A phase II study indicates that sacituzumab govitecan (IMMU-132), a Trop-2–specific antibody linked to the irinotecan metabolite SN-38, prolongs the progression-free survival of patients with advanced triple-negative breast cancer. IMMU-132 is well tolerated, causing fewer and more manageable side effects than irinotecan.
Results from a multicenter phase II study suggest that sacituzumab govitecan (IMMU-132; Immunomedics), an antibody–drug conjugate (ADC) targeting Trop-2, may be effective in patients with metastatic triple-negative breast cancer (TNBC). The data were presented by David Goldenberg, MD, founder and chairman of Immunomedics in Morris Plains, NJ, during the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held in Boston, MA, November 5–9.
Trop-2 is a little-known protein that's involved in calcium metabolism and thought to be a potential oncogene. It's “upregulated on the surface and inside a large number of cancer cells,” Goldenberg said; the study enrolled patients with diverse solid tumors, and over 80% had moderate to strong expression of this cancer antigen.
IMMU-132 consists of a Trop-2–specific antibody linked to SN-38, the active metabolite of irinotecan, a drug derived from the cytotoxic alkaloid camptothecin that interferes with DNA replication by blocking topoisomerase I. “Preclinically, we've shown that our ADC delivers approximately 136 times more SN-38 than the amount that reaches the tumors of patients given irinotecan,” Goldenberg said.
As of October, the objective response rate to IMMU-132 among 54 assessable patients—all with advanced TNBC and treated with an average of five prior regimens—was 31.5%. Two patients responded completely, and 15 had partial responses, eight of which were confirmed. Another 24 patients experienced stable disease. The median progression-free survival (PFS) was 7 months, which was “interim data, yet already almost double the typical PFS of 3 to 4 months for TNBC treated with standard agents,” Goldenberg pointed out. The median overall survival has not been reached.
“Considering that TNBC is the most lethal of breast cancers, I'm impressed that nearly a third of our study patients achieved an objective response that has been durable so far,” Goldenberg said. He and his colleagues are also gratified that IMMU-132 has a very manageable toxicity profile—the main side effects are neutropenia and diarrhea, but the latter is far less severe than with irinotecan, which carries a black-box warning from the FDA.
“It's very well tolerated, so patients can receive long and repeated courses of treatment, at higher than usual doses,” Goldenberg said. “Although IMMU-132 works quickly, the longer it's given, the more tumor shrinkage you see.” IMMU-132 has received fast track designation from the FDA, he added, with a pending randomized phase III trial to further evaluate this drug in TNBC.
According to Goldenberg, IMMU-132 “isn't limited to TNBC”—the researchers have seen promising activity in small cell and non–small cell lung cancers, as well as urothelial, endometrial, and esophageal cancers. The company has also developed cell lines to more closely investigate various mechanisms of camptothecin resistance, in hopes of eventually overcoming this problem. In addition, Goldenberg and his group are probing preclinical data that suggest synergy between IMMU-132 and PARP inhibitors, which target DNA repair.
“Irinotecan is an active drug, but problematic because the diarrhea it induces can be intolerable,” said Lee Helman, MD, acting director of the NCI's Center for Cancer Research in Bethesda, MD. “Developing SN-38 into an ADC is a brilliant idea; in some sense, this is taking a stupid drug and making it smarter.”
- ©2015 American Association for Cancer Research.