Initial encouraging news from a first-in-human trial suggests that the antibody-drug conjugate rovalpituzumab tesirine (Rova-T) may turn out to be a new option for patients with small cell lung cancer (SCLC) whose tumors overexpress delta-like protein 3 (DLL3). Study results were presented at the 2016 ASCO Annual Meeting.1 Not only is rovalpituzumab tesirine the first molecularly targeted agent to show promise in SCLC, but also preliminary results suggest that DLL3 will be a marker for patient selection for this treatment. If so, it would be the first predictive marker for SCLC.
We think that this drug [rovalpituzumab tesirine] may hit both bulk tumor and a subpopulation of cancer stem cells. Ultimately, this type of therapy may offer long-term benefit.— Charles M. Rudin, MD, PhD
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“The goal is to give the right patient the right drug at the right time,” said lead author Charles M. Rudin, MD, PhD, Chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center in New York. “These results justify going forward in developing this drug for SCLC, particularly in DLL3 overexpressors.”
“Take these results with caution, but they look promising for a new class of agent in SCLC. SCLC is a terrible disease, with a median survival of 9 months for patients with extensive-stage disease. Topotecan is the only approved drug for recurrent disease. There is lots of room for improvement,” Dr. Rudin told listeners.
“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, who was not involved in this study.
Rovalpituzumab tesirine is an antibody-drug conjugate targeted to DLL3 on the surface of tumor cells, delivering a toxic payload of pyrrolobenzodiazepine, an agent too potent to give on its own but safer when delivered in this tumor-directed way. Rovalpituzumab tesirine targets DLL3, which is highly expressed in about two-thirds of SCLC cases but not in normal cells, limiting the toxicity to normal tissue.
The first-in-human trial included 74 patients with SCLC that had progressed on at least one prior therapy. Of 60 patients treated with doses of rovalpituzumab tesirine in the range of 0.2 to 0.4 mg/kg, 68% achieved clinical benefit (response plus stable disease), and the overall response rate was 18% according to RECIST (Response Evaluation Criteria in Solid Tumors).
In a subset of 48 patients with archived tumor tissue available for DLL3 testing, the protein was detectable in 88%, and 67% of patients’ tumors had high expression of DLL3 (ie, immunohistochemistry ≥ 50% of tumor cells). In DLL3 overexpressors receiving either second- or third-line therapy with rovaltpituzumab tesirine, 89% achieved clinical benefit, and the overall response rate was 38% according to RECIST.
Among 12 DLL3 overexpressors receiving third-line therapy with rovalpituzumab tesirine, responses were particularly robust. A total of 92% received clinical benefit, and the overall response rate was 50% according to RECIST. Despite the small numbers, these are encouraging results, given there are no currently approved therapies for third-line treatment of SCLC.
Of the 74 enrollees, 50% were chemosensitive, about one-third were chemoresistant, and 9% were primary chemorefractory. Patients were allowed one to two prior therapies, and the study population was evenly split in this regard.
Toxicity of rovalpituzumab tesirine was manageable. The most common grade 3 and higher toxicities were thrombocytopenia in 12%, serosal effusions in 11%, and skin reactions in 8%. Skin reactions of any grade were seen in 49%.
Median overall survival was 5.8 months, and 1-year overall survival was 32% in DLL3 high expressors. “This is a very encouraging early signal,” Dr. Rudin emphasized. “[Rovalpituzumab tesirine] looks good compared to expected outcomes with available drugs for SCLC.”
If these results are confirmed in subsequent clinical trials, rovalpituzumab tesirine could be the first biomarker-directed therapy for SCLC. “A number of studies of [rovalpituzumab tesirine] are on the launch pad, including a basket trial for other tumors that express DLL3. We will also be studying [rovalpituzumab tesirine] in combination with other drugs and with immunotherapy,” revealed Dr. Rudin.
“The numbers are small. We think that this drug may hit both bulk tumor and a subpopulation of cancer stem cells. Ultimately, this type of therapy may offer long-term benefit. The tail of the curve will be important. Remember, the median is not the message,” Dr. Rudin said. ■
Disclosure: The study was sponsored by AbbVie Stemcentrx. Dr. Rudin has consulted for AbbVie, AVEO, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Merck, and Novartis and has received research funding from BioMarin. Dr. Masters reported no potential conflicts of interest.
To me, what is intriguing about these data is the efficacy signal in the third-line setting, especially for the biomarker-positive patients, with a clinical benefit of 92%.— Taofeek Kunle Owonikoko, MD
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Formal discussant Taofeek Kunle Owonikoko, MD, of...!-->!-->