ASH: Anti–PD-1 Immunotherapy Shows Activity in Relapsed Lymphoma Patients

The combination of rituximab (Rituxan) and the novel immunotherapy pidilizumab (CT-011) is both active and well tolerated in follicular lymphoma patients, according to results of a phase II trial presented by Jason R. Westin, MD, of the MD Anderson Cancer Center in Houston, at the American Society of Hematology (ASH) meeting in Atlanta.

Follicular lymphoma; source: Patho, Wikimedia Commons

Data from 29 patients from the single-arm trial in relapsed follicular lymphoma patients showed a 66% (19 patients) overall response rate-15 patients were complete responses and 4 patients were partial responses. The combination improved upon the 40% overall response rate seen for monotherapy rituximab treatment in relapsed follicular lymphoma patients. Responses to the combination therapy did not correlated with prior chemotherapy, the number of prior rituximab doses, or duration of response to prior therapy.

“There are currently many exciting therapies including conventional chemotherapies, small molecule inhibitor tyrosine kinase inhibitors and immune modulating therapies under development in follicular lymphoma,” Westin told Cancer Network. “Our data with pidilizumab compare favorably with previous clinical trials that utilized rituximab retreatment in patients with relapsed follicular lymphoma who had previously responded to rituximab.” In a similar patient population, previous complete responses were only 11% with rituximab alone.

“The impressive and durable response of the single patient with follicular lymphoma on the phase I trial of this agent spoke to its potential in this disease,” Westin added.

The median time to response was 88 days with a total of 17% of patients seeing an initial response to treatment more than 3 months after starting the therapy. The progression-free survival at a median of 14 months of follow-up was 21.1 months but the progression-free survival for the responders, currently 19 patients, has not yet been reached.

Patients in the trial had a median age of 61 and had had from one to four previous therapies. All of the patients had received rituximab single-agent therapy previously for a median of six doses, 21% had had prior rituximab maintenance therapy and 69% had prior chemotherapy or chemoimmunotherapy. In the current combination regimen, patients received a median of 10 infusions of CT-011. The highest number of infusions per patient was 12.

Patients received 3 mg/kg CT-011 every 4 weeks for four infusions and rituximab at 375 mg/m² IV on a weekly basis for 3 weeks starting 2 weeks after the first CT-011 infusion. Those patients who achieved a complete or partial response or stable disease could get an additional eight infusions every 4 weeks. Blood and tumor samples were also taken for immune cell response analyses.

According to the study authors, there were no high-grade toxicities and no patient discontinued therapy due to toxicity.

While clinical response did not correlate with either the Follicular Lymphoma International Prognostic Index 1 (FLIPI1) or FLIPI2, progression-free survival was significantly associated with both FLIPI1 and FLIPI2 (P = .0056 and P = .0344, respectively). Both of these indices were developed as treatment decision tools, based on prospective clinical data. The independent factors used to predict progression free survival include levels of beta2-microglobulin, longest diameter of the largest lymph node involved, bone marrow involvement, and hemoglobin levels.

Follicular lymphoma is a type of B-cell lymphoma and a form of non-Hodgkin lymphoma, that is slow growing and indolent. Follicular lymphoma accounts for approximately 20% to 30% of all non-Hodgkin lymphoma, and although not curable, patients can live for years with this type of lymphoma. Current treatment options for patients, aside from watchful waiting, include chemotherapy and rituximab, which was approved for first-line follicular lymphoma in 2006. Rituximab is a monoclonal antibody that targets the CD20 protein found on B cells.

According to Dr. Westin, follicular lymphoma is one of the most immune-responsive cancers. Follicular lymphoma can regress without therapy, which is assumed to be related to a spontaneous immune response and is also responsive to certain immune-based therapies. “We believe a major reason that follicular lymphoma is so amenable to immunotherapy is that there is a significant interaction between FL and the intact immune system,” said Westin. “FL has the strongest data to date to support investigation of immune therapies.”

The rationale for using CT-011, an immunotherapy antibody that blocks the programmed death (PD)-1 receptor, is to boost the function of the immune system by inhibiting PD-1 whose function, in part, is to inhibit T-cell response.

CT-011 is a humanized anti–PD-1 antibody that blocks the interaction of PD-1 with its ligand, PDL-1, enhancing the antitumor function of both T cells and natural killer cells. Rituximab is thought to function through activation of natural killer cells, resulting in cellular cytotoxicity. The current trial aimed to test whether the combination of the two antibodies was additive or synergistic.

Whether pidilizumab is effective on its own in follicular lymphoma is unclear, as not enough patients have been treated. “The mechanism of action of pidilizumab should allow for single agent activity, although we believe the combination of rituximab and pidilizumab should yield greater results than with CT-011 alone,” said Westin.

Understanding which patients will respond well to immunotherapy is important and thus far has proved difficult. A study to identify a predictive gene signature in the follicular lymphoma patients treated with pidilizumab in the current trial to facilitate identification of patients who are most likely to respond to the therapy. The preliminary results were presented at the ASH meeting. “Further identification and validation of the selection methods will allow for future improvements in outcomes with immunotherapies, both for hematologic and solid tumor malignancies,” said Westin.

CT-011, developed by Israel-based Curetech Ltd, is also being tested in phase II trials in metastatic melanoma, colorectal cancer in combination with chemotherapy, advanced renal cell and prostate cancers, as well as in acute myeloid leukemia.