SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15 percent of all lung cancers and is aggressive. The five year survival rate for extensive stage SCLC is less than 5% with a median survival of 9 to 10 months from the time of diagnosis. Patients are often treated with chemotherapy and radiation in the first and second line setting. The Overall Response Rate (ORR) in the third line setting is approximately 18% and the one year Overall Survival is approximately 12%. These patients typically have a poor prognosis with limited treatment options. Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 80% of the tumors).
Rovalpituzumab Tesirine (Rova-T) is a first-in-class DLL3-targeted Antibody-Drug Conjugate (ADC) comprised of a humanized anti-DLL3 monoclonal antibody, conjugated to a DNA-damaging PyrroloBenzoDiazepine (PBD) dimer toxin. Rova-T delivers the cytotoxin directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.
The authors in this open-label, Phase 1a/1b, multicenter study, included seventy four (N=74) patients with SCLC who had progressed after at least one previous systemic therapy. Previous therapies included Platinum/Etoposide (96%) and radiation therapy (82%). The majority of patients (76%) had extensive disease at presentation, with 28% having CNS metastases. Over 85% of patients had DLL3 expression on 1% or more of tumor cells and 67% of the patients had DLL3 expression on 50% or more of tumor cells (DLL3-high expression). Patients received Rova-T at doses ranging from 0.05 to 0.8 mg/kg every 3 or 6 weeks. The median age was 61 years. The primary endpoints of the study were Overall Response Rate (ORR) and Maximum Tolerated Dose and secondary endpoints included Overall Survival (OS) and Progression Free Survival (PFS).
Rova-T demonstrated an Overall Response Rate of 39% and Clinical Benefit Rate (stable disease or better) of 89%, in patients with recurrent or refractory Small Cell Lung Cancer identified with high expression of DLL3. The one year Overall Survival rate was 32% in the patient group identified with high expression of DLL3. The most common adverse events were rash, fatigue, nausea, decreased appetite, pleural effusion, peripheral edema and thrombocytopenia.
The authors concluded that Rovalpituzumab Tesirine (Rova-T) has significant single-agent anti-tumor activity with manageable toxicity, in recurrent or refractory SCLC, and is the first biomarker-directed therapy to be defined, for the treatment of Small Cell Lung Cancer. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). Rudin CM, Pietanza MC, Bauer TM, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA8505)