Rovalpituzumab Tesirine Demonstrates Encouraging Activity in Small Cell Lung Cancer


Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, demonstrated encouraging single-agent antitumor activity with a manageable safety profile in the treatment of patients with recurrent small cell lung cancer.

Charles M. Rudin, MD, PhD

Charles M. Rudin, MD, PhD

Rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, demonstrated encouraging single-agent antitumor activity with a manageable safety profile in the treatment of patients with recurrent small cell lung cancer (SCLC), according to the results of a phase I study published inThe Lancet Oncology.

Eleven of 60 assessable patients (18%) who received an active dose of Rova-T (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) achieved a confirmed objective response, and 30 patients (50%) had stable disease. The median progression-free survival (PFS) was 2.8 months (95% CI, 2.5-4.0).

An exploratory analysis of available tumor tissue samples (n = 34) showed an overall response rate of 38% (n = 10) among 26 DLL3-high patients (tumor expression levels ≥50%) compared with 0% in DLL3-low patients. The median PFS was 4.3 months (95% CI, 2.8-5.6) versus 2.2 months (95% CI, 1.3-2.5), respectively.

“The impressive responses seen on our initial clinical trial appear to be restricted to those patients whose tumors had a high level expression of the DLL3 target,” lead study author Charles M. Rudin, MD, PhD, chief, Thoracic Oncology Service; co-director, Druckenmiller Center for Lung Cancer Research; Sylvia Hassenfeld Chair in Lung Cancer Research, Memorial Sloan Kettering Cancer Center, said in an interview withOncLive.

This first-in-human, first-in-class, open-label phase I study was carried out across 10 cancer centers in the United States. Eligible patients were aged 18 years or older and had to have histologically or cytologically confirmed SCLC or large-cell neuroendocrine tumors with progressive measurable disease, assessed by RECIST 1.1. Patients also had to have been previously treated with 1 or 2 chemotherapeutic regimens, including a platinum-based treatment.

Eighty-two patients were enrolled in the study between July 2013 and August 2015. This included 74 patients with SCLC and 8 patients with large-cell neuroendocrine carcinoma. All patients received at least 1 dose of Rova-T.

Patients were assigned to dose-escalation or expansion cohorts. Doses of Rova-T ranged from 0.05 mg/kg to 0.8 mg/kg intravenously every 3 weeks or every 6 weeks. Following that was an 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.

At the time of data cutoff in May 2016, the median duration of follow-up was 3.9 months (IQR 2.2-7.4; range, 0.4-22.0). At that time, no patients remained on active treatment, and 7 patients (9%) remained in follow-up.

The whole study cohort received a median of 2 doses (IQR 1-3; range 1-14) of Rova-T. Patients with large-cell neuroendocrine tumors were excluded from endpoint analyses, as they comprised a small proportion of the study population (10%), and their outcomes can differ significantly from those of patients with SCLC.

Of 65 patients with SCLC who were assessable for activity analyses and received any dose of Rova-T, 11 (17%) achieved a confirmed objective response, and 35 (54%) had stable disease. Thus, 46 patients (71%) achieved disease control.

Thirty-nine patients provided samples for exploratory analysis of DLL3 expression in tumor tissue. Of 29 assessable DLL3-high patients, 10 (35%) had a confirmed objective response and 26 (90%) achieved disease control. Of the 10 assessable patients defined as DLL3-low, none achieved a confirmed objective response, though 6 (60%) had disease control.

Among all 65 assessable patients, the median duration of response was 5.6 months (95% CI, 2.5-8.3), based on 9 of 11 responders with uncensored progression. Of these patients, 59 had disease progression or had died, and the median PFS was 3.1 months (95% CI, 2.7-4.1). In an exploratory analysis, the median PFS was 4.5 months (95% CI, 3.0-5.4) for DLL3-high patients (based on 26 of 29 patients who had disease progression or died) and 2.3 months (95% CI, 1.3-3.3) for DLL3-low patients (based on 9 of 10 patients who had disease progression or died).

In the 68 patients treated with active dose levels of Rova-T, overall survival (OS) was 4.6 months (95% CI, 3.9-7.1; based on 54 deaths). In an exploratory analysis of DLL3 expression, 29 patients in the DLL3-high subset had a median OS of 5.8 months (95% CI, 4.4-11.6; based on 22 deaths); in 10 patients in the DLL3-low subset, the median OS was 2.7 months (95% CI, 1.2-10; based on 9 deaths).

The 1-year OS rate was 18% (95% CI, 9-29) in patients treated at the active dose levels, 32% (95% CI, 15-49) in DLL3-high patients, and 0% in DLL3-low patients. A posthoc analysis of chemotherapy-sensitive versus refractory or resistant patients showed a 1-year OS rate of 21% in patients with resistant/refractory disease; the rates were 29% in DLL3-high patients and 0% in DLL3-low patients. One-year OS was 17% in patients with chemotherapy-sensitive disease—33% in the DLL3-high patients and 23% in the DLL3-low patients.

“DLL3 may prove to be the first predictive biomarker for SCLC—a biomarker we can use to direct therapy to those patients most likely to benefit from a given treatment,” said Rudin.

Dose-limiting toxic effects of Rova-T occurred at a dose of 0.8 mg/kg administered every 3 weeks, including grade 4 thrombocytopenia (in 2 of 2 patients receiving that dose) and grade 3 liver function test abnormalities (in 1 patient). The maximum-tolerated dose of Rova-T was 0.4 mg/kg every 3 weeks. For future studies, Rudin et al’s recommended dose and schedule of Rova-T was 2 cycles of 0.3 mg/kg every 6 weeks.

In the 74 patients with SCLC, Rova-T was generally well tolerated. Treatment-related adverse events of any grade were observed in 65 patients (88%), with grade 3 or worse events reported in 28 patients (38%). The most common grade 3 or worse treatment-related adverse events included thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%).

Patients with DLL3-high expression experienced a greater frequency of treatment-related adverse events compared with patients with DLL3-low expression (97% vs 69%, respectively), as well as adverse events of grade 3 or worse (41% vs 23%). It is important to note, however, that DLL3-high patients had a longer duration of treatment and follow-up (mean, 7.6 months vs 2.9 months).

For 6 of 82 patients (7%), dose reductions due to adverse events were carried out. Rova-T was withdrawn due to adverse events in 18 patients (22%), the most frequent causes including pleural effusion (n = 4), pericardial effusion (n = 2), and maculopapular rash (n = 2).

Drug-related serious adverse events were seen in 35 of 82 patients (43%). The most frequent events included pleural effusion in 14 patients (19%) and pericardial effusion in 5 patients (7%).

Sixty-five of 82 patients (79%) died during the study. Fifty-six patients (86%) died because of disease; 4 patient deaths (6%) were due to an adverse event; 1 death (2%) was caused by a bleeding ulcer. Four patients (6%) died for unknown reasons.

According to Rudin, the next steps for this therapy include a number of confirmatory biomarker-guided clinical trials in patients with SCLC, combination studies with other active agents, as well as studies to explore potential activity of Rova-T in other tumor types expressing the target, DLL3.


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(1):42-51. doi:10.1016/S1470-2045(16)30565-4.

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