Glofit+R-CHOP Shows Promise for High-Risk LBCL

About one-third of patients (pts) with first-line (1L) diffuse large B-cell lymphoma (LBCL) treated with R-CHOP face challenges in achieving long-term remission or cure, with outcomes often reliant on the disease stage. The predictive accuracy beyond the International Prognostic Index (IPI) score is hindered by the reproducibility issues of common biomarkers. Circulating tumor DNA (ctDNA) emerges as a promising, sensitive biomarker for identifying newly diagnosed pts with suboptimal chemoimmunotherapy responses.

Previous observations indicate that a reduction in ctDNA levels after 1–2 therapy cycles correlates with improved survival in 1L diffuse LBCL (DLBCL)  pts (Kurtz et al. J Clin Oncol 2018). The unknown potential of early intervention to enhance outcomes for  pts with elevated on-treatment ctDNA levels prompted the investigation. Glofitamab, a CD20xCD3 bispecific antibody, approved by FDA and EMA as monotherapy for relapsed/refractory DLBCL after ≥2 prior lines of therapy, shows favorable safety and efficacy in 1L DLBCL.

Lorenzo Falchi and his team aim to assess the impact of Glofitamab plus R-CHOP in improving outcomes for 1L LBCL  pts with high-risk ctDNA profiles.

Their objective was to explore the potential of early intervention with this combination therapy to enhance responses and survival outcomes in a population where traditional prognostic markers may fall short.

The study included pts  with 1L CD20+ LBCL, Eastern Cooperative Oncology Group performance (ECOG) status 0–2, and an IPI of 0–5 (IPI 0 for  pts with bulky disease; IPI 2–5 for USA patients). During ctDNA screening,  pts received R-CHOP on Day 1 of Cycle 1 and Cycle 2 (21-day cycles). For  pts identified as high risk by ctDNA (<2-log [100×-fold] reduction in plasma ctDNA after 1 R-CHOP cycle), R-CHOP continued until Cycle 6. 

Glofitamab was administered with step-up dosing in Cycle 3 (Day 8, 2.5mg; Day 15, 10mg), at the target dose (30mg) on Day 8 of Cycles 4–6, and on Day 1 of Cycles 7–10 (21-day cycles). Hospitalization for the first dose of glofitamab to assess cytokine release syndrome (CRS) was at the investigator’s discretion, with granulocyte colony-stimulating factors advised for neutropenia prophylaxis. 

Real-time ctDNA analysis utilized the AVENIO Oncology Assay for Non-Hodgkin’s Lymphoma. Responses were investigator-assessed after Cycle 2 and at end of treatment (EOT) by positron emission tomography using Lugano criteria (Cheson et al. J Clin Oncol 2014). CRS was graded according to ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019), and other adverse events (AEs) were assessed by CTCAE v5.0.

The study revealed that out of 121 screened  pts, 24 (19.8%) were identified as high risk by ctDNA, while 47 (38.8%) were categorized as low risk, and 49 (40.5%) were either missing or not evaluable (safety population). Among the 24 high-risk  pts, 15 reached the end-of-treatment (EOT) assessment, with 14 completing the treatment and 1 discontinuing due to progressive disease (PD); 9  pts were ongoing on treatment. Of these 24  pts, 2 had double-hit, and 4 had triple-hit cytogenetics, with a median age of 61.5 years (range: 39–77). Sixty-two point five percent (62.5%) of  pts had an  IPI score of 1–2 (IPI 1: 12.5%, IPI 2: 50.0%), and 37.5% had an IPI score of 3–5 (IPI 3: 25.0%, IPI 4: 8.3%, IPI 5: 4.2%).

In the safety population, 83.3% of  pts experienced AEs of any grade, with 62.5% having Grade 3/4 AEs, including neutropenia in 45.8% of  pts. Notably, febrile neutropenia was not observed. The most common treatment-emergent AEs (any grade) were neutropenia (54.2% of patients) and diarrhea (25.0% of patients). No Grade 5 AEs were reported.

About 33.3% of  pts in the safety population had Grade ≥3 glofitamab-related AEs, with 20.8% experiencing CRS events. Among the CRS events, 16.7% of  pts had Grade 1 fever, 4.2% had Grade 2 fever and hypotension. CRS events occurred early and were resolved by the data cut-off; treatment (tocilizumab and dexamethasone) was administered for the Grade 2 CRS event only. One patient (4.2%) had a non-immunotoxic Grade 3 neurologic AE (presyncope, glofitamab-unrelated) that resolved by the data cut-off. One patient died due to PD during treatment follow-up after discontinuing glofitamab.

The interim complete response (CR) rate was 46.7% (95% confidence interval [CI]: 21.3–73.4); CR at EOT was 80.0% (95% CI: 51.9–95.7), and both the interim and EOT overall response rate were 93.3% (95% CI: 68.1–99.8)

From this analysis, Glofitamab plus R-CHOP demonstrated a manageable safety profile and elicited high response rates in 1L diffuse LBCL defined as high risk by ctDNA. The interim analysis and end-of-treatment (EOT) outcomes underscore the efficacy of dynamic on-treatment risk assessment using ctDNA, offering potential for the identification of high-risk  pts with LBCL, independent of baseline characteristics.

The study is sponsored by Hoffmann-La Roche

Source: https://ash.confex.com/ash/2023/webprogram/Paper173953.html

Clinical Trial: https://clinicaltrials.gov/study/NCT04980222

Falchi  L, Jardin F, Haioun C, et al. (2023).”Glofitamab (Glