preface
Nature Reviews Clinical Oncology（IF=81.1）发布综述“Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer”，对目前HR+转移性乳腺癌的精准治疗和新兴策略进行了系统阐述，上一期，医脉通小编已整理文章内分泌治疗与靶向/联合治疗部分。
Literature Intensive Reading丨Come and recharge! Emerging Treatments for HR-Positive Advanced Breast Cancer (Anti-Estrogen Therapy)
Literature Intensive Reading丨Come and recharge! Emerging Therapies for HR-Positive Advanced Breast Cancer (Targeted and Combination Therapies)
This article will continue to share with you the research status and progress of antibody-drug conjugates (ADCs).
1
background
At present, breast cancer can be divided into three subtypes according to receptor status and protein expression: hormone receptor positive (HR+, about 70%), HER2 positive (HER2+, about 20%), and triple negative (TNBC, about 10%). As the most common subtype of breast cancer, gaining a deep understanding of the genomic and molecular factors that control HR tumor progression and using these insights to develop novel individualized therapies has become a key area of research. Estrogen-related intracellular signaling pathways regulate the expression of a variety of genes that are essential for cell survival and proliferation, including key cell cycle regulatory components. Modern medicine is dedicated to the management of patients with early and advanced HR+ breast cancer, prioritizing the weakening of related endocrine and targeted therapies, while minimizing treatment-related adverse effects.
Antibody-drug conjugates (ADCs) are a unique class of drugs that combine monoclonal antibodies with cytotoxic payloads. This design allows the payload to be precisely delivered to tumor cells expressing specific cell surface antigens, ideally achieving anti-tumor activity while minimizing the risk of off-target AEs. In addition, ADCs may further enhance the killing effect on tumor cells through the bystander effect. At present, some drugs have been approved for marketing.
2
Novel drugs entering clinical practice
德曲妥珠单抗（T-DXd）
T-DXd is a HER2-targeting ADC with a payload of novel topoisomerase I inhibitors. In addition to being approved for patients with HER2+ tumors, T-DXd is also approved for patients with advanced breast cancer with low HER2- expression based on the results of the DESTINY-Breast04 study.
DESTINY-Breast04 is a randomized phase III trial to compare T-DXd with physician-choice chemotherapy in patients with unresectable or metastatic HER2-low expression breast cancer following prior chemotherapy, with the majority (88.7%) of enrolled patients presenting with HR+ disease and approximately 65% of patients having received a CDK4/6 inhibitor. The results showed that T-DXd was associated with a significant improvement in median PFS (10.1 versus 5.4 months; HR 0.51, 95% CI 0.40-0.64; P < 0.001), with a median OS improvement (23.9 versus 17.5 months; HR 0.64，95% CI 0.48–0.86；P = 0.003）。 ≥Grade 3 AEs occurred in 52.6% of patients in the T-DXd group compared with 67.4% in the chemotherapy group.
In the DESTINY-Breast06 trial, the use of T-DXd prior to cytotoxic chemotherapy was evaluated in patients with endocrine-refractory HER2-low HER2-expressing advanced breast cancer. The phase III trial enrolled patients with HR+/HER2- low or ultra-low HER2 (IHC > 0 but <1+) breast cancer who had progressed on endocrine therapy and were randomly assigned to receive either T-DXd or clinician-choice chemotherapy. Compared with clinician-selected chemotherapy, T-DXd was associated with improvement in median PFS in the HER2- low expression subgroup (13.2 versus 8.1 months; HR 0.62; 95% CI 0.51–0.74; P < 0.0001), with a similar trend observed in patients with ultra-low HER2- (13.2 versus 8.3 months; HR 0.78；95% CI 0.50–1.21）。 All patients who received T-DXd had a longer duration of treatment (11 versus 5.6 months) and a higher ORR (HER2-low: 56.5 versus 32.2 percent) compared with those who received chemotherapy (HER2-low; HER2 - ultra-low: 61.8% vs 26.3%).
