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Datopotamab Deruxtecan Shows Activity in Advanced Triple-Negative Breast Cancer


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Datopotamab deruxtecan, an antibody-drug conjugate directed against trophoblast cell surface antigen-2 (Trop-2), is showing activity as a treatment for relapsed or refractory advanced triple-negative breast cancer, according to early findings from the phase I TROPION-PanTumor01 trial presented during the 2021 San Antonio Breast Cancer Symposium by Ian E. Krop, MD, PhD.1

Ian E. Krop, MD, PhD

Ian E. Krop, MD, PhD

“In heavily pretreated patients with triple-negative breast cancer, datopotamab deruxtecan showed highly encouraging levels ofdurable efficacy” based on objective response rates, said Dr. Krop, who is Associate Chief in the Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancers and Clinical Research Director of the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, and Associate Professor of Medicine at Harvard Medical School.

Responses, by blinded independent central review, were seen in 34% of all patients, and 52% among patients who had not previously received another a topoisomerase 1 inhibitor–based antibody-drug conjugate (eg, sacituzumab govitecan-hziy). -Sacituzumab govitecan has been approved by the U.S. Food and Drug Administration for patients with previously treated metastatic triple-negative breast cancer.

Underlying Mechanism

Trop-2 is highly expressed in various malignancies, including breast cancer. The TROPION-PanTumor01 study is evaluating the safety and efficacy of the Trop-2–directed antibody-drug conjugate datopotamab deruxtecan in patients with various solid tumors, including advanced or metastatic breast cancer.

Datopotamab deruxtecan is an antibody-drug conjugate with three components: a humanized anti–Trop-2 IgG1 monoclonal antibody attached to a topoisomerase 1 inhibitor payload via a tetrapeptide-based cleavable linker. It was designed with these key attributes: topoisomerase 1 inhibition as the payload mechanism of action; a payload with high potency, short systemic half-life, and stable linker; optimized drug-to-antibody ratio; tumor-selective cleavable linker; and bystander antitumor effect, Dr. Krop said.

Efficacy in Triple-Negative Breast Cancer

In San Antonio, Dr. Krop presented data for the cohort of 44 patients with triple-negative breast cancer. Within that cohort, after a median follow-up of 7.6 months, the objective response rate of 34% included confirmed complete or partial responses in 14 patients (32%) and 1 pending confirmation in another (2%). A total of 17 patients (39%) had stable disease, and 2 patients (5%) were not evaluable. The disease control rate was 77%.

“The median duration of response was not reached (range = 2.7 to 7.4+ months), with the majority of responses ongoing at data cutoff,” he said.

“Because a full 30% of the patients on this study had received prior treatment with topoisomerase 1 inhibitor–based antibody-drug conjugates—which is the same class of payload as datopotamab deruxtecan—there is a possibility of cross-resistance. Therefore, we wanted to look specifically at the subset of patients who had not had one of these prior agents,” Dr. Krop said.

For that group of 27 patients, after a median follow-up of 8.8 months, the objective response rate was 52%, which included 13 patients (48%) with confirmed complete or partial responses and 1 patient (4%) with pending confirmation. Nine patients (33%) had stable disease, yielding a disease control rate of 81%.

“There is potential room for looking at this drug both in pretreated patients, like what was seen here, as well as in earlier lines of therapy,” Dr. Krop commented. “We have come a long way in triple-negative breast cancer when we’re talking about comparing different targeted therapies, when up until a few years ago, there were no targeted therapies at all. This is good progress.”

About TROPION-PanTumor01

Participants from the United States (70%) and Japan (30%) with relapsed or refractory advanced or metastatic solid tumors were unselected for TROP-2 expression. A total of 11% of patients had stable, treated brain metastases.

In the triple-negative breast cancer cohort, 42 of 44 patients received datopotamab deruxtecan intravenously at 6 mg/kg every 3 weeks, and the other 2 patients received the drug at 8 mg/kg every 3 weeks. The primary endpoints were safety and tolerability; secondary endpoints included efficacy, pharmacokinetics, and antidrug antibodies.

The median number of prior therapies in the metastatic setting was three (range = 1–10), and 68% of patients had received at least two prior lines. Previous treatments included taxanes (91%), platinum-based chemotherapy (52%), immunotherapy (43%), poly (ADP-ribose) polymerase inhibitors (16%), and topoisomerase 1–directed antibody-drug conjugates (30%).

At data cutoff, 31 patients (70%) had discontinued treatment, including 30 due to disease progression and 1 due to an adverse event. A total of 13 patients (30%) remained on treatment at the time of the presentation.

KEY POINTS

  • The Trop-2–targeting antibody-drug conjugate datopotamab deruxtecan shows promising activity in triple-negative breast cancer.
  • In the phase I TROPION PanTumor01 trial, among 44 patients with previously treated advanced triple-negative breast cancer, responses were achieved in 34% of patients, rising to 52% for patients not previously exposed to a topoisomerase 1 inhibitor antibody-drug conjugate.
  • The drug is also being studied in hormone receptor–positive/HER2-negative disease.

Datopotamab deruxtecan had a manageable safety profile with no new safety signals. The most frequent treatment-emergent adverse events included nausea, stomatitis, vomiting, and fatigue. Neutropenia and diarrhea were both uncommon. No cases adjudicated as treatment-related interstitial lung disease were observed. Treatment-related grade ≥ 3 adverse events were seen in 23%; dose reductions were required for 18% of patients, and 14% of patients had doses interrupted. One patient discontinued treatment due to toxicity.

Future Studies of Datopotamab Deruxtecan

In triple-negative breast cancer, a phase III trial is being planned, and the ongoing BEGONIA trial is testing datopotamab deruxtecan in combination with the checkpoint inhibitor durvalumab in the first line. In patients with hormone receptor–positive, HER2-negative disease, this cohort from TROPION-PanTumor01 is now fully enrolled, and the phase III TROPION-Breast01 trial is kicking off as well. 

DISCLOSURE: Dr. Krop has received honoraria or consulting fees from AstraZeneca, Genentech/Roche, Seattle Genetics, Daiichi Sankyo, MacroGenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, Ionis Pharmaceuticals, Bristol Myers Squibb, and Celltrion; and his spouse has held leadership roles or has ownership interests in AMAG Pharmaceuticals, Freeline Therapeutics, and Vertex.

REFERENCE

1. Krop I, Juric D, Shimizu T, et al: Datopotamab deruxtecan in advanced/metastatic HER2 negative breast cancer: Triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-05. Presented December 7, 2021.


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