Biomarker for Immune Response Identified in Relapsed/Refractory DLBCL

In patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), findings from the ongoing phase 2 SPiReL study (NCT03349450) demonstrated that certain gene expressions are associated with response to immunotherapy with the combination of DPX-Survivac, pembrolizumab (Keytruda), and intermittent, low-dose cyclophosphamide. In two subgroups, the combination induced clinical responses and led to disease control.¹

The R/R DLBCL population is often resistant to standard chemotherapy and sometimes to autologous stem cell transplant, representing an area of unmet medical need for new treatments for these patients. Also, due to the toxicities of chimeric antigen receptor T-cell therapy, patients with R/R DLBCL may not derive as much benefit from the treatment as patients with other lymphomas.

It was hypothesized that adding DPX-Survivac to an immunotherapy regimen would benefit this patient population. DPX-Survivac is a T-cell activating therapy that targets the expression of the antigen survivin on cancer cells. As an evaluation of the theory, clinical activity was set as the primary end point of the SPiReL trial.

"Biomarkers are critical for the development of precision medicine in oncology. Not only can they improve the outcome of cancer patients receiving treatments, but they also can greatly reduce the risk inherent in late-stage clinical trials and facilitate the path to market for new treatments such as our new T cell therapy,” said Joanne Schindler, chief medical officer at IMV, Inc, in a statement.² "DLBCL is the most common form of non-Hodgkin lymphoma and relapsed/refractory patients need more accessible and better treatment options. Identifying a biomarker predictive of response for these patients was an important objective of our clinical plan and path to approval.”

The study’s secondary and exploratory end point aimed to determine the safety of the regimen as well as the biologic and immune effects associated with the combination.Additionally, investigators are seeking to identify biomarkers or response in patients with R/R DLBCL.

The target enrollment for the trial is 25 evaluable patients who have an ECOG performance status of 0 to 1 and confirmed survivin expression. In the current analysis, 40 patients were screened and 22 were enrolled. A group of 11 patients were evaluable for efficacy and safety.

Baseline demographics showed the enrolled study population to be 36.4% male and 63.6% female. The median age of the population was 75.5 years (range, 50-82). Disease characteristic screened at baseline showed an ECOG performance status of 1 in 54.5% of patients and a performance status of 2 was observed in 45.5%. Stage III/IV disease was found in 72.7% of patients. The lactate dehydrogenase levels were a median of 248.5 U/L (range, 154-730). Germinal center B-cell–like (GCB) disease was seen in 59.1% of patients, nonGCB subtype was seen in 36.4%, and leg-type disease was found in 4.5% of patients at baseline. The percentage of survivin-positive DLBCL cells was a median of 97% (range, 50%-100%).

In terms of DLBCL type, 27.3% of subjects had transformed disease, 68.2% were relapsed, and 31.8% were refractory.

Prior treatment included prior autologous stem cell transplantation for 18.2% of patients. The population had received a median of 2 prior treatments (range 1-7), and the time from end of last treatment to start of therapy in the study was 235.5 days (range, 21-3423).

Patients were treated with 2 doses of 0.5 mL of DPX-Survivac subcutaneously 3 weeks apart and then up to 6 doses at 0.1 mL every 8 weeks plus intermittent cyclophosphamide at 50 mg twice daily for one week on and one week off as well as 200 mg of intravenous pembrolizumab every 3 weeks. Patients were considered to be evaluable if they had received 3 doses of DPX-Survivac, 4 of pembrolizumab, and had an on-treatment CT scan completed for response assessment.

Seven of the per protocol evaluable patients achieved a response. The percentage of patients with a complete response was 27.3% while 36.4% achieved a partial response, and 18.2% had stable disease. Progressive disease was observed in 18.2% of patients.

Immune infiltrate response was assessed in 10 patients and 6 patients had PD-L1 positive responses, 6 had CD4 positive responses, and 5 had CD8 positive responses. Additionally, 8 of 15 patients were positive for ELIspot responses of survivin-specific cytokine release.

In 33 screened patients, 100% survivin positivity was found by immunohistochemistry. The survivin expression level observed in the 22 enrolled patients was ≥70%. However, no association was observed between survivin expression and response.

Clinical responses were associated with baseline expression levels of PD-L1, however. Patients with higher PD-L1 expression levels were more likely to experience a response to the triplet regimen. The same was true for patients with PD-L1 expression and CD20 positivity in tumor cells.

Overall, these findings suggest that CD20+ and PD-L1 expression at baseline can indicate which patients may respond to immunotherapy. In addition, correlation between PD-L1 expression and T cell response is a novel mechanism of action for immunotherapy.

_References:

_{1. Beristein NL, Brence-Bruckler IA, Forwad N, et al. Baseline PD-L1 expression and tumor immune infiltration is associated with clinical response in patients with r/r DLBCL treated with DPX-Survivac, low-dose cyclophosphamide and pembrolizumab. Presented at the 2020 SITC Virtual Annual Meeting; November 9-14, 2020.}

_{2. IMV’s T Cell Therapy demonstrates 86% objective response rate in combination with Merck’s Keytruda® in PD-L1 positive patients with R/R DLBCL. News release. IMV, Inc. November 9, 2020. Accessed November 11, 2020. https://bwnews.pr/35uxCPD​}