MBC Applying New Developments

CE / CME

Applying the Latest Developments in Metastatic Breast Cancer Through Education of Healthcare Professionals, Patients, and Caregivers

Nurses: 1.50 Nursing contact hours

Physicians: maximum of 1.50 AMA PRA Category 1 Credits

Pharmacists: 1.50 contact hours (0.15 CEUs)

Released: October 19, 2023

Expiration: October 18, 2024

Joyce O'Shaughnessy
Joyce O'Shaughnessy, MD

Activity

Progress
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Course Completed

Current Approach to Recurrent TNBC

We have the ADC sacituzumab govitecan in the second- or later-line setting based on the phase III ASCENT trial, which showed an improvement for median OS (12.1 vs 6.7 months; hazard ratio: 0.52; P <.001) compared with investigator’s choice of chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine).46

We now have T-DXd for the TNBC population based on data from an exploratory analysis from DESTINY-Breast04 of 58 patients with HR-negative/HER2-low disease showing improved median PFS (8.5 vs 2.9 months; hazard ratio: 0.46) and median OS (18.2 vs 8.3 months; hazard ratio: 0.48).52

If patients have a germline BRCA1/2 or PALB2 mutation, or a somatic BRCA1/2 mutation, we could treat them with a PARP inhibitor.5,25,26

We also have agnostic approval of the single-agent immunotherapies dostarlimab and pembrolizumab for patients with TMB-H or MSI-H disease.5,22

We have larotrectinib or entrectinib for disease with NTRK gene fusions.5,57,58 In addition, we have selpercatinib for disease with RET gene fusions.5,59 Also coming, but not yet approved, is another anti–TROP-2 ADC, datopotamab deruxtecan (dato-DXd).

Datopotamab Deruxtecan (DS-1062; Dato-DXd): TROP-2 Antibody–Drug Conjugate in TNBC

Dato-DXd is an exciting new agent currently being evaluated in phase III trials for patients with locally recurrent inoperable or metastatic TNBC (NCT05374512; N = 600). The therapy contains deruxtecan, a topoisomerase I inhibitor, which is the same payload that is used in T-DXd against HER2, but dato-DXd is targeted against TROP-2, like sacituzumab govitecan.60 Dato-DXd has a high drug-to-antibody ratio and a tetrapeptide-based cleavable linker. The agent also produces a bystander effect, as does sacituzumab govitecan. Dato-DXd is administered intravenously once every 3 weeks.

TROPION-PanTumor01: Datopotamab Deruxtecan in TNBC Cohort

The clinical development of dato-DXd was supported by data from the international, open-label phase I TROPION-PanTumor01 trial, which was conducted in a heavily pretreated group of patients. In that study, patients with metastatic TNBC who relapsed/progressed on standard therapy received dato-DXd 6 mg/kg IV every 3 weeks (N = 24).60 The primary endpoint was safety and tolerability, with secondary endpoints of efficacy and pharmacokinetics. By data cutoff on January 8, 2021, 18 of 24 patients remained on treatment, and 6 had discontinued because of progressive disease.

TROPION-PanTumor01 TNBC Cohort:
Antitumor Activity per BICR

When we take a closer look at the response data in the TNBC cohort, we see a very impressive 43% response rate and waterfall plot.60 Thus, this is a very active agent. 

Sacituzumab Govitecan vs Single-Agent CT in mTNBC After ≥2 Prior CT Regimens (ASCENT): Study Design

ASCENT was a phase III trial comparing the TROP-2–directed antibody–drug conjugate sacituzumab govitecan vs single-agent chemotherapy in patients with unresectable locally advanced or metastatic TNBC previously treated with ≥2 systemic therapies.61  This trial enrolled 529 patients who were stratified by geography, number of previous lines of chemotherapy, and presence of brain metastases, then randomized 1:1 to receive either sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 of each 21-day cycle vs physician’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary endpoint of the study was PFS by independent review in patients without brain metastases. Secondary endpoints included investigator-assessed PFS, OS, overall response rate (ORR), duration of response (DoR), time to response, and safety.

ASCENT Primary Analyses: Efficacy and Safety Summary

The results of the primary analysis of ASCENT were very exciting. Sacituzumab govitecan significantly improved both median PFS (5.6 vs 1.7 months with chemotherapy; HR: 0.41; 95% CI: 0.32-0.52; P <.001) and OS (12.1 vs 6.7 months, respectively; HR: 0.48; 95% CI: 0.38-0.59; P <.001).

Sacituzumab govitecan also exhibited an improved ORR of 35% vs 5% with chemotherapy.

ASCENT was halted early based on efficacy by unanimous recommendation of the data and safety monitoring committee. Based on these positive results, in April 2021 the FDA expanded the indications for sacituzumab govitecan to include treatment of adults with unresectable locally advanced or metastatic TNBC previously treated with ≥2 previous systemic therapies, of which ≥1 therapy must have been for metastatic disease.61,62