Phase I Trial Demonstrates Activity of Antibody-Drug Conjugate Targeting LIV-1 in TNBC

Jennifer Specht, MD

Treatment with ladiratuzumab vedotin demonstrated an estimated median progression-free survival (PFS) of 11.6 weeks for patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) treated  with the recommended phase II dose of the antibody—drug conjugate, according to results of a phase I study presented during the 2017 San Antonio Breast Cancer Symposium. 

The estimated 3-month PFS was 49%. The 6-month estimated PFS was 24%, and the 9-month estimated PFS was 10%. Among all treated patients with metastatic TNBC, the median duration of response was 13.3 weeks and the PFS was 11.0 weeks.

“This is a heavily pretreated population, so these were all patients who had at least 2 lines of prior cytotoxic therapy and the range was quite wide; some patients had up to 10 lines of prior therapy,” said Jennifer Specht, MD, when presenting the findings of the study. “The response rates in those setting are very small, from 10 to 15%, and PFS is usually a couple of months. So this is very promising.”

Interestingly, there was no relationship between LIV-1 tumor expression and response, said Specht, associate professor and breast medical oncologist at the University of Washington in Seattle. “LIV-1 tumor expression is seen in a variety of types of breast cancer, and doesn’t necessarily seem to be at the H score that was used for a cut point for determining positivity in this trial,” she said. An H score ≥100 defined LIV-1 positivity.

Ladiratuzumab vedotin is an antibody—drug conjugate composed of a humanized IgG1 and anti-LIV1 monoclonal antibody, a microtubule-disrupting agent (monomethyl auristatin E [MMAE]), and a protease-cleavable valine-citrulline maleimidocaproyl linker. LIV-1 is a transmembrane protein with zinc transporter and metalloproteinase activity. After activation by the STAT3 pathway, LIV-1 promotes an epithelial to mesenchymal transition. LIV-1 is expressed in more than 90% of breast tumors and has limited expression in normal tissues.

“The idea is that you have binding of the antibody to the cell surface to deliver the molecule in a specific fashion. There’s a payload of chemotherapy that’s brought with it, and that gets taken up into the cell and the chemotherapy is released,” Specht said. “The chemotherapy payload is MMAE, which is an anti-tubulin compound. It’s a smarter way to deliver chemotherapy more specifically to the cancer cell.”

The phase I study consisted of a dose-escalation phase that enrolled 81 patients and a phase 1b portion that included 63 patients with metastatic TNBC. In the dose-escalation phase, ladiratuzumab vedotin was administered at 0.5 to 2.8 mg/kg every 3 weeks. The recommended dose for the expansion phase was 2.5 mg/kg, with a maximum dose of 200 mg per cycle.

Patients enrolled had ≥2 cytotoxic regimens in the setting of unresectable, locally advanced, or metastatic disease. Patients with pre-existing neuropathy grade ≥2 at baseline were excluded from entering.

LIV-1 expression (H-score ≥100) was confirmed by central pathology review of 614 archived or fresh tumor samples. Ninety percent of metastatic breast tumor samples screened were positive for LIV-1 expression, with moderate to high expression present in 68% of metastatic TNBC samples. The mean LIV-1 H-score in patients with metastatic TNBC was 190.

The median number of months since diagnosis of metastatic disease was 20.9. Patients were treated with a median of 4 prior systemic therapies.

In the dose escalation phase, the maximum tolerated dose was not reached and there were no dose-limiting toxicities. The median duration of treatment was 9 weeks. Fourteen patients (16%) required dose reduction, and 7 patients (8.6%) required treatment discontinuation in due to adverse events (AEs). Sixteen patients experienced peripheral neuropathy but these were mostly grades 1 and 2 and were manageable, Specht said.

Twelve patients (38.7%) in the 2.5-mg/kg cohort developed neutropenia. Two patients treated with 2.5 mg/kg who received an overall dose >200 mg experienced febrile neutropenia, and investigators found that the rate of neutropenia with the 2.5-mg/kg dose was higher when the total dose exceeded 200 mg per cycle.

The best treatment (doses ≥2.0 mg/kg) response in metastatic TNBC patients was partial response (25.0%), followed by stable disease (33.3%). Most patinets (41.7% had progressive disease. The objective response rate was 25.0% and the disease control rate was 35%.

Ladiratuzumab vedotin is being explored as monotherapy and in combination in various populations with breast cancer, Specht added.

Reference:

Modi S, Pusztai L, Forero A, et al. Phase 1 study of the antibody-drug conjugate ladiratuzumab vedotin (SGN-LIV1A) in patients with heavily pretreated triple-negative metastatic breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-14.