Smoking causes most cases of SCLC, a highly malignant form of lung cancer. Credit: Phanie / Alamy Stock Photo

AbbVie will acquire South San Francisco, California–based Stemcentrx in a deal that may be worth as much as $10 billion. The buyout announced in April gives the North Chicago–based pharma the drug Rova-T (rovalpituzumab tesirine). This is Stemcentrx's most advanced drug and could become the first biomarker-directed agent for small cell lung cancer (SCLC), a malignancy that has not seen a novel treatment in several decades. Stemcentrx will receive $5.8 billion in cash and stock upfront, and up to $4 billion in cash on achieving certain regulatory and clinical milestones.

But Rova-T's recently presented survival data could disappoint investors, Geoff Meacham, stock analyst at Barclays said in a note to clients following a presentation in June at the ASCO Annual Meeting in Chicago. Stemcentrx showed that in a phase 1 trial of 74 patients with SCLC, 18% achieved either a complete response or a partial response with median overall survival at 4.6 months. In patients who had a DLL3 expression level of at least 50%, 39% had a response, with an overall survival of 5.8 months.

Charles Rudin, chief of thoracic oncology at Memorial Sloan Kettering Cancer Center in New York City, who presented the data at the meeting, says the results are “substantially better than we would expect” with conventional therapy. One-year survival of patients on Rova-T was 32% compared with the 12% historically seen with the chemotherapeutic agent Hycamtin (topotecan) from GlaxoSmithKline, the current standard of care, says Rudin. SCLC, a pulmonary neuroendocrine tumor, accounts for about 10–15% of all lung cancers, according to the American Cancer Society. It is among the most difficult cancers to treat.

Rova-T is a Trojan horse. The antibody–drug conjugate is made up of three components: an antibody, a linker and the active chemotherapy, DNA-damaging pyrrolobenzodiazepine dimer. The anti-DLL3 humanized monoclonal antibody attaches to the cell, and the cytotoxic agent is then swept into the tumor.

Evidence implicating DLL3 in SCLC has been mounting. Normal DLL3 expression is highest in fetal brain but, in adulthood, it is present in SCLC and other lung neuroendocrine tumors that develop mainly in patients with a history of smoking (Thorac. Surg. Clin. 24, 257–266, 2014). DLL3 presence is associated with the transcription factor ASCL1, known to be implicated in fetal lung development and activated in human SCLC tumors (Cancer Res. 69, 845–854, 2009).

DLL3 also contributes to the neuroendocrine cancer phenotype by acting as a ligand for the Notch pathway, which is downstream of ASCL1 and is also dysregulated in many cancers. Rova-T does not inhibit DLL3 or the Notch pathway; it just uses DLL3 as a way to hitchhike into the cell and deliver its load of a chemical toxin that kills the cell from inside (Sci. Transl. Med. 7, 302ra136, 2015).

As an antibody–drug conjugate, Rova-T is comparable to Roche's Kadcyla (ado-trastuzumab emtansine), a monoclonal antibody–drug conjugate to treat HER2-positive metastatic breast cancer, says Scott Dylla, CSO at Stemcentrx and one of the company's founders. There is one strategic difference, though. Because DLL3 is a target not expressed in normal tissues, the chemotoxic agent works only on cancer stem cells, which maximizes the efficacy and minimizes the toxicity of the drug, according to Dylla.

“We think we may be able to focus therapy on patients that will benefit,” says Rudin. AbbVie is planning to study Rova-T across multiple solid tumor types that express DLL3, including metastatic melanoma, glioblastoma multiforme, prostate and pancreatic cancers. In addition to Rova-T, Stemcentrx has four early-stage compounds targeting solid tumors, and a stem cell technology platform to identify and screen targets.