Agent Shows Promise and Safety in Small Cell Lung Cancer

There was encouraging single-agent antitumor activity — and a manageble safety profile – when patients with recurrent small cell lung cancer (SCLC) were treated with rovalpituzumab tesirine (Rova-T), according to the results of a phase 1 study published in The Lancet Oncology.

Eleven of 60 assessable patients (18 percent) who received an active dose of Rova-T (0.2 mg/kg or 0.4 mg/kg every three weeks or 0.3 mg/kg or 0.4 mg/kg every six weeks) achieved a confirmed objective response, and 30 patients (50 percent) had stable disease. The median progression-free survival (PFS) was 2.8 months.

An exploratory analysis of available tumor tissue samples (34 patients) showed an overall response rate of 38 percent (10 patients) among 26 DLL3-high patients (tumor expression levels of at least 50 percent) compared with 0 percent in DLL3-low patients. The median PFS was 4.3 months versus 2.2 months, 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, M.D., Ph.D., 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 with CURE.

This first-in-human, first-in-class, open-label phase 1 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 one or two 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 three weeks or every six 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 three weeks.

At the time of data cutoff in May 2016, the median duration of follow-up was 3.9 months. At that time, no patients remained on active treatment, and seven patients (9 percent) remained in follow-up.

The whole study cohort received a median of two doses 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 percent), 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 percent) achieved a confirmed objective response, and 35 (54 percent) had stable disease. Thus, 46 patients (71 percent) 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 percent) had a confirmed objective response and 26 (90 percent) achieved disease control. Of the 10 assessable patients defined as DLL3-low, none achieved a confirmed objective response, though six (60 percent) had disease control.

Among all 65 assessable patients, the median duration of response was 5.6 months, based on nine of 11 responders with uncensored progression. Of these patients, 59 had disease progression or had died, and the median PFS was 3.1 months. In an exploratory analysis, the median PFS was 4.5 months for DLL3-high patients (based on 26 of 29 patients who had disease progression or died) and 2.3 months for DLL3-low patients (based on nine 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. In an exploratory analysis of DLL3 expression, 29 patients in the DLL3-high subset had a median OS of 5.8 months; in 10 patients in the DLL3-low subset, the median OS was 2.7 months (based on nine deaths).

The one-year OS rate was 18 percent in patients treated at the active dose levels, 32 percent in DLL3-high patients, and 0 percent in DLL3-low patients. A posthoc analysis of chemotherapy-sensitive versus refractory or resistant patients showed a one-year OS rate of 21 percent in patients with resistant/refractory disease; the rates were 29 percent in DLL3-high patients and 0 percent in DLL3-low patients. One-year OS was 17 percent in patients with chemotherapy-sensitive disease—33 percent in the DLL3-high patients and 23 percent 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 three weeks, including grade 4 thrombocytopenia (in two of two patients receiving that dose) and grade 3 liver function test abnormalities (in one patient). The maximum-tolerated dose of Rova-T was 0.4 mg/kg every three weeks. For future studies, Rudin et al’s recommended dose and schedule of Rova-T was two cycles of 0.3 mg/kg every six 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 percent), with grade 3 or worse events reported in 28 patients (38 percent). The most common grade 3 or worse treatment-related adverse events included thrombocytopenia (11 percent), pleural effusion (8 percent) and increased lipase (7 percent).

Patients with DLL3-high expression experienced a greater frequency of treatment-related adverse events compared with patients with DLL3-low expression (97 percent vs 69 percent, respectively), as well as adverse events of grade 3 or worse (41 percent vs 23 percent). 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 six of 82 patients (7 percent), dose reductions due to adverse events were carried out. Rova-T was withdrawn due to adverse events in 18 patients (22 percent), the most frequent causes including pleural effusion (four patients), pericardial effusion (two patients) and maculopapular rash (two patients).

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

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