medwireNews: Rovalpituzumab tesirine, a first-in-class antibody–drug conjugate directed against delta-like protein 3 (DLL3), shows promising antitumor activity in patients with recurrent small-cell lung cancer, US researchers report.
Charles Rudin (Memorial Sloan Kettering Cancer Center, New York) and colleagues explain that DLL3 is a “novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer.”
For the phase I open-label study, 74 patients with small-cell lung cancer, who had progressed after one or two previous regimens, were assigned to participate in dose-escalation or expansion cohorts, ranging from 0.05 to 0.8 mg/kg rovalpituzumab tesirine intravenously every 3 or 6 weeks.
During dose escalation, dose-limiting toxicity occurred in two of two patients receiving 0.8 mg/kg rovalpituzumab tesirine every 3 weeks. The toxic effects included grade 4 thrombocytopenia in both patients and grade 4 liver function test abnormalities in one patient.
No dose-limiting toxic effects occurred at other dose levels and the maximum tolerated dose was therefore determined to be 0.4 mg/kg every 3 weeks.
Using this information and pharmacokinetic data showing the rovalpituzumab tesirine half-life to be 10–14 days, the researchers recommend that two cycles of 0.3 mg/kg rovalpituzumab tesirine every 6 weeks should be the dosing schedule used in future studies.
Rudin and team report in The Lancet Oncology that rovalpituzumab tesirine was “generally well-tolerated” with grade 3 or worse treatment-related adverse events occurring in 38% of the 74 patients. These were most commonly thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%).
During a median follow-up of 3.9 months, 18% of 60 assessable patients receiving an active dose of rovalpituzumab tesirine (0.2 or 0.4 mg/kg every 3 weeks or 0.3 or 0.4 mg/kg every 6 weeks) achieved a confirmed objective response and 50% had stable disease. This gave an overall disease control rate of 68%.
Exploratory analyses of 34 available tumor tissue samples showed that the 26 patients with high DLL3 expression (≥50% tumor cells) were more likely to achieve an objective response than the eight with lower expression, at 38% versus 0%.
Similar patterns were seen for progression-free and overall survival, with a 1-year overall survival rate of 18% for patients treated at the active dose level, 32% for DLL3-high patients and 0% for DLL3-low patients.
Therefore “[e]xpression of DLL3 in tumours can identify patients who are more likely to achieve a response and better long-term outcomes during treatment with rovalpituzumab tesirine, suggesting DLL3 as a potential biomarker and tractable therapeutic target in small-cell lung cancer,” Rudin and co-authors remark.
They conclude that their findings “are especially encouraging in third-line small-cell lung cancer, for which no currently approved treatment exists,” but add that rovalpituzumab tesirine’s ability to target tumor-initiating cells suggest it may also be useful in first-line treatment.
By Laura Cowen
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