Dr. Charles M. Rudin
These early-phase findings are generating considerable excitement considering that SCLC is a notoriously recalcitrant disease with a dearth of therapeutic options. Since the 1970s, little progress has been made with regard to clinically meaningful endpoints for for SCLC. “Importantly, there’s been no biomarker-directed therapies defined for this patient population, which I think has limited progress for the field,” explained Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center, who presented the rovalpituzumab tesirine results.
To gain ground against this highly deadly malignancy, researchers endeavored to capitalize on the recent observation that DLL3, an atypical inhibitory Notch ligand implicated in regulating cancer stem cells, is highly expressed on neuroendocrine tumors, including more than 80% of SCLCs and large-cell neuroendocrine cancers. What makes DLL3 so attractive as a potential drug target is that the ligand is replete on the surface of both cancer stem cells and mature neuroendocrine tumor cells, but not on normal cells comprising adult tissues.
Rovalpituzumab tesirine works by relying on the DLL3-targeting ability of the SC16 humanized monoclonal antibody to deliver a lethal payload to SCLC cells in the form of the pyrrolobenzodiazepine (PBD) dimer toxin, an agent far too toxic to be used on its own. SC16 acts as a Trojan horse that brings the PBD warhead to malignant cells and facilitates its internalization, upon which PBD is liberated from the antibody, binds to DNA, and exerts irreparable damage.
The current first-in-human study aimed to test the safety and efficacy of rovalpituzumab tesirine in patients with progressive metastatic SCLC after at least one prior line of systemic therapy. High DLL3 expression in tumor tissue was not a prerequisite for study entry. However, all available archived tumor tissue was retrospectively evaluated for DLL3 expression by immunohistochemistry.
In total, 74 patients with SCLC were enrolled at dose levels ranging from 0.05 to 0.8 mg/kg delivered either every 3 weeks or every 6 weeks. Among 48 patients with archived tissue, 88% of patients had tumors with DLL3 expressed on at least 1% of tumor cells, and 67% had tumors with DLL3 expressed on at least 50% tumor cells.
The overall response rate (ORR) among patients who received rovalpituzumab tesirine at doses of 0.2 to 0.4 mg/kg—on par with the recommended phase II dose of 0.3 mg/kg—turned out to be 18% among all 60 individuals and 39% among the 26 individuals with at least 50% DLL3 tumor expression. When factoring in stable disease, the clinical benefit rate (CBR) for these two respective groups was 68% and 89%.
“If you look at the patients in whom we did have available tissue for analysis, all of the responses are within the group that had DLL3 high [expression],” suggesting that DLL3 can be used as a selective biomarker to pick out those patients who potentially stand to benefit from administration of rovalpituzumab tesirine (Fig. 1), Dr. Rudin explained.
Dr. Taofeek Kunle Owonikoko
The toxicity associated with rovalpituzumab tesirine was deemed manageable. The most common treatment-related toxicities of grade 3 or higher included thrombocytopenia (11%); serosal effusions consisting of pleural or pericardial effusion, ascites, or capillary leak syndrome (11%); and skin reactions (8%).
“I think these results clearly justify further clinical development, and in fact that clinical development has already launched,” Dr. Rudin indicated. Registrational trials of rovalpituzumab tesirine in the subset of patients with relapsed/refractory, DLL3-expressing SCLC are planned and ongoing, as well as an early-phase study exploring potential first-line use of rovalpituzumab tesirine in multiple DLL3-expressing tumor types.
In his critique of Dr. Rudin’s study, Taofeek Kunle Owonikoko, MD, PhD, of Emory University School of Medicine, commented, “The future of rovalpituzumab tesirine I think will be defined by how well the investigators are able to further improve on its strengths and minimize its weakness… I think the convenient infusion schedule and activity seen in the third-line setting are really encouraging.” However, he sees the treatment-related thrombocytopenia as a potential challenge to patients with extensive bone involvement. He further noted that the DLL3 biomarker definition of greater than 50% expression must be confirmed in the prospective randomized study, which is currently ongoing.
-- Kara Nyberg, PhD