Abstract
The anti-PD-1 antibody drug BMS-936558 (Bristol-Myers Squibb) demonstrated encouraging results in a phase I clinical trial as a targeted immune therapy for patients who had been heavily treated for several forms of solid tumors.
Immune therapy reduces tumor size in several types of advanced cancer.
The anti–PD-1 antibody drug BMS-936558 (Bristol-Myers Squibb) demonstrated encouraging results in a phase I clinical trial as a targeted immune therapy for patients who had been heavily treated for several forms of solid tumors. Suzanne Topalian, MD, professor of surgery and oncology at Johns Hopkins University School of Medicine, presented data on the trial's outcomes at a press conference on June 1 at the American Society of Clinical Oncology annual meeting in Chicago. The trial, which enrolled 296 patients, also was reported in the New England Journal of Medicine.
Topalian and her colleagues found that BMS-936558 reduced tumor size in 28% of melanoma patients, 27% of kidney cancer patients, and 18% of non–small cell lung cancer (NSCLC) patients. Additionally, 6% of melanoma patients, 7% of NSCLC patients, and 27% of kidney cancer patients experienced stable disease for a period of at least 6 months following BMS-936558 treatment. Response to the drug lasted for a year or longer in 20 of 31 patients in the trial.
The researchers were particularly struck by the results in treating advanced lung cancer, with Topalian noting that the findings show what is probably the strongest anti–lung cancer activity observed to date with any immunotherapy.
The agent binds to and inhibits the activation of programmed death-1 (PD-1), a protein expressed on the surface of T cells that acts to repress immune activity. When PD-1 interacts with programmed death ligand-1 (PD-L1), which is often expressed by cancer cells, the cells are protected from immune destruction. BMS-936558, however, aims to prevent this shield activity, releasing the PD-1 brake on the immune system and enabling it to mount an attack on the cancer cells.
Analyses of tumor biopsies collected during the trial suggested that PD-L1 indeed may be a predictive biomarker for patient response to BMS-936558. About one third of patients with PD-L1–positive tumors responded to the antibody; no response was observed in any patients whose tumors were negative for PD-L1. Topalian stressed, however, that these correlations represent very preliminary data and require further investigation.
In the trial, patients were given the drug intravenously over a mean period of 15 weeks. Side effects were similar to those of other immune-related therapies, Topalian said, and included fatigue, rash, and diarrhea. About 14% of the patients suffered from serious toxicities consistent with immune-related causality, and 3 patients died from lung inflammation thought to be associated with the drug.
In a separate trial, also reported in the New England Journal of Medicine, a blocking antibody against PD-L1 produced responses in melanoma, lung cancer, and kidney cancer.
“We feel that these 2 studies are, in a sense, bookends,” said Topalian. “They both point to the importance of the PD-1 pathway in cancer therapy across multiple histologies.”
However, in both trials, patients with colon and pancreatic cancers did not show tumor shrinkage.
Many biotech and pharmaceutical firms are developing anti-PD-1 therapies. Evidence suggests that these agents may provide greater activity and fewer side effects than previous immunotherapies that targeted the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune cell checkpoint protein, said Antoni Ribas, MD, PhD, of the University of California, Los Angeles in an accompanying comment in the New England Journal of Medicine.
“The use of PD-1 blockade—with its reduced rate of toxic effects and potential ability to further select patients who have an increased likelihood of tumor response—may well have a major effect on cancer treatment,” Ribas suggested.
