An experimental drug that activates T-cells and promotes an immune response to fight tumors has shown promising early results in patients with kidney cancer, melanoma and non-small cell lung cancer.
Vanderbilt-Ingram Cancer Center investigators Leora Horn, M.D., Jeffrey Sosman, M.D., and researchers from several other cancer centers tested the new compound. The results of the Phase I/II clinical trial, led by investigators at Johns Hopkins Kimmel Cancer Center, Baltimore, were published in the June 28 issue of the New England Journal of Medicine and were presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).
The body’s own immune system normally acts as a defense against dangerous organisms or defective cells. However, there are important controls on these immune responses so they do not go out of control. In cancer, tumors adopt these same controls to prevent the immune system’s attacks.
One of the proteins that shield tumors is called PD-L1 (short for programmed death ligand 1). Bristol-Myers Squibb has developed an antibody drug (BMS-936558) which blocks PD-1, which normally binds to PD-L1.
Investigators tested the drug in 296 patients whose cancers had not responded to previous therapies. The drug was given as an infusion every two weeks and patients were assessed every eight weeks.
There was evidence of tumor regression in 18 percent of non-small cell lung cancer patients, 28 percent of melanoma patients and 27 percent of renal-cell (kidney cancer) patients.
Even more striking was the 33 percent response rate in squamous cell cancer of the lung, a disease for which there are limited treatment options.
“Lung cancer has never before been considered a tumor that would respond to immune-based therapy, so this makes the findings even more exciting,” said Sosman, director of the Melanoma and Tumor Immunotherapy Program at VICC.
The response to the antibody therapy also was durable — 20 of 31 responses lasted at least a year in patients who were followed for a year or more.
While the drug appeared to have a positive response in lung, melanoma and kidney cancer, it did not produce the same effect in patients with advanced prostate cancer or colorectal cancer.
“We, and more so, our patients, are encouraged by the positive response from one antibody therapy drug for three different forms of cancer,” said Horn, clinical director of the Thoracic Oncology Program at VICC.
“Based on this early data, additional clinical trials are being initiated in lung cancer, renal cancer and melanoma.”
The researchers wanted to know if the presence of PD-L1 on the surface of tumor cells could help predict whose tumors may respond to this therapy. They tested pretreatment tumor specimens from 42 patients. None of the 17 patients whose tumors were PD-L1 negative had a response to therapy while 36 percent of those with PD-L1 positive tumors had an objective response.
“These data indicate that we may be able to select those patients who are most likely to respond to the new drug, based on whether their tumors are positive or negative for the PD-L1 protein. This would be the first such biomarker we have ever had in cancer immunotherapy,” explained Sosman.
Three of the 296 patients (1 percent) died after developing a lung condition called pneumonitis. The most common problems were fatigue, decreased appetite, gastrointestinal distress, rash, fever and headache.
The clinical trial was funded by Bristol-Myers Squibb and Ono Pharmaceutical, and through grants from the National Institutes of Health (5R01 CA142779) and the Melanoma Research Alliance.
Other research centers involved in the study included Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center, Boston, Mass., Yale Cancer Center, New Haven, Ct., University of Michigan, Ann Arbor, Mich., Carolina BioOncology Institute, Huntersville, N.C., Memorial Sloan-Kettering Cancer Center, New York, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tenn., Cincinnati Hematology-Oncology, Cincinnati, Ohio, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fl., Bristol-Myers Squibb, Milpitas, Calif., and Princeton, N.J.
