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Targeted therapy brings fresh hope for small-cell lung cancer treatment


 

AT EUROPEAN CANCER CONGRESS 2015

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VIENNA – Rovalpituzumab tesirine, an antibody drug conjugate that targets delta-like protein 3, produced responses in a range of patients with previously treated small-cell lung cancer in a phase I study.

Responses to rovalpituzumab tesirine (Rova-T) were higher and more durable in patients with tumors positive for DLL3, a protein previously shown to be over-expressed in about 70% of small-cell lung cancers (SCLCs).

Dr. M. Catherine Pietanza

Dr. M. Catherine Pietanza

“DLL3 may be the first predictive biomarker associated with treatment efficacy in small-cell lung cancer,” Dr. M. Catherine Pietanza of Memorial Sloan Kettering Cancer Center, New York City, said during a presidential session at the European Cancer Congress 2015.

While SCLC is initially sensitive to chemotherapy and radiation, resistance develops quickly. Topotecan (Hycamtin) is the only approved agent in the second-line setting. None are available in the third-line setting and outcomes remain dismal, with 5-year survival rates of 6%, she said.

The study enrolled 73 patients with recurrent or progressive SCLC after first- or second-line therapy and administered escalating doses of rovalpituzumab tesirine (0.05 mg/kg to 0.8 mg/kg) once every 3 weeks. Confirmed responses were observed at the 0.2-mg/kg, 0.3-mg/kg, and 0.4-mg/kg dose levels.

The maximum tolerated dose was 0.4 mg/kg, but continued dosing revealed cumulative toxicities, most often serosal effusions, Dr. Pietanza said. The agent was also found to have a prolonged half-life, prompting the researchers to proceed with rovalpituzumab tesirine 0.2 mg/kg every 3 weeks and 0.3 mg/kg every 6 weeks in the phase Ib expansion cohorts.

The patients median age was 61 years and 56% were male. Of the 49 tumor samples available for analysis, 71% were positive for high DLL3 expression using an H score cutoff of at least 180 on a scale of 300.

For all patients and at all dose levels, the overall response rate was 24% in the second-line setting, 20% in the third-line setting, 28% for those sensitive to first-line combination chemotherapy, and 16% for those refractory or resistant to chemotherapy, Dr. Pietanza reported.

For the DLL3-positive patients in the expansion cohorts, the overall response rate reached 64% for those sensitive to first-line chemotherapy, 44% in the second-line setting, 45% in the third-line setting, and 23% for those refractory or resistant to chemotherapy.

Importantly, responses were durable, Dr. Pietanza observed. At the 0.3 mg/kg 6-week dosing schedule, patients had ongoing responses 189 days after confirmatory CT scans and survival remains prolonged. For these reasons, the dose of 0.3 mg/kg every 6 weeks was chosen as the randomized phase II dose, she added.

Dr. Pietanza highlighted the benefits of rovalpituzumab tesirine by describing one patient who had a partial response to the first dose that continued, with a 51% reduction in tumor volume and a negative PET scan at 120 days. An adrenalectomy was performed at about 220 days due to ongoing response and disease presence only in the adrenal gland.

“Upon pathology review, there was a 95% treatment effect on the tumor,” she said. “When the adrenal gland was stained for Ki67, which is a marker of proliferative index, it was completely negative, noting and underscoring that possibly Rova-T affects tumor initiating cells.

“My patient remains alive with no evidence of disease over 1 year after first administration of Rova-T.”

The drug has a manageable safety profile, with unique reactions being pleural effusions and photosensitivity, she said.

Among 69 evaluable patients in the dose-escalation cohorts, the most common treatment-related adverse events of any grade were fatigue (28%), peripheral edema (17%), maculopapular rash (14%), thrombocytopenia (14%), pleural effusion (13%), and photosensitivity (12%), Dr. Pietanza said.

The most frequent grade 3/4 events were thrombocytopenia (9%), fatigue (6%), maculopapular rash (4%), and pleural effusion (4%).

“These results support biomarker-guided phase II studies,” she concluded.

Discussant Dr. Martin Reck, of the Lung Clinic Grosshansdorf (Germany), said, “We have seen very interesting results, perhaps the first targeted treatment in small-cell lung cancer. The data are very much superior to topotecan.”

More clinical data are needed, however, and the results must be put into perspective with the immunotherapies, where encouraging results have also been seen in SCLC, he said. The optimal treatment setting also has to be determined for rovalpituzumab tesirine, whether it is maintenance or perhaps a combination strategy.

Professor Peter Naredi, scientific cochair of the congress, said in a statement that the early results are “remarkable” in a malignancy where there has been no novel treatment options for years.

pwendling@frontlinemedcom.com

On Twitter @pwendl

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