Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2– and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study

Author(s): Aditya Bardia, MD, PhD¹; Ian E. Krop, MD, PhD^2,3; Takahiro Kogawa, MD, PhD⁴; Dejan Juric, MD¹; Anthony W. Tolcher, MD^5,6,7; Erika P. Hamilton, MD^8,9; Toru Mukohara, MD, DMedSci¹⁰; Aaron Lisberg, MD¹¹; Toshio Shimizu, MD, PhD^12,13; Alexander I. Spira, MD¹⁴; Junji Tsurutani, MD, PhD¹; Senthil Damodaran, MD, PhD¹⁵; Kyriakos P. Papadopoulos, MD¹⁶; Jonathan Greenberg, MD, MA, BA^17,18; Fumiaki Kobayashi, PhD, MS²²; Hong Zebger-Gong, MD, PhD¹⁸; Rie Wong, BS²⁰; Yui Kawasaki, PhD¹⁷; Tadakatsu Nakamura, MS¹⁹; Funda Meric-Bernstam, MD¹⁵

Source: https://doi.org/10.1200/JCO.23.01909

Dr. Anjan Patel's Thoughts

Datopotamab Deruxtecan is a new ADC that will likely be approved in the near future. The payload is the same as used in Enhertu, but the antibody is directed at TROP2. This report is from the TROPION-pan tumor study and shows a promising ORR in HR+/HER2- MBC. There is reasonable data for this compound in 2L met-NSCLC in the TROPION-LUNG01 study with an improvement in PFS compared to docetaxel of 4.4 vs 3.7 months. Dato also is effective in patients with actionable genetic alterations in the 2L setting. There is also an ongoing study on its use in the 1L setting for met-NSCLC in combination with pembrolizumab and chemotherapy.

PURPOSE

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker.

PATIENTS AND METHODS

TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer (BC) or triple-negative BC (TNBC) are reported.

RESULTS

At data cutoff (July 22, 2022), 85 patients (HR+/HER2– BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2– BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2– BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2– BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2– BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2– BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts.

CONCLUSION

In patients with heavily pretreated advanced HR+/HER2– BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Author Affiliations

¹Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; ²Yale Cancer Center, New Haven, CT; ³Dana-Farber Cancer Institute, Boston, MA; ⁴Department of Advanced Medical Development, Cancer Institute Hospital of JFCR, Tokyo, Japan; ⁵South Texas Accelerated Research Therapeutics, San Antonio, TX; ⁶NEXT Oncology, San Antonio, TX; ⁷Texas Oncology, San Antonio, TX; ⁸Sarah Cannon Research Institute, Nashville, TN; ⁹Tennessee Oncology, PLLC, Nashville, TN; ¹⁰Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan; ¹¹Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA; ¹²Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan; ¹³Department of Pulmonary Medicine and Medical Oncology, Wakayama Medical University Hospital, Wakayama, Japan; ¹⁴Virginia Cancer Specialists (VCS) Research Institute, Fairfax, VA; ¹⁵Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; ¹⁶Clinical Research, START, San Antonio, TX; ¹⁷Global Oncology Clinical Development, Daiichi Sankyo, Inc, Basking Ridge, NJ; ¹⁸Global Oncology Clinical Development, Daiichi Sankyo Europe GmbH, Munich, Germany; ¹⁹Data Intelligence, Daiichi Sankyo, Co, Ltd, Tokyo, Japan; ²⁰Global Oncology Clinical Development, Daiichi Sankyo, Co, Ltd, Tokyo, Japan

Low-Dose Tamoxifen in Noninvasive Breast Neoplasia: Long-Term Results From an Individual-Participant Data Pooled Analysis

Among 1,545 women included with a median follow-up of 9.4 years in postmenopausal women, breast cancer events occurred in 40 of 335 receiving low-dose tamoxifen versus 93 of 401 controls HR, 0.51, with a 10-year absolute reduction of 11.2%. Among premenopausal women, no significant reduction was observed dose was 5mg daily of 10mg every other day in ductal carcinoma in situ (DCIS) and high-risk pts. Less is as good.

Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial

644 patients who are triple-negative breast cancer (TNBC) not candidates for immunotherapy were randomly assigned to receive Dato-DXd (n = 323) or chemotherapy (n = 321). Median progression-free survival (PFS) was 10.8 months with Dato-DXd and 5.6 months with chemotherapy. Median overall survival (OS) was 23.7 months and 18.7 months with Dato-DXd and chemotherapy, respectively HR 0.79; P = 0.029]. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in 105 (33%) and 89 (29%) patients who received Dato-DXd and chemotherapy, respectively, they were more treatment discontinuation in the chemotherapy arm secondary to treatment related adverse events in 14 (4%) and 23 (7%) patients. There were no treatment-related deaths in either arm. New standard of care? Recall this is on patients not eligible for immunotherapy.

Hypo- Versus Standard Fractionated Locoregional Radiotherapy of Patients With High-Risk Breast Cancer in the Randomized Phase III Trial: The Danish Breast Cancer Group Skagen Trial 1

Less radiation (40Gy vs 50 Gy) was non inferior in preventing locoregional recurrence and distant mets, also lymphedema rates were not worse. Would love feedback from our rad onc, but it seems less is as good.

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.