Trastuzumab Deruxtecan Impresses in HER2 Expressing Breast Cancers

Shanu Modi, MD

Trastuzumab deruxtecan (ds-8201a), a HER2-targeting antibody-drug conjugate, demonstrated significant clinical activity in heavily pretreated patients with HER2-expressing metastatic breast cancers who previously received ado-trastuzumab emtansine (T-DM1; Kadcyla).

In an ongoing 2-part phase I study, the overall response rate (ORR) to trastuzumab deruxtecan in 57 evaluable patients with HER2-positive tumors was 61.4%. In 19 evaluable patients with HER2-low tumors, the median progression-free survival (PFS) had not yet been reached and the ORR was 31.6%, reported Shanu Modi, MD, at the 2017 San Antonio Breast Cancer Symposium.

In August 2017, trastuzumab deruxtecan received an FDA breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab (Herceptin) and pertuzumab (Perjeta) and have disease progression after T-DM1.

Whereas T-DM1 is a tubulin-targeting chemotherapy, trastuzumab deruxtecan is a topoisomerase 1 inhibitor. It is highly potent, with a drug-to-antibody ratio of 7.8, compared with 3.5 for T-DM1, said Modi, a breast medical oncologist at Memorial Sloan Kettering Cancer Center.

“Overall, we’re happy to report that this is a really active drug,” she said. The 60% confirmed rate “is in patients who had some of the most potent HER2-targeted therapies already. It’s pretty exciting to see that kind of result. More importantly, is how durable the benefit is.” The Median PFS in the HER2-positive cohort was 10.4 months.

The study was conducted in 2 parts. In part 1, a modified continuous reassessment method was used to identify an expansion dose in patients with breast or gastric cancer. Based on part 1 results, doses of 5.4 and 6.4 mg/kg administered every 3 weeks were selected for part 2, which was designed to evaluate the safety and efficacy in 4 expansion cohorts: HER2-positive breast cancer previously treated with T-DM1, HER2-positive gastric cancer treated with trastuzumab, low-HER2—expressing breast cancer, and other HER2-expressing solid tumors. Modi’s presentation at SABCS focused on the 130 patients with breast cancer, 96 with HER2-positive tumors and 34 with low expression of HER2.

In the HER2-positive cohort, the ORR was 56.4% (22 of 39) among those with hormone receptor (HR)-positive disease and 75.0% (12 of 16) in those with HR-negative disease. Notably, the ORR was 62.5% among the 50 patients in this cohort with prior pertuzumab treatment.

The disease control rate (DCR) was 94.7% overall in the HER2-positive subset: 92.3% in the HR-positive group, 100.0% in the HR-negative group, and 94.0% among those who had received prior pertuzumab. “The responses were durable regardless of HR status,” said Modi. Median PFS was not yet reached in the HR-positive group and was 10.3 months in the HR-negative group. Median PFS was 10.3 months in the HER2-positive cohort who had received prior pertuzumab.

In the HER2-low cohort, 6 of 19 patients (31.6%) had a response, including 5 of 16 patients (31.3%) with HR-positive tumors. In the HER2-low subset, the DCR was 84.2%. By hormone receptor status, the DCR was 14 of 16 (87.5%) in those with HR-positive disease and 1 of 2 (50%) in patients with HR-negative disease. Median PFS was not reached in the HR-positive subset and was 7.6 months in the HR-negative group.

“These patients can stay on therapy for a long time,” said Modi. “We have some patients who are now up to a year and a half maintaining their response.”

The main toxicity was grade 1/2 gastrointestinal toxicity, which was “very manageable,” she said. Grade 1/2 nausea was reported by 67.9%. Grade 3 and 4 events were hematologic in nature. The rates of grade 3/4 anemia were 8.7% in the HER2-positive group and 0.9% in the HER2-low group. The rates of grade 3 decreases in neutrophil count and white blood cell count were each 10.4%. Across the study, 5 patients (4.3%) had a grade 4 decrease in neutrophil count.

An ongoing pivotal phase II trial called DESTINY-Breast01 is examining the efficacy and safety of trastuzumab deruxtecan in patients with HER2-positive unresectable and/or metastatic breast cancer who are resistant or refractory to T-DM1.

Modi S, Tsurutani J, Takahashi S, et al. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-07.