“Smart Bomb” Drug: Rova-T Promising in SCLC

ASCO

The antibody-drug conjugate rovalpituzumab tesirine (Rova-T) may be a new option for treatment of small cell lung cancer (SCLC), a disease with a very poor prognosis and few treatment options. Rova-T looked particularly promising in SCLC tumors that overexpress delta-like protein 3 (DLL3), according to a first-in-human trial presented at the 2016 ASCO Annual Meeting.

If the results from this preliminary study are confirmed in phase 2 and 3 trials, Rova-T would 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 agent in SCLC. SCLC is an aggressive disease with a median survival of 9 months. Topotecan is the only approved drug for recurrent disease. There is lots of room for improvement,” said lead author Charles M. Rudin, MD, PhD, Chief of Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, New York City.

“These results justify going forward in developing this drug for SCLC in DLL3 overexpressors,” he added.

Rova-T is an antibody-drug conjugate targeted to the DLL3 protein on the surface of tumor cells. Once it binds to DLL3, the drug delivers a payload of chemotherapy with pyrrolobenzodiazepine, which is too toxic to be given to patients directly. DLL3 is overexpressed in 80% of SCLC but it is not expressed on normal cells, theoretically limiting toxicity to normal tissue.

The trial enrolled 74 patients with SCLC who had progressed on at least 1 prior therapy. Fifty percent of the 74 enrollees were chemosensitive, one-third were chemoresistant, and 9% were primary chemorefractory. Patients were allowed 1 to 2 prior therapies, and approximately 50% fell into each of these categories.

Of 60 patients treated with doses in a range of 0.2 to 0.4 mg/kg, 68% achieved clinical benefit (response plus stable disease), and the overall response rate (ORR) was 18% according to Response Evaluation Criteria In Solid Tumors (RECIST).

In a subset of 48 patients with archived tumor tissue available for DLL3 testing, the protein was detectable in 88%, and 67% of tumors had high expression of DLL3 (>50% tumor cells by immunohistochemistry). In DLL3 overexpressors, 89% achieved clinical benefit, and ORR was 38% according to RECIST.

Among 12 patients whose tumors overexpressed DLL3 treated with Rova-T as third-line therapy, 92% received clinical benefit, and ORR was 50% according to RECIST. Currently, there are no approved therapies for third-line treatment of SCLC.

Overall, median survival was 5.8 months, and 1-year survival was 32% in DLL3 high expressors. Dr Rudin said these results were encouraging and compared favorably with outcomes with available drugs.

The most common grade 3 and higher toxicities were thrombocytopenia in 12%, effusions (particularly pleural effusions) in 11%, and skin reactions in 85%. Skin reactions of any grade were seen in 49% but are preventable with medication, he said.

Rova-T is going forward in clinical development. “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,” he said.

“This is another example of a new wave of targeted treatment, which 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 Masters, MD, Christiana Care Helen F. Graham Cancer Center, Wilmington, DE, who was not involved in this study.

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