Roxanne Nelson, BSN, RN

June 07, 2016

CHICAGO — A new antibody-drug conjugate (ADC) has shown promising efficacy in recurrent small-cell lung cancer (SCLC), say researcher reporting early findings from a phase 1 trial.

Rovalpituzumab tesirine (Rova-T, AbbVie) is a first-in-class ADC that is comprised of a humanized monoclonal antibody against delta-like protein 3 (DLL3), a dipeptide linker, and a pyrrolobenzodiazepine dimer toxin.

DLL3 is highly expressed in neuroendocrine tumors, including approximately 80% of SCLC tumors.

Among patients who expressed high levels of DLL3 in their tumors, there was a confirmed clinical benefit (stable disease or better) in 89% of the cohort and 68% in the entire group.

The study results were presented here at the American Society of Clinical Oncology 2016 Annual Meeting.

"This is the first biomarker-directed therapy in SCLC," said lead study 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 City. "It showed single-agent activity in recurrent/refractory SCLC, and improved responses and survival compared with historical approved treatment outcomes."

However, Dr Rudin emphasized that these results "must be taken with caution."

"These are early data with a small number of patients, and these data are not for comparison with standard care," he said.

Dr Charles Rudin

SCLC accounts for 10% to 15% of lung cancers and has a dismal prognosis. Two-year survival is less than 15%; this has remained essentially unchanged for more than 4 decades, Dr Rudin explained.

Topotecan is, thus far, the only therapy approved by the US Food and Drug Administration for recurrent SCLC, so there is "a lot of room for improvement here," he said.

Promising Responses in "DLL3-High" Patients

The study involved 74 patients with SCLC that had progressed after at least one previous systemic therapy.

In the first phase of the study, doses of 0.05 to 0.08 mg/kg were tested. Doses of 0.4 mg/kg were not considered tolerable, and expansion cohorts included doses of 0.2 and 0.3 mg/kg.

The current analysis focused on 0.2 to 0.4 mg/kg doses and, when possible, tumor tissue was tested for DLL3 expression.

Of the 48 patients with DLL3 expression, 42 (88%) patients had expression in at least 1% of tumor cells. And 32 (67%) of these 48 patients were "DLL3-high," indicating expression in at least 50% of tumor cells.

Confirmed responses were seen in 39% of DLL3-high patients and in 18% overall, regardless of DLL3 status.

The 1-year survival was 32% in DLL3-high patients and 18% in the overall group.

Second- and Third-Line Settings

Dr Rudin and his team also compared rovalpituzumab tesirine with conventional therapy in second- and third-line settings.

In the second-line setting, the confirmed response rate was 43% in chemotherapy-sensitive patients for the experimental agent, compared with 17% for those treated with standard therapy. One-year survival was 38% and 27%, respectively.

There are no approved drugs for the third-line setting in SCLC, Dr Rudin explained, so the team looked at data from patients who had been treated with a variety of chemotherapy agents.

These findings showed a strong advantage for rovalpituzumab tesirine in this population. The confirmed response rate was 50%, compared with 18%, and 1-year survival was 33%, compared with 12%.

Toxicities were generally manageable. For all patients, the most common toxic effects of grade 3 or higher that were considered to be related to the study drug were serosal effusions (14%), thrombocytopenia (12%), and skin reactions (8%).

The findings from this early-stage trial will need to be confirmed in larger clinical trials, he pointed out.

A single-group phase 2 trial of patients with DLL3-positive SCLC that has progressed after at least two other therapies was launched earlier this year. Other upcoming trials will evaluate rovalpituzumab tesirine in first-line SCLC and other DLL3-expressing neuroendocrine cancers.

These are promising results for patients with high expression of DLL3, said Taofeek Kunle Owonikoko, MD, PhD, from Emory University in Atlanta.

"To me, what is more intriguing are the responses in the third-line setting, especially for those who are biomarker-positive, as defined by more than 50% expression of DLL3," he said.

"The future of [rovalpituzumab tesirine] depends on whether investigators are able to improve on its strengths and minimize its weaknesses," Dr Owonikoko noted.

For example, strengths include the convenient infusion schedule, and activity in the frontline setting is really encouraging.

Thrombocytopenia, however, is a challenge, and "the biomarker of more than 50% has to be confirmed in a randomized prospective study, which is currently ongoing," he said.

"The tipping point is that [rovalpituzumab tesirine] is a new first-in-class ADC with established safety and promising efficacy. Ongoing studies will help us better characterize efficacy and better define a subset of patients," Dr Owonikoko concluded.

This study received funding from Stemcentrx, Inc. Dr Rudin reports consulting or advisory roles with AbbVie, AVEO, Boehringer Ingelheim, GlaxoSmithKline, Merck, Celgene, and Novartis; and receiving research funding from Biomarin. Some of his coauthors report relationships with industry, as detailed in the abstract. Dr Owonikoko reports consulting or advisory roles with Bayer, Celgene, Genentech/Roche, and Novartis; receiving research funding from Astellas Pharma (Inst), Bayer (Inst), Celgene (Inst), and Novartis (Inst); and patents, royalties, other intellectual property for a genetic predictor of chemotherapy sensitivity (Inst).

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting. Abstract LBA8505. Presented June 5, 2016.

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