SAN FRANCISCO—There may be a ray of hope for high-grade glioma patients who progress through multiple lines of drug therapy.
Nektar Therapeutics—a biopharmaceutical company developing novel therapeutics in pain, oncology and other areas based on its PEGylation and advanced polymer conjugation technology platforms—announced new data from an investigator-sponsored study at the recent American Society of Clinical Oncology meeting. The study was conducted at Stanford Cancer Institute under the direction of Dr. Lawrence Recht, a professor of neurology and neurosurgery at the Stanford University School of Medicine, with co-investigator Dr. Seema Nagpal, a clinical assistant professor of neurology and neurological sciences at the medical school.
The Phase 2 study of the company’s NKTR-102 (etirinotecan pegol) in patients with Avastin-refractory (resistant) high-grade glioma has produced positive results, with 55 percent of patients achieving six-week progression-free survival and 15 percent of the patients achieving a partial response. Because researchers were aiming for at least 25 percent of patients to show six-week progression-free survival, the study has exceeded expectations.
NKTR-102 is a topoisomerase I inhibitor intended to interfere with the action of topoisomerase enzymes, which break and rejoin DNA strands so that a cell can divide and grow. NKTR-102 is designed to concentrate in the tumor tissue, increasing its antitumor activity and reducing the peak exposures seen in some other chemotherapy drugs that diffuse more quickly through the body.
“Patients with Avastin-refractory high-grade glioma currently have little to no treatment options to help them manage their disease,” says Recht. “High-grade gliomas are the most common and most aggressive primary brain tumors. Prognosis for patients with high-grade gliomas remains poor with estimated median survival of 12 to 18 months.”
Recht adds that recurrence of the cancer after initial therapy with temozolomide and radiation is nearly universal. Since May 2009, the majority of patients in the United States with an initial recurrence of high-grade glioma receive bevacizumab, which has response rates from 32 percent to 62 percent and has improved median overall survival in patients with recurrent high-grade gliomas. Normally, the response to bevacizumab is short-lived, and almost 100 percent of patients eventually lose their battle despite their initial positive reaction to the drug.
“No chemotherapeutic agent administered following progression through bevacizumab has made a significant impact on survival,” according to Recht. “Patients progress to death within one to five months after resistance develops. Patients with high-grade gliomas who have progressed through bevacizumab represent a population in dire need of new therapies.”
Etirinotecan pegol is a targeted topoisomerase I inhibitor designed for prolonged tumor cell exposure. Etirinotecan pegol is believed to penetrate the vasculature of the tumor environment more readily than normal vasculature, increasing the concentration of active drug within tumor tissue to enhance antitumor activity.
The trial enrolled 20 patients with high-grade glioma from August 2012 to May 2013. Patients had a median Karnofsky Performance Status Scale score of 70—the scale is a standard way of measuring the ability of cancer patients to perform ordinary tasks. Patients had received a median of three lines of prior therapy, including recurrence following treatment with Avastin.
Patients received a median of three cycles of NKTR-102 once every three weeks as monotherapy. Six-week progression-free survival in at least 25 percent of the patients was needed to reject the null hypothesis for the primary endpoint.
“In this study we saw three patients—15 percent, all with glioblastoma—with confirmed partial responses on single-agent NKTR-102 and an additional eight patients—40 percent—who had stable disease as a best response,” Recht says.
“Though participants in this trial were heavily pretreated and more neurologically symptomatic than many clinical trial patients, we observed low toxicity with three partial responses,” Nagpal adds.
The pharmacokinetic profile of NKTR-102 provides continuous exposure of active drug throughout the entire chemotherapy cycle, with reduced peak exposures that can be associated with toxicities, according to Nektar. NKTR-102 is currently being evaluated in a pivotal Phase 3 clinical study in patients with advanced breast cancer (the BEACON study). In November 2012, NKTR-102 was designated a Fast Track development program by the U.S. Food and Drug Administration for the treatment of patients with locally recurrent or metastatic breast cancer progressing after treatment with ATC. Additional investigator-sponsored studies at Roswell Park Cancer Institute and the University of Pennsylvania Abramson Cancer Center are ongoing to evaluate NKTR-102 in patients with small-cell lung cancer and non-small cell lung cancer, respectively.