%, and 77% of patients in the SG group, respectively, TEAEs leading to dose reduction were observed in 11%, 24%, and 41% of patients, and TEAEs leading to treatment discontinuation were observed in 4%, 3%, and 8% of patients, respectively.
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Conclusions of the study
This is the first study to evaluate the effect of BMI on ADC treatment. SG showed better efficacy and a manageable safety profile compared to TPC in all BMI subgroups assessed by ASCENT. Although a greater proportion of SG dose reductions were seen in patients with high BMI (especially obesity), this did not translate into a reduction in efficacy.
The 159TiP-TROPION-Breast04 study: A phase III study of neoadjuvant Dato-DXd+ durvalumab (D) followed by adjuvant D versus standard of care (SoC) in treatment-naïve, triple-negative (TN), and HR-low expression/HER2-negative breast cancer
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Background:
For patients with untreated stage II-III TNBC, the current regimen is neoadjuvant pembrolizumab (pembro) plus chemotherapy (CT) followed by surgery and sequential adjuvant pembro. However, there is still a need to develop a treatment to improve pathologic complete response (pCR) rates and long-term survival in patients, while reducing traditional chemotherapy-related toxicity. Dato-DXd consists of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a potent topoisomerase I inhibitor by a plasma-stable, tetrapeptide, tumor-selective, cleavable linker. In the Phase Ib/II BEGONIA study, Dato-DXd+D demonstrated a durable treatment response in inoperable patients with advanced TNBC. The ongoing Phase III TROPION-Breast03 study is evaluating Dato-DXd±D versus existing treatment regimens as adjuvant therapy for patients with stage I-III TNBC who still have residual invasive disease at the time of surgery after neoadjuvant therapy. TROPION-Breast04 (NCT06112379) is designed to determine the efficacy of neoadjuvant Dato-DXd+D therapy followed by adjuvant therapy versus current treatment regimens in patients with untreated early-stage TNBC or HR-low expression/HER2-negative breast cancer.
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Research Methods:
TROPION-Breast04 is a two-arm, parallel-controlled, randomized, open-label, multicenter phase III study. ∼1728 patients (≥ 18 years of age) with previously untreated stage II-III, unilateral/bilateral, primary infiltrative TNBC or low HR (ER and/or PR1% - <10%； Patients with HR≥10%)/HER2-BC and ECOG PS 0-1. Randomized 1:1 to treatment groups (neoadjuvant Dato-DXd+D, 8 cycles; postoperative adjuvant SoC) or control group (both neoadjuvant therapy and postoperative adjuvant therapy are SoC), stratified by lymph node status, tumor stage, HR status and region. Primary endpoints: pCR and event-free survival (EFS). Secondary endpoints: OS, distant disease-free survival, patient-reported outcomes, pharmacokinetics, immunogenicity, safety/tolerability. Planned enrollment in 26 countries; At the time of submission of the abstract, recruitment is underway in Canada, South Korea, and Taiwan.
261TiP-TROPION-Breast05 Study: A Phase III Study of Neoadjuvant Dato-DXd+ Duvalumab (D) Followed by Adjuvant D vs Standard of Care (SoC) in Treatment-naïve, Triple-negative (TN), and HR-Low Expression/HER2-Negative Breast Cancer
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Background:
The standard of care for patients with metastatic PD-L1-positive (composite positive score [CPS] ≥10) TNBC is CT+pembro, but the prognosis remains poor. Dato-DXd contains a humanized anti-TROP2 IgG1 antibody conjugated to a potent topoisomerase I (Topo-1) inhibitor via a plasma-stable, tetrapeptide-based tumor-selective cleavable linker. D is a high-affinity human IgG1 monoclonal antibody that can block the interaction of PD-L1 with PD-1 and CD80 by binding to PD-L1. In the Phase I TROPION-PanTumor01 study, Dato-DXd demonstrated a manageable safety profile and encouraging efficacy in patients with mTNBC who had undergone extensive pretreatment. In the Phase Ib/II BEGONIA study, Dato-DXd+D demonstrated durable response in unresectable advanced TNBC. TROPION-Breast05 (NCT06103864) will compare the efficacy and safety of Dato-DXd±D versus the investigator's choice of CT+pembro regimen in PD-L1-positive locally recurrent, inoperable, or metastatic TNBC.
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Research Methods:
TROPION-Breast05 is a randomized, open-label, three-arm, multicenter Phase III study of 625 patients (≥ 18 years of age) with pathological/cytologically confirmed locally recurrent inoperable or metastatic PD-L1-positive (CPS≥10) TNBC naïve with chemotherapy or targeted systemic anticancer therapy. Patients with active brain metastases or prior Topo-I ADC or TROP2-targeted therapy were excluded. Patients will be randomized in a 1:1 ratio to either the first group (Dato-DXd 6mg/kg IV q3w + D 1120mg IV q3w) or the second group (ICC [paclitaxel, nab-P or gemcitabine + carboplatin] + pembro), or in selected countries, to the first, second, or third groups (Dato-DXd alone) in a 1:1:1 ratio. When about 75 patients are randomized to a third group, the group will be closed and 1:1 randomization will continue for all countries. Primary endpoint: Blinded independently centrally assessed PFS performed according to RECIST v1.1 criteria. Secondary endpoints: OS, ORR, duration of response, investigator-assessed PFS, PFS2, 24-week clinical benefit rate, patient-reported outcomes, pharmacokinetics, immunogenicity, and safety. Recruitment is planned in 20 countries; At the time of submission of the abstract, the United Kingdom, South Korea, and Taiwan are actively recruiting.
编辑:Ryland
审校:Faline
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