NEW YORK – Analyzing circulating tumor DNA could help predict which newly diagnosed lymphoma patients might benefit from adding Roche's bispecific antibody Columvi (glofitamab) to a first-line chemotherapy regimen, according to data from a Phase II trial presented at the American Society of Hematology's annual meeting on Monday.
Lorenzo Falchi, a lymphoma oncologist at Memorial Sloan Kettering, presented results from the study, in which patients with large B-cell lymphoma (LBCL) defined as high-risk based on circulating tumor DNA (ctDNA) testing, received Columvi in addition to the commonly prescribed first-line chemotherapy-containing regimen R-CHOP. As Falchi explained in his presentation, R-CHOP, comprising Biogen and Genentech's monoclonal antibody Rituxan (rituximab) and cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone, can be curative on its own or at least lead to long-term remissions in two-thirds of newly diagnosed LBCL patients. But identifying the one-third who won't benefit from R-CHOP alone has been challenging for oncologists.
"There is an unmet need in this space, and ctDNA testing could be an accurate, noninvasive tool to monitor the dynamics of tumor response and potentially identify high-risk patients who will have a suboptimal response to chemotherapy and a worse outcome," Falchi said. "With this background in mind, we thought [Columvi] could be a potential tool to overcome some of these adverse prognostic factors."
Columvi, which is a CD20- and CD3-directed bispecific antibody, is designed to engage and redirect T cells to attack and kill cancerous B cells. As a monotherapy, its benefit has been established in heavily pretreated lymphoma patients, and earlier this year, it netted accelerated approval from the US Food and Drug Administration as treatment for third- or later-line lymphoma patients.
In the study presented at the meeting, Falchi and colleagues enrolled patients with CD20-positive LBCL. Using Avenio Oncology's next-generation sequencing assay for non-Hodgkin lymphoma, they analyzed patients' ctDNA at baseline, then again at the end of their first and second cycles of R-CHOP. They determined that patients were at high risk of relapse when they had less than a 100-fold reduction in ctDNA at the end of the first cycle.
For these high-risk patients, Falchi and colleagues added Columvi to the treatment regimen beginning with the third R-CHOP cycle.
Out of 115 patients, 29 had high-risk LBCL according to the prespecified criteria and 70 had low-risk disease. Sixteen patients from this group could not have their ctDNA tested due to various reasons such as a missing germline sample or workflow problems. Most of these problems limiting ctDNA analysis have since been addressed — for instance, by requiring additional peripheral blood mononuclear cells — and Falchi expressed confidence that similar problems wouldn't occur if the study were repeated today.
Investigators then tracked how many of the 29 high-risk LBLC patients responded once Columvi was added to R-CHOP. Although researchers are still following patients, Falchi reported "encouraging" early data that 95 percent of patients had an objective response to Columvi plus R-CHOP and 60 percent had a complete metabolic response, which increased to 85 percent of patients by the end of treatment. Despite the limited follow-up, the responses were durable, according to Falchi.
In terms of Columvi and R-CHOP's safety and tolerability, around three-quarters of patients experienced adverse events related to Columvi, but just nine patients experienced grade 3 or 4 toxicities and none of the patients died on the study. Other than cytokine release syndrome, which affected one-fifth of Columvi-treated patients and were mostly low grade, Falchi said that the combination treatment's toxicity profile was similar to standard R-CHOP.
"In this early, limited experience, coming from an international Phase II study, we proved that ctDNA assessment is feasible on an on-treatment basis for patients with frontline, diffuse B-cell lymphoma," Falchi said. The high response rates observed, he noted, "compared favorably" to a population of patients with high-risk ctDNA who'd been treated with R-CHOP alone in an earlier Roche study dubbed POLARIX. In that study, he noted, patients had a complete response rate of 68 percent.
Based in part on these encouraging data, he said that Roche is comparing the activity of first-line Columvi plus R-CHOP against R-CHOP in large B-cell lymphoma patients in a Phase III randomized trial.