New data suggest that immunotherapy with pidilizumab, an experimental agent that inhibits programmed death (PD), offers promise in the treatment of patients with diffuse large B-cell lymphoma who have undergone autologous hematopoietic stem cell transplantation.
In the past few years, studies have shown dramatic results in several cancer types when the PD pathway is blocked. This has generated a lot of excitement in the oncology community.
In an international phase 2 trial of 66 patients, the 16-month progression-free survival rate was 72% (90% confidence interval [CI], 0.60 - 0.82) with pidilizumab, and the 16-month overall survival rate was 85% (90% CI, 0.74 - 0.92).
The results were "improved compared with historic controls," said senior investigator Leo I. Gordon, MD, professor of cancer research at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago.
"This is the first demonstration of clinical activity of PD-1 blockade in diffuse large B-cell lymphoma," Dr. Gordon toldMedscape Medical News. "Given our results, PD-1 blockade after autologous hematopoietic stem cell transplantation with pidilizumab may represent a promising therapeutic strategy in this disease."
Dr. Gordon added that pidilizumab is safe and points to a new direction for cancer-fighting agents, but cautioned that "we need to confirm these results in larger phase 3 trials."
The study was published online October 14 in the Journal of Clinical Oncology.
Pidilizumab (CureTech) is an anti-PD-1 humanized immunoglobulin monoclonal antibody that has shown antitumor activity in animal experiments, and has demonstrated safety and early evidence of clinical activity in a phase 1 trial of patients with advanced hematologic malignancies.
Essentially, the agent increases the immune response by inhibiting apoptosis in cancer-fighting cells. There is also a suggestion that the antibody, besides having an enhancing effect on the immune system, also directly kills tumor cells, Dr. Gordon said.
Previous studies of this treatment strategy have shown dramatic results in several cancer types, includingmelanoma (nivolumab, Bristol Myers Squibb) and non-small cell lung cancer (MPDL3280A, Genentech).
Two other PD-1 agents have shown what experts have described as "remarkable" results in colorectal cancer, prostate cancer, and renal cancer that has progressed despite standard therapies.
Dr. Gordon and colleagues postulated that reconstituting the immune landscape after autologous hematopoietic stem cell transplantation could break immune tolerance through PD-1 blockade.
Their study involved patients with chemotherapy-sensitive disease who showed at least partial remission on CT after salvage therapy.
For the 24 high-risk patients who showed signs of disease on PET after salvage chemotherapy, 16 months after the first treatment with pidilizumab, progression-free survival was 0.70 (90% CI, 0.51 - 0.82). For the 35 patients with measurable disease after autologous hematopoietic stem cell transplantation, the overall response rate was 51%.
Treatment was associated with increases in circulating lymphocyte subsets, including PD-L1E-bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab.
"Many tumors exhibit increased PD-1 expression," said Alain H. Rook, MD, professor of dermatology at the University of Pennsylvania in Philadelphia, who was asked by Medscape Medical News to comment on the study.
"Emerging data for several tumors indicate that removing this particular immune checkpoint inhibitor with anti-PD-1 can take the brake off the immune response, leading to improved outcomes," he explained.
Dr. Rook emphasized that he is a dermatologist and treats Sézary syndrome and similar diseases, but not hematologic malignancies. However, his research has focused on PD-1 blockade, and his lab was the first to publish on the increased expression of PD-1 in certain T-cell lymphomas.
"Metastatic melanoma treatment is now in phase 3 trial with anti-PD-1," he added.
"This is an important study because it illustrates how the T-cell immune checkpoint antibodies may hold promise in hematologic malignancies as well," added Madhav Dhodapkar, MD, Arthur H. and Isabel Bunker professor of medicine and immunobiology and chief of the section of hematology at the Yale Cancer Center, Yale School of Medicine, in New Haven, Connecticut.
"I think clinicians should stay tuned for rapidly growing data about this and other similar antibodies in hematologic malignancies," said Dr. Dhodapkar.
Dr. Gordon reports a financial relationship with CureTech. Dr. Rook and Dr. Dhodapkar have disclosed no relevant financial relationships.
J Clin Oncol. Published online October 14, 2013. Abstract
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