Updated data from an ongoing Phase I clinical trial evaluating ladiratuzumab vedotin (SGN-LIV1A) in patients with metastatic triple negative breast cancer (mTNBC), was presented at the 2017 San Antonio Breast Cancer Symposium (SABCS), taking place December 5-9, 2017, show 29% objective response rate (ORR) at the recommended dose in patients with heavily pretreated disease. The novel investigational drug is being developed by Seattle Genetics.
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 percent will be metastatic triple negative breast cancer or TNBC, which has a particularly poor prognosis.
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).
Metastatic triple negative breast cancer 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. This represents a major unmet medical need. New treatment approaches are needed to improve outcomes for women with TNBC, where there are currently no available targeted therapies.
Ladiratuzumab vedotin is an investigational antibody-drug conjugate or ADC designed to deliver a potent and clinically validated cell-killing, microtubule-disrupting, agent, called monomethyl auristatin E (MMAE) via a protease-cleavable linker, to cancer cells which express the protein LIV-1. This protein, expressed by most metastatic breast cancers, is also detected on multiple solid tumors including prostate, melanoma, ovarian, uterine, and cervical cancers.
In addition to the generally best understood mode of action, ladiratuzumab vedotin may also cause antitumor activity through other mechanisms, including activation of an immune response. The drug, being developed by Seattle Genetics, is currently has four clinical studies with additional trials evaluating ladiratuzumab vedotin as a neoadjuvant treatment and in combination with checkpoint inhibitors planned. The focus of these trials is treatment of patients with (metastatic) triple negative breast cancer.
“Overall, the phase I results we’ve presented at 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.”
For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual San Antonio Breast Cancer Symposium, December 5-9, 2017, Click here.
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 today in a spotlight poster presentation (Poster PD3-14) describe the safety, tolerability, and antitumor activity of ladiratuzumab vedotin in 28 additional patients with TNBC.
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.
Key findings in this heavily pretreated patient population were presented by Jennifer M. Specht, MD., a medical oncologist who specializes in treating women with breast cancers working at the Seattle Cancer Care Alliance. In her presentation she confirmed that among the 60 efficacy-evaluable patients with metastatic triple negative breast cancer (mTNBC), the objective response rate (ORR) was 25%, representing all partial responses (PR). 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%.
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%. 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.