Approximately 10% to 15% of all lung cancers are small-cell lung cancer (SCLC), an aggressive disease with relative 5-year survival rates ranging from 31% for stage I SCLC to 2% for metastatic SCLC.1 Because most patients with SCLC have metastatic disease at the time of diagnosis, surgical resection is rarely viable.
Cytotoxic chemotherapy and radiation are the most common forms of treatment for SCLC. Topotecan (Hycamtin), which was approved by the FDA in 1998 for second-line treatment of SCLC, remains the only treatment indicated for this use.
Delta-like protein 3 (DLL3) is a novel and actionable target for drug development in SCLC. DLL3 is an atypical inhibitor of the Notch ligand and is expressed on the surface of tumor cells in high-grade neuroendocrine carcinomas, including SCLC; approximately 85% of patients with SCLC express DLL3. In contrast, DLL3 is not expressed in healthy tissue or in cancer cells of nonneuroendocrine malignancies.2 Rovalpituzumab tesirine (Rova-T) is a first-in-class antibody-drug conjugate directed against DLL3.
To assess the safety and activity of Rova-T in patients with SCLC who progressed after ≥1 previous regimens, a phase 1 open-label study was conducted at 10 cancer centers in the United States.2 Eligible patients had confirmed SCLC or large-cell neuroendocrine carcinoma (LCNEC) tumors with progressive measurable disease and had relapsed after treatment with 1 or 2 chemotherapy regimens, including a platinum-based combination. Patients with SCLC and evidence of brain metastases were ineligible for this study.
A total of 82 patients enrolled in the study, including 74 patients with SCLC and 8 patients with LCNEC. At the time of data analysis, median duration of follow-up was 3.9 months (range, 0.4-22.0 months). Patients with LCNEC were assessed for safety but were excluded from efficacy end point analyses.
Of 65 patients with SCLC who were assessable, 71% achieved disease control with Rova-T: 17% had confirmed objective response and 54% had stable disease. In 39 patients who provided biopsy samples, retrospective testing of DLL3 expression showed a relationship between DLL3 expression and response. Of the 29 patients who were found to be DLL3-high (DLL3 expression in ≥50% of cells), 35% had a confirmed objective response, and 90% achieved disease control with Rova-T. Of the 10 assessable patients who were DLL3-low, none achieved a confirmed objective response, and 6 of 10 experienced disease control. In the 68 patients treated with active dose levels of Rova-T, overall survival (OS) was 4.6 months (95% confidence interval [CI], 3.9-7.1 months). The 1-year OS rate was higher in DLL3-high patients, 32% (95% CI, 15%-49%), compared with 0% in DLL3-low patients.
Adverse events (AEs) of any grade were observed in 88% of patients with SCLC who received Rova-T, with grade ≥3 AEs noted in 38%. The most common grade ≥3 treatment-related AEs were thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%). AEs were attributed to death in 4 patients.
Patients with DLL3-high expression were more likely to experience treatment-related AEs compared with patients with DLL3-low expression (97% vs 69%, respectively), as well as AEs grade ≥3 (41% vs 23%). DLL3-high patients had a longer duration of treatment with Rova-T and longer follow-up.
An open-label phase 2 trial of Rova-T patients with relapsed or refractory SCLC whose cancer cells express a high level of DLL3, known as TRINITY, is currently underway.3 Results of this trial are expected in early 2018.
1. American Cancer Society. Key statistics for small cell lung cancer. Last revised January 4, 2018. www.cancer.org/cancer/small-cell-lung-cancer/about/key-statistics.html. Accessed January 29, 2018.
2. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18:42-51.
3. ClinicalTrials.gov. Study of rovalpituzumab tesirine (SC16LD6.5) for third-line and later treatment of subjects with relapsed or refractory delta-like protein 3-expressing small cell lung cancer (TRINITY). https://clinicaltrials.gov/ct2/show/NCT02674568. Accessed January 29, 2018.