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

Abstract

Summary Background Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. Methods We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. Findings Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). Interpretation Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted.

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

“…DLL3 expression is tightly linked to expression of ASCL1 and NE differentiation. Rovalpituzumab tesirine (ROVA-T) is a DLL3-targeted antibody-drug conjugate, which has shown encouraging single agent anti-tumor activity in DLL3 expressing lung NE carcinomas (58). Our results would suggest that SCLC tumors that have lost NE (and DLL3) expression would be resistant to ROVA-T therapy.…”

Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer

“…The staining percentage (0-100%) was then evaluated and divided into two intensity levels (high, ≥50%; and low, 0-49%), according to the previous study (20).…”

“…DLL3 is highly expressed in the majority of SCLCs and inhibits the Notch receptor pathway, promoting SCLC tumorigenesis (19). A recent clinical trial demonstrated that rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, exhibited marked antitumor activity and durability in recurrent or refractory SCLC (20). EZH2 is also highly expressed in SCLC, and its inhibition by EZH2 inhibitor enhances the effectiveness of current standard chemotherapy (21).…”

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

“…22 However, some ADCs have much longer half-lives; rovalpituzumab tesirine has a half-life between 10 and 14 days and is administered every 6 weeks. 31 …”