Updated Phase I Data for Ladiratuzumab Vedotin in Patients with Triple Negative Breast Cancer

Data from an ongoing phase I clinical trial evaluating ladiratuzumab vedotin, also known as SGN-LIV1A, in patients with metastatic triple negative breast cancer presented at the 2017 San Antonio Breast Cancer Symposium (SABCS), taking place December 5-9, 2017 in San Antonio, Texas, show 29% Objective Response Rate (ORR) at the recommended monotherapy dose in patients with heavily pretreated disease.

Enrollment for the trial is ongoing. [1]

Breast cancer is the most common cancer among women in the United States, excluding some forms of skin cancer. Of the more than 250,000 new cases expected in the United States this year, about 15% to 20% will be diagnosed a tripple negative breast cancer or TNBC, which has a particularly poor prognosis.

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Breast cancers are commonly categorized by the expression (or lack thereof) of three proteins, which include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). However, TNBC lacks expression of these three breast cancer-associated proteins that serve as key therapeutic targets. About one-third of breast cancer patients will eventually develop recurrent or metastatic disease, and current therapies for metastatic TNBC only delay progression. New treatment approaches are needed to improve outcomes for women with TNBC, where there are currently no available targeted therapies.

Investigational agent
Ladiratuzumab vedotin, being developed by Seattle Genetics, is an investigational antibody-drug conjugate or ADC designed to deliver a potent and clinically validated microtubule-disrupting agent (read: cell killing drug), monomethyl auristatin E or MMAE, to cancer cells which express the protein LIV-1.  This protein is a transmembrane protein and downstream target of STAT3 and is expressed on multiple solid tumors including breast, prostate, melanoma, ovarian, uterine, and cervical cancers. In breast cancer, LIV-1 is associated with lymph node involvement and metastatic progression. [1]

Linked via a protease-cleavable linker, using the same technology as brentuximab vedotin (Adcetris®; Seattle Genetics), ladiratuzumab vedotin bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. The investigational agent may also cause antitumor activity through other mechanisms, including activation of an immune response.

Phase I results
“Overall, the phase I results we’ve presented at the annual SABCS confirm previous findings that single-agent treatment with ladiratuzumab vedotin was generally well-tolerated and showed encouraging antitumor activity in patients with heavily-pretreated metastatic TNBC,” said Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics.

“We continue to evaluate ladiratuzumab vedotin monotherapy in TNBC, with planned combination studies in earlier lines of treatment, demonstrating our overarching commitment to improve the health of women with this devastating disease,” Lechleider added.

Findings from this ongoing phase I study of ladiratuzumab vedotin in patients with metastatic breast cancer were last presented at the 2016 SABCS. The updated results presented this year in a spotlight session describe the safety, tolerability, and antitumor activity of ladiratuzumab vedotin in 28 additional patients with TNBC.

Trial design
A total of 81 patients with LIV-1-expressing metastatic breast cancer were treated with ladiratuzumab vedotin monotherapy given every three weeks. Patients enrolled in the study had received a median of four prior systemic metastatic therapies.

Of these patients, 63 were diagnosed with TNBC and 18 had hormone receptor-positive / human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer.

At the completion of dose escalation at doses ranging from 0.5 to 2.8 milligrams per kilogram (mg/kg), TNBC expansion cohorts were opened at 2.0 and 2.5 mg/kg to further evaluate safety and antitumor activity of ladiratuzumab vedotin in metastatic TNBC patients. Based on efficacy and safety, the recommended dose is 2.5 mg/kg with a maximum dose of 200 mg per cycle.

During the annual breast cancer symposium, key findings in this heavily pre-treated patient population were presented by Jennifer M. Specht, MD, a medical oncologist who specializes in treating women with breast cancer at the Seattle Cancer Care Alliance.

These findings based on response assessed per RECIST v1.1 in which patients with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity, confirmed that among the 60 efficacy-evaluable patients with metastatic TNBC, the objective response rate (ORR) was 25%, representing all partial responses (PR).

In addition, the findings showed that the clinical benefit rate (CBR), defined as patients achieving complete response (CR) or PR of any duration, plus patients achieving stable disease (SD) lasting at least 24 weeks, was 28%. Furthermore:

  • Of the 17 efficacy-evaluable patients treated at the recommended dose, 29% achieved an objective response (confirmed and unconfirmed), and the CBR was 29%.
  • The median progression-free survival (PFS) and median duration of response (DOR) for patients treated across all dose levels were 11 weeks and 13.3 weeks, respectively. In 19 patients treated at the recommended dose, the median PFS was 12.1 weeks, and the median DOR was 17.4 weeks.
  • At the recommended dose, ladiratuzumab vedotin was generally well-tolerated and most adverse events were Grade 1/2.
  • Of the 81 patients treated in the study, peripheral neuropathy events occurred in 16 patients (19.8%) and were generally low grade (Grades 1/2) and manageable. Seven patients discontinued treatment due to adverse events.
  • Grade 3/4 adverse events included neutropenia and anemia. The Grade 3/4 incidence of neutropenia at the 2.5 mg/kg dose was 38.7 percent. As previously reported, two patients experienced febrile neutropenia, and there was one treatment-related death due to presumed sepsis among patients who received doses greater than 200 mg. No other treatment-related deaths occurred in the study.

Enrollment continues for patients with metastatic TNBC at the recommended dose of 2.5 mg/kg, with a maximum dose of 200 mg per cycle.