LBA1 Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study

Cortés, Javier; Kim, SB; Chung, W-P.; Im, Sungbin; Park, Y.H.; Hegg, Roberto; Kim, M.H.; Tseng, L-M; Petry, Vanessa; Chung, C-F.; Iwata, Hiroji; Hamilton, E.; Curigliano, Giuseppe; Xu, Binghe; Lee, C.; Liu, Y.; Cathcart, Jillian; Bako, Emarjola; Verma, Sunil; Hurvitz, Sara A.

doi:10.1016/j.annonc.2021.08.2087

Cited by 94 publications

(121 citation statements)

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“…Interestingly, in this analysis the median time to onset of ILD was much earlier at 5.6 months, but after 12 months the risk was low [32]. In the DESTINY-Breast03 trial, the rate of interstitial lung disease was lower than in previous trials at 10.5%, with no grade 4/5 ILD [18]. The lower rates of ILD in this study may be related to less exposure to prior chemotherapy.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 64%

“…In this trial, T-DXd was compared with T-DM1 in the second-line setting in patients with HER2 + MBC who had progressed on a taxane and trastuzumab. At 16 months, median PFS was not reached with T-DXd but was 6.8 months with T-DM1 (HR = 0.28; P = 7.8 × 10 −22 ) [18]. T-DM1 can also be used in the first-line setting for patients who cannot tolerate THP, as it is less toxic and patients maintain health-related quality of life (HRQOL) longer [19].…”

Section: Er − or Er + With Visceral Crisis Or Hormone Refractorymentioning

confidence: 99%

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Anti-HER2 therapy in metastatic breast cancer: many choices and future directions

Wynn

Tang

2022

Cancer Metastasis Rev

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Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action.

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Section: Antibody-drug Conjugatesmentioning

confidence: 64%

Section: Er − or Er + With Visceral Crisis Or Hormone Refractorymentioning

confidence: 99%

Anti-HER2 therapy in metastatic breast cancer: many choices and future directions

Wynn

Tang

2022

Cancer Metastasis Rev

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“…In a subgroup analysis of patients with brain metastases of the DESTINY-Breast01 trial, the objective response rate and the median PFS were 58% and 18 months, respectively [18]. DESTINY-Breast03, in the post hoc analysis, demonstrated an improvement in PFS from 5.7 months with T-DM1 to 15 months with T-Dxd towards brain metastases [19]. These trials evidence the benefit of targeted therapy in brain metastases; even though no trial has been conducted in the IBC subtype, our patient benefited from T-DM1 with a 71% reduction in brain lesions after just two cycles.…”

Section: Discussionmentioning

confidence: 97%

HER2-Positive Inflammatory Breast Cancer Challenges of Clinical Practices

Magalhães¹,

Rangel²,

Mesquita³

2022

Cureus

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HER2-positive inflammatory breast cancer (IBC) is associated with poor overall survival. Targeted therapies have led to improved outcomes. IBC is underrepresented in clinical trials due to its rareness. This case reports a 52-year-old woman diagnosed with IBC of 119x89mm, axillar node-positive, hormone receptornegative, HER2 positive. The patient underwent neoadjuvant chemotherapy with dual HER2 blockage. Mastectomy histology showed pathological complete response. After two cycles of adjuvant trastuzumab, the patient developed asymptomatic cardiotoxicity leading to the therapeutic suspension. Early recurrence and persisting cardiac alterations prevented treatment with anti-HER2 therapy. At the time of brain recurrence, with cardio-oncology collaboration, it was possible to start TDM-1, with a reduction of 71% of brain lesions size, after two cycles. This case highlights the effectiveness of anti-HER therapy in IBC and the importance of multidisciplinary discussion in treatment choice and toxicity management.

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“…Based on the clinical efficacy of tucatinib with letrozole and palbociclib in heavily treated patients with brain metastases, our study would further investigate the efficacy of the triplet regimen in this population in the front-line setting. Recently, T-DXd was recommended as the new standard second-line therapy by guidelines based on DESTINY-Breast03 trial with highly clinically meaningful and statistically significant improvement in PFS compared with T-DM1 in patients with HER2-positive MBC (PFS HR of 0.28 ( P = 7.8×10 -22 )), similarly in HR-positive subgroup (22.4 months vs 6.9 months; hazard ratio: 0.3191) ( 32 , 33 ). Since T-DXd has made a breakthrough in HER2-positive breast cancer, anti-HER2 ADC combined with CDK4/6 inhibitor and endocrine therapy may be the future exploring direction of HR-positive/HER2-positive breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study

et al. 2022

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PurposeThe LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting.Patients and MethodsPostmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination.ResultsA total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months).ConclusionsThe fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03772353.

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LBA1 Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study

Cited by 94 publications

References 0 publications

Anti-HER2 therapy in metastatic breast cancer: many choices and future directions

Anti-HER2 therapy in metastatic breast cancer: many choices and future directions

HER2-Positive Inflammatory Breast Cancer Challenges of Clinical Practices

Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study

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