Gosatuzumab (SG)
SG is an ADC that binds an anti-TROP2 monoclonal antibody to the topoisomerase inhibitor SN-38 and has shown activity in preclinical models of a variety of solid tumors, including breast cancer. TROP2 is closely related to the adhesion and proliferation of cancer cells, and is expressed in all breast cancer subtypes, and is expressed at a higher level than HER2+ breast cancer in triple-negative breast cancer (TNBC) and HR+ breast cancer.
Based on the significant improvements in PFS and OS observed in the randomized phase III ASCENT trial, SG was initially approved for patients with metastatic TNBC. In the phase III TROPiCS-02 trial, SG was compared to physician-selected chemotherapy in patients with endocrine therapy-resistant HR+/HER2- advanced breast cancer who had previously received CDK4/6 inhibitors and taxanes.
The results showed a significant improvement in median PFS in patients treated with SG (5.5 versus 4 months; HR 0.66, 95% CI 0.53-0.83; P = 0.0003), and median OS improved (14.4 versus 11.2 months; HR 0.7，95% CI 0.65–0.96；P = 0.02）。 The majority of patients developed grade ≥3 AEs, 74% in the study group and 60% in the control group, with the most common AEs being neutropenia and diarrhea.
Currently, the Phase III ASCENT-07 trial is recruiting patients with metastatic ER+/HER2- breast cancer who are resistant to endocrine therapy but have not received chemotherapy. In this trial, patients were randomly assigned to either SG or physician-selected chemotherapy, with the primary endpoint being PFS.
3
Drugs in exploration
Datopotamab deruxtecan(Dato-DXd)
Dato-DXd is a TROP2-targeting ADC that combines the payload deruxtecan. Dato-DXd shows significant antitumor activity in preclinical models expressing TROP2.
The Phase I TROPION-PanTumor01 trial is evaluating Dato-DXd in patients with solid tumors who have received multiple prior lines of therapy, 95% of whom have received third-line therapy, including CDK4/6 inhibitors. Preliminary data showed that patients had a CBR of 41%, and 98% had AEs (41% were grade 3≥ AEs), with the most common AEs including fatigue, nausea, and stomatitis; One patient developed grade 2 interstitial lung disease and was thought to be treatment-related.
The results of TROPION-PanTumor01 led to the Phase III TROPION-Breast01 trial, which compared Dato-DXd with investigator-selected chemotherapy in patients with HR+/HER2- metastatic breast cancer who had progressed on prior endocrine therapy and first- or second-line chemotherapy. The results showed a significant improvement in median PFS in patients who received Dato-DXd (6.9 versus 4.9 months; HR 0.63，95% CI 0.52-0.76；P < 0.0001）。 In addition, patients receiving Dato-DXd also had a lower incidence of ≥ grade 3 AEs (20.8 versus 44.7 percent). Currently, OS data is immature.
Patritumab deruxtecan（HER3-DXd）
HER3-DXd is an anti-HER3 monoclonal antibody (patritumab) ADC that binds to deruxtecan. The drug is able to inhibit the growth of ERBB3 wild-type and mutant breast cancer cells. The single-arm Phase II ICARUS-Breast01 trial evaluated the efficacy and safety of HER3-DXd in patients with HR+/HER2- breast cancer who had received prior endocrine therapy, CDK4/6 inhibitors, and metastatic chemotherapy, regardless of HER3 status. Of the 56 patients who were studied and could be preliminarily analyzed, 16 achieved partial response (PR) and 30 had stable disease (SD). The most common AEs included fatigue and nausea, with one patient developing grade 1 interstitial lung disease.
Sacituzumab tirumotecan（SKB264）
SKB264 is an antibody-drug conjugate (ADC) targeting TROP2 with a payload of a topoisomerase I inhibitor currently in clinical development for the treatment of patients with multiple solid tumors, including advanced breast cancer. Two phase III clinical trials are enrolling patients with HR+/HER2- advanced breast cancer (NCT06312176, NCT06081959).
Bibliography:
Lloyd, M.R., Jhaveri, K., Kalinsky, K. et al. Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00935-6
Editor: Ryland
Reviewer: Uni
Typography: Ryland
Executive: Babel
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