Immune Checkpoint Inhibitor Shows Promise for Lymphoma, Other Cancers

Immune Checkpoint Inhibitor Shows Promise for Lymphoma, Other Cancers
The immune checkpoint inhibitor BMS-986016 has shown promising results in patients with multiple hematological and solid malignancies either alone or in combination with Opdivo (nivolumab), according to interim results from two Phase 1/2a clinical trials.
The findings were recently presented at the Society for Immunotherapy of Cancer (SITC) meeting Nov. 9-13 in National Harbor, Maryland, in a poster presentation titled “Initial Experience Administering BMS-986016, a Monoclonal Antibody That Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination With Nivolumab to Patients With Hematologic and Solid Malignancies.”
Although PD-1 and CTLA4 are the most studied immune checkpoints, researchers have identified several other molecules that seem to prevent cytotoxic T-cells from recognizing and attacking tumor cells.
One of them that has recently emerged as promising in the cancer immunotherapy field is the LAG-3 protein, which not only activates effector T-cells but also inhibits the immunosupressive regulatory T-cells (called Tregs).
Preclinical data has suggested that blocking LAG-3 and PD-1 simultaneously may function synergistically to restore effector T-cell activation and improve anti-tumor immunity, which encouraged researchers to take the LAG-3 inhibitor BMS-986016 into clinical trials.
The CA224020 Phase 1/2a trial (NCT01968109) is a dose-escalation and cohort expansion study designed to assess the safety, tolerability, and effectiveness of BMS-986016 alone or in combination with Opdivo in patients with advanced solid tumors. In the single therapy arm, the study enrolled six to 12 patients with non-small cell lung cancer (NSCLC) who have already received anti-PD-1 therapy, and six to 12 patients with renal cell carcinoma.
The combination arm included patients with either gastric cancer, liver cancer, head and neck cancer, and renal cell carcinoma who never had immunotherapy, as well as melanoma and NSCLC patients who are newly diagnosed or who have received prior immunotherapy. The study was designed to include 26 to 39 patients with each tumor type. Patients received BMS-986016 every two weeks for up to 96 weeks.
At the time of data cut-off in October 2016, 80 patients had been treated in this trial. Results suggest that the anti-PD-1 plus anti-LAG-3 combo worked in the solid tumor group, with 28 of the study patients still receiving treatment at the time of data cut-off. The combo treatment demonstrated a manageable safety profile, and the maximum tolerated dose was not identified.
The CA224022 Phase 1/2a trial (NCT02061761) is a dose-escalation and cohort expansion study designed to evaluate BMS-986016 alone or in combination with Opdivo in patients with relapsed or refractory B-cell malignancies.
The study included patients with chronic lymphocytic leukemia, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma in the single therapy arm, while Hodgkin’s lymphoma patients who had not been treated with anti-PD-1/PD-L1 therapies or with diffuse large B-cell lymphoma (DLBCL) were assigned to the combination arm.
In addition, the study was designed to include three to six patients with each tumor type in the monotherapy arm and 15 to 25 patients with each tumor type in the anti-LAG-3 plus Opdivo arm. Patients received treatment every two weeks for up to 96 weeks.
Results showed preliminary evidence of clinical benefit in patients with DLBCL, marginal zone lymphoma, and Hodgkin’s lymphoma, with no Grade 3 or higher adverse events observed in more than two patients. The maximum tolerated dose of BMS-986016 was not determined.
Three additional case studies were also shown in the poster presentation. The first was a 61-year-old man with advanced melanoma (without BRAF mutations) who progressed after three months on Opdivo. After being treated with BMS-986016 and Opdivo, the patient showed marked decreases in the volume of a skin lesion in the right leg and in the associated lymph node.
A second case report from a 67-year-old man with KRAS-positive lung adenocarcinoma who was refractory to chemotherapy and Opdivo, showed a partial response that lasted for two months following anti-LAG-3 monotherapy.
Finally, the researchers reported the case of a 54-year-old woman with marginal zone B-cell lymphoma who was refractory to chemotherapy and autologous stem cell transplant. The patient received anti-LAG-3 monotherapy for 96 weeks and achieved a complete response at eight months, which is still ongoing at 19 months.
Together, these case studies support the clinical activity of BMS-986016 monotherapy and in combination with Opdivo, including in patients refractory to anti-PD-1 therapies.

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