Antibody Drug Conjugate Shows Promise in Small-Cell Lung Cancer

An antibody-drug conjugate, rovalpituzumab tesirine, shows promising efficacy against recurrent small-cell lung cancer.

[[{"type":"media","view_mode":"media_crop","fid":"49201","attributes":{"alt":"Dr. Rudin presenting the results at a press conference","class":"media-image","id":"media_crop_150691425513","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5926","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","title":"Dr. Rudin presenting the results at a press conference","typeof":"foaf:Image"}}]]CHICAGO-An antibody-drug conjugate, rovalpituzumab tesirine, shows promising efficacy against recurrent small-cell lung cancer (SCLC), according to early findings from a first-in-human clinical trial.

The treatment combines a novel delta-like protein 3 (DLL3)-targeted antibody with a powerful anticancer agent, a pyrrolobenzodiazepine dimer toxin. The antibody component serves to deliver the anticancer agent to the tumor and into cancer cells.

“Rovalpituzumab tesirine shows single-agent activity in recurrent refractory SCLC with comparable responses in second-line and third-line therapy,” said lead author Charles M. Rudin, MD, PhD, a medical oncologist and chief of the thoracic oncology service at Memorial Sloan Kettering Cancer Center in New York. “We’ve seen too few successes in recent years for SCLC, which makes these early signs of efficacy all the more encouraging.”

Rudin presented the study results (abstract LBA8505) at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago.

SCLC has a “dismal prognosis,” he said, with unchanged survival of less than 15% at 2 years over the past 4 decades. Only one drug, topotecan, is approved for recurrent disease by the US Food and Drug Administration.

About two-thirds of SCLC patients have high levels of DLL3 on the surface of cancer cells. The protein is essentially absent from healthy adult tissues, Rudin said. DLL3 is known to regulate cancer stem cell biology in SCLC. Rovalpituzumab tesirine is the first agent to target DLL3.

The phase I study enrolled 74 patients with SCLC who had all failed at least standard therapy. About two-thirds of patients had extensive-stage disease at diagnosis; the other one-third had limited-stage disease. When tissue samples were available, the researchers assessed levels of DLL3 in the tumor tissue.

Eleven out of 60 (18%) evaluable patients experienced tumor shrinkage, and 41 (68%) achieved clinical benefit, having at least stable disease. Nearly all the patients who responded to the treatment had elevated levels of DLL3 in their tumor.

Among the 26 patients with the highest levels of DLL3, 10 (39%) responded to therapy. Their median overall survival was 5.8 months, with a 1-year survival rate of 32%. In this group, the 12 patients who received the treatment as third-line therapy responded particularly well, with 50% having a confirmed objective response.

The most common severe treatment-related toxicities included serosal effusion, low platelet counts, and skin reactions, which were generally manageable with medications, or resolved without specific interventions.

Although these results are preliminary, “Rovalpituzumab tesirine seems to be the first targeted therapy to show efficacy in SCLC. We may have identified DLL3 as the first predictive biomarker in this disease, and it may be of utilization for the management of these patients,” said Rudin.

The results justify confirmation in larger clinical trials. A single-arm phase II pivotal trial in patients with DLL3-positive SCLC that has worsened despite at least 2 prior therapies was launched earlier this year. Other trials will evaluate rovalpituzumab tesirine in first-line SCLC and in combination with immunotherapies, Rudin said, as well as in other DLL3-expressing neuroendocrine cancers.