Rovalpitizumab tesirine: promising phase I results in small cell lung cancer
Small cell lung cancer (SCLC) is an aggressive, difficult-to-treat cancer type that is often diagnosed in an advanced disease stage. The treatment options for these patients are limited, which results in a very low 5-year survival rate of only 6%. During the 2015 European Cancer Congress, first-in-human results with the new antibody-drug conjugate (ADC) rovalpitizumab tesirine (Rova-T) showed strong, single-agent responses in the second- and third-line treatment of SCLC.
The standard treatment for early stage non-small cell lung cancer (NSCLC) consists of surgery. However, as SCLC is often diagnosed in an advanced stage, surgery is usually not an option. Currently, SCLC patients are treated with chemotherapy consisting of etoposide and a platinum-based agent, often in combination with radiotherapy. When this first-line therapy fails, chemotherapy with topotecan is the only remaining treatment option. Given the fact that SCLCs frequently metastasize to the brain, cranial radiotherapy is also used in this setting. Currently, there are no third-line treatment options for these patients. Rova-T is an ADC designed to bind to delta-like protein 3 (DLL3), which is expressed at high levels in a large proportion of SCLC tumors. The cytotoxic payload of the ADC is a pyrrolbenzodiazepine dimer that cross-links DNA. To assess the potential of Rova-T in the treatment of recurrent SCLC, a phase I study was set up, including 73 patients with disease progression after first or second- line therapy.
The median age of patients in the trial was 62 years (range 44 to 81 years). Patients in the study were treated with Rova-T in a dose escalation schedule until unacceptable toxicity. Using an antibody to investigate DLL3 expression in archived tumor samples, 35/49 (71%) of the specimens were found to be high DLL3 expressers (DLL3+). Among the 27 confirmed DLL3+ patients treated at the expansion cohort doses of 0.2 mg/kg and 0.3 mg/kg, 44% had a partial response and 34% achieved stable disease. This results in a clinical benefit rate of 78%.
At the recommended phase II dose of 0.3 mg/kg, 6 out of 7 responders remain free of progression (with a follow-up ranging from 38 to 353 days) and all of them are still alive. In the third-line setting, the response was 20% in 25 unselected patients and 45% in the 11 DLL3+ patients.
The most frequent adverse events with Rova-T were fatigue (30%, grade 3/4 in 7%), peripheral edema (18%, grade 3/4 in 2%), macular and papular rash (16%, grade 3/4 in 7%), and thrombocytopenia (20%, grade 3/4 in 14%). In addition to this, low grade appetite loss (18%), anemia (11%), erythema (14%), and light sensitivity reactions (14%) were also reported.
In summary, Rova-T shows promising single-agent activity in the treatment of recurrent SCLC, a patient population with a high medical need. These findings are remarkable given the aggressive nature of these tumors usually leading to rapid disease progression. As such, these results form a firm basis for evaluation of Rov-T in a larger, randomized setting.
Referentie
Pietanza MC, et al. Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC), in small cell lung cancer (SCLC). Presented at ECC 2015; Abstract #LBA7.
