Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer: Primary Results From TROPION-Breast01

Author(s): Aditya Bardia, MD, MPH^1,2; Komal Jhaveri, MD, FACP^3,4; Seock-Ah Im, MD, PhD⁵; Sonia Pernas, MD, PhD⁶; Michelino De Laurentiis, MD⁷; Shusen Wang, MD⁸; Noelia Martínez Jañez, MD, PhD⁹; Giuliano Borges, MD¹⁰; David W. Cescon, MD, PhD¹¹; Masaya Hattori, MD¹²; Yen-Shen Lu, MD, PhD¹³; Erika Hamilton, MD¹⁴; Qingyuan Zhang, MD, PhD¹⁵; Junji Tsurutani, MD, PhD¹⁶; Kevin Kalinsky, MD, MS¹⁷; Pedro Emanuel Rubini Liedke, MD^18,19,20; Lu Xu, PhD²¹; Rick M. Fairhurst, MD, PhD²¹; Sabrina Khan, MD, MPH²¹; Neelima Denduluri, MD²¹; Hope S. Rugo, MD²²; Binghe Xu, MD, PhD²³; Barbara Pistilli, MD²⁴;

Source: https://doi.org/10.1200/JCO.24.00920

Dr. Anjan Patel's Thoughts

Dato-DXd is now approved in HR+, HER2-neg, metastatic breast cancer after prior therapy with endocrine-based therapy and chemotherapy. There was an impressive reduction in the risk of death or progression with an HR of 0.63. Watch out for ocular and pulmonary toxicity. HER2-ultra low testing will be burdensome but must be done for drug approval.

PURPOSE

The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2–directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator’s choice of chemotherapy (ICC) in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

METHODS

Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS).

RESULTS

Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC.

CONCLUSION

Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

Author Affiliations

¹Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA; ²Massachusetts General Hospital Cancer Center, Boston, MA; ³Memorial Sloan Kettering Cancer Center, New York, NY; ⁴Weill Cornell Medical College, New York, NY; ⁵Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea; ⁶Institut Català d’Oncologia-IDIBELL, L’Hospitalet, Barcelona, Spain; ⁷Istituto Nazionale Tumori Napoli IRCCS “Fondazione Pascale”, Napoli, Italy; ⁸Cancer Center of Sun Yat-sen University, Guangzhou, China; ⁹Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; ¹⁰Catarina Pesquisa Clínica, Santa Catarina, Brazil; ¹¹Princess Margaret Cancer Centre/UHN, Toronto, ON, Canada; ¹²Aichi Cancer Center, Nagoya, Japan; ¹³National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; ¹⁴Sarah Cannon Research Institute, Nashville, TN; ¹⁵Harbin Medical University Cancer Hospital, Harbin, China; ¹⁶Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan; ¹⁷Winship Cancer Institute at Emory University, Atlanta, GA; ¹⁸Hospital das Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil; ¹⁹UPCO—Pesquisa Clinica em Oncologia, Porto Alegre, Brazil; ²⁰Oncoclinicas Porto Alegre, Porto Alegre, Brazil; ²¹AstraZeneca, Gaithersburg, MD; ²²University of California San Francisco Comprehensive Cancer Center, San Francisco, CA; ²³National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; ²⁴Gustave Roussy Cancer Center, Villejuif, France;

HER2CLIMB-05: A Phase III Study of Tucatinib Versus Placebo in Combination With Trastuzumab and Pertuzumab as First-Line Maintenance Therapy for HER2+ Metastatic Breast Cancer

Progression-free survival (PFS) was statistically significantly improved with addition of tucatinib versus placebo 24.9 v 16.3 months regardless of the presence/absence of BM or hormone receptor status.

Role of neoadjuvant versus adjuvant chemotherapy, dose density, and treatment schedule in biologically high-risk HR+/HER2- breast cancer: A pooled analysis of the WSG ADAPT-HR+/HER2- and PlanB trials.

1467 pts with RS > 25 and 551 with clinically (neoadjuvant cohort in ADAPT-HR+/HER2-) or pathologically N2, (longer) docetaxel-based CTx showed better distant, invasive disease-free survival in N2-3 pts patients with RS ≤25, OS was also shown in pts with RS>25 anthracycline regimens did not show a significant survival difference in high-risk HR+/HER2 whether used in neoadjuvant or adjuvant setting. So may be no anthracycline for HR+ve pts who are high risk disease.

The Pathologic Response Evaluation and Detection in Circulating Tumor-DNA Study: Ultrasensitive Circulating Tumor-DNA Assessment of Breast Cancer Minimal Residual Disease

Primary objective not met, ctDNA clearance post- neoadjuvant therapy (NAT) cannot reliably predict pathologic complete response (pCR) and shouldn't be used to defer surgery. But the prognostic data are striking: post-NAT ctDNA positivity independently predicted recurrence in triple-negative breast cancer (TNBC) (HR 8.9), and the postsurgical landmark analysis is essentially binary, 100% of ctDNA-positive patients recurred while 94% of ctDNA-negative patients were disease-free at 5 years (HR 128). Not practice-changing yet pending prospective utility trials, but this strongly validates ultrasensitive ctDNA as a prognostic tool and a smart enrollment biomarker for future escalation/de-escalation trials.

VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor–Positive/HER2−/PIK3CA Wild-Type Advanced Breast Cancer

Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway. PFS was 9.3 m in the gedatolisib-triplet group vs 2.0 m in the fulvestrant group (hazard ratio) HR 0.24, and 7.4 m in the gedatolisib-doublet group HR 0.33 v fulvestrant.

Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer

This is impressive. However, there is no reported placebo trastuzumab deruxtecan arm, so this is not truly a “no chemotherapy” regimen. It is important to remember that deruxtecan is itself a chemotherapy agent. So, this is really comparing deruxtecan vs taxol or more accurately, a comparison of chemotherapy delivery systems.