M. Catherine Pietanza, MD,
The antibody-drug conjugate rovalpituzumab tesirine (Rova-T) showed activity across a range of patients with relapsed and refractory small-cell lung cancer (SCLC), representing the first demonstration of efficacy for a targeted therapy in this setting, according to a presentation at the 2015 European Cancer Congress.
In the phase I study, patients with SCLC who were sensitive to first-line combination chemotherapy and were positive for delta-like 3 (DLL3) gene expression experienced an objective response rate (ORR) of 64% with Rova-T. In the third-line setting, where a standard treatment is currently not available, the ORR in DLL3-expressing patients (n = 15) was 45%. Across all patients in the third-line setting (n = 35), the ORR was 20%.
“The high response rate is exciting, in itself, and above that we have been able to identify a biomarker for SCLC in DLL3+, thus enabling us to ‘target’ treatment in SCLC,” said lead investigator M. Catherine Pietanza, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center. “The activity of the drug that we have seen is remarkable, and importantly, the durable, long-term responses are notable in such an aggressive disease where progression is normally very rapid.”
Several studies have shown that approximately 70% of treatment-exposed SCLC tumors exhibit high levels of DLL3 expression. Rovalpituzumab tesirine consists of a monoclonal antibody against DLL3 linked to the cytotoxic agent tesirine, a DNA-damaging pyrrolobenzodiazepine dimer toxin.
In the phase I study, 73 patients with previously treated SCLC received two doses of Rova-T: 0.2 mg/kg every 3 weeks or 0.3 mg/kg every 6 weeks. Consistent with expectations, 69% of the patients were found to have high expression of DLL3 (n = 33).
The results showed that a majority of patients had some degree of tumor shrinkage. All patients with tumor regression correlated with high-level expression of DLL3. Multiple patients had responses that persisted beyond 300 days, a level of activity unheard of it SCLC, said Pietanza.
“These were unselected patients, and it is notable even though all patients who were treated at various dose levels had responses, the responses were higher and more durable in patients who had DLL3-positivity in their tumors,” she said. “This was true whether patients were treated in second-line or third-line and whether they had sensitive or refractory disease.”
Tumor shrinkage was observed across all subgroups of patients with DLL3-expressing SCLC. In the second-line setting across all patients enrolled, the ORR was 24%. The ORR was 28% and 16%, in those who were sensitive and refractory to frontline therapy, respectively.
In the second-line setting, patients with DLL3+ SCLC who received Rova-T had an ORR of 44%. In those who demonstrated sensitivity to first-line combination chemotherapy, the ORR with Rova-T was 64%. Patients who were refractory or resistant to first-line therapy had an ORR of 23%.
In patients with DLL3-expressing tumors who received the recommended phase II dose (RP2D) of 0.3 mg/kg every 6 weeks, 34% met the criteria for partial response across all treatment settings. Among responding patients, the median duration of response was 189 days.
The level of response correlated with the expression of DLL3, with most partial responses seen in those with high-levels of DLL3 expression. Patients who achieved stable disease had generally moderate levels of DLL3 expression, and low-level expression of the biomarker was associated with progressive disease with Rova-T.
The side-effect profile of Rova-T was similar to that of other chemotherapeutic agents, said Pietanza. Agent-specific all-grade adverse events (AEs) included pleural effusion (13%) and photosensitivity (12%). The most frequently observed grade 3/4 AEs at the RP2D were thrombocytopenia (14%), fatigue (7%), maculo-papular rash (7%), peripheral edema (2%), and anemia (2%).
To illustrate the dramatic effects Rova-T has achieved in some patients, Pietanza described a patient who had a partial response to the first administration of the antibody-drug conjugate, reflected by a 43% reduction in tumor volume. The second administration of Rova-T led to further reductions in tumor volume, reaching a maximum decrease from baseline of 66% at day 300 after the initial dose. The patient remains in follow-up and has maintained the reduction in tumor volume.
“The first-line therapy has not changed for four decades, and there is no third-line treatment at present, so it is clear that Rova-T is likely to fulfill an unmet need for these patients," Pietanza said. "I would like to see additional, larger trials to develop it further in settings where there is a clear need in this disease. We are looking forward to further assisting in its development and to gaining a better understanding of its value in all cases of SCLC.”