An experimental antibody–drug conjugate (ADC) showed efficacy in an early-phase trial involving patients with relapsed or refractory small cell lung cancer (SCLC), according to results presented recently at the 2015 European Cancer Congress in Vienna, Austria. Researchers say the findings will spur additional studies because these patients have so few treatment options.
In the phase I trial, 73 patients with recurrent SCLC were given rovalpituzumab tesirine (Rova-T; Stemcentrx), an ADC that binds to the ligand of delta-like protein 3 (DLL3), an atypical Notch ligand. Among 27 confirmed DLL3-high positive patients, 44% had a partial response and 34% achieved stable disease compared with 23% and 68%, respectively, in unselected patients, indicating that DLL3-high expression may be a biomarker of response. Further, in the third-line setting, for which there are no approved treatment options, the response rate was 45% in patients whose tumors had DLL3-high expression.
“The high response rates in DLL3-positive patients are remarkable,” says M. Catherine Pietanza, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, NY, who presented the findings. “The fact that there is a possible biomarker to predict response is significant because for the first time, we actually may be able to target SCLC. In the past, numerous studies have failed to identify biomarkers in this malignancy.”
SCLC, which accounts for about 14% of all lung cancers and has a 5-year survival rate of about 6%, is often diagnosed after it has metastasized, and most patients develop resistance to chemotherapy and radiation. Only one chemotherapy drug, topotecan, is approved as a second-line therapy.
Rova-T consists of three components: an antibody, a linker, and a cytotoxic payload. The antibody portion recognizes and binds to cell surface–available Notch ligand DLL3—overexpressed in approximately 70% of SCLCs. Once inside the cell, the linker is cleaved off, resulting in release of the cytotoxic agent pyrrolobenzodiazepine, which cross-links DNA to cause DNA damage and cell death.
“Rova-T is not a Notch pathway inhibitor,” says Pietanza. “Instead, it uses the Notch ligand to enter the cell and deliver chemotherapy directly to the tumor.”
The median duration of response among the 27 DLL3-positive patients was 178 days at data cutoff. “Toxicity was manageable at the maximum tolerated doses of 0.2 mg/kg every 3 weeks and 0.3 mg/kg every 6 weeks. The most commonly reported treatment-related adverse events were fatigue, peripheral edema, rash, thrombocytopenia, pleural effusion, and nausea.”
“The activity of the drug that we have seen is impressive,” says Pietanza. “Importantly, the durable, long-term responses are notable in such an aggressive disease, where progression is normally very rapid.”
A phase II trial of Rova-T for patients with SCLC is slated to launch in January 2016.
- ©2015 American Association for Cancer Research.
Volume 5, Issue 12
