The first-in-class antibody-drug conjugate rovalpituzumab tesirine (Rova-T) may be a new treatment option for patients with small-cell lung cancer (SCLC), which has a very poor prognosis and few treatment options. Rova-T is particularly promising in SCLC tumors that overexpress the delta-like (DLL) 3 protein, according to first-in-human study results presented at ASCO 2016.
If this preliminary study holds up in phase 2 and phase 3 clinical trials, Rova-T will be the first molecularly targeted agent for SCLC, and DLL3 will be the first predictive biomarker to be discovered for SCLC.
“Take these results with caution, but these results look promising for a new class of agents in SCLC. SCLC is an aggressive disease with a median survival of 9 months. Topotecan (Hycamtin) is the only approved drug for recurrent disease. There is lots of room for improvement,” said lead investigator Charles M. Rudin, MD, PhD, Chief of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, who presented the study results at the meeting.
“These results justify going forward in developing this drug for SCLC in DLL3 overexpressers,” Dr Rudin added.
Rova-T targets the DLL3 protein located on the surface of tumor cells. Once it binds to DLL3, Rova-T delivers a payload of chemotherapy with a pyrrolobenzodiazepine, which is too toxic to be given to patients directly. DLL3 is overexpressed in 80% of patients with SCLC, but it is not expressed on normal cells, which limits the toxicity to normal tissue.
First-in-Human Study with Rova-T
The study enrolled 74 patients with SCLC that had progressed after ≥1 previous therapies. Of the 74 participants, 50% had chemosensitive disease, 33% had chemoresistant disease, and 9% had primary chemorefractory disease. Patients received 1 or 2 previous therapies, and approximately 50% of patients fit into each of these categories.
Of the 60 patients who received Rova-T doses ranging from 0.2 mg/kg to 0.4 mg/kg, 68% achieved clinical benefit (response plus stable disease), and the overall response rate (ORR) was 18%, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
In a subset of 48 patients with archived tumor tissue available for DLL3 testing, DLL3 was detectable in 88% of patients, and 67% of patients’ tumors had high expression levels of DLL3 (≥50% of tumor cells as assessed by immunohistochemistry). In patients whose SCLC tumors overexpressed DLL3, 89% achieved clinical benefit and the ORR was 38% according to RECIST criteria.
Among 12 patients who received Rova-T as third-line therapy and whose tumors overexpressed DLL3, 92% had clinical benefit, and the ORR was 50%. There are currently no approved therapies for third-line treatment of patients with SCLC.
The median survival was 5.8 months, and the 1-year survival rate was 32% in patients whose tumors had high expression levels of DLL3. These results are encouraging and compare favorably with the outcomes of available drugs, said Dr Rudin.
The most common grade ≥3 toxicities were effusions, particularly pleural effusions (11%), thrombocytopenia (12%), and skin reactions (85%). Skin reactions of any grade were reported in 49% of patients, but these reactions are preventable with medication, Dr Rudin reported.
“A number of studies of Rova-T are on the launch pad, including a basket trial of tumors that express DLL3. We will also be studying Rova-T in combination with other drugs and with immunotherapy,” Dr Rudin said. Phase 2 clinical trials with Rova-T are recruiting participants whose tumors express the DLL3 protein.
“This is another example of a new wave of targeted treatments that deliver anticancer drugs precisely to where they are needed. These results mark a good, early sign of success against a cancer for which we urgently need better therapy options,” stated ASCO spokesperson Gregory A. Masters, MD, Helen F. Graham Cancer Center, Newark, DE, who was not involved in this study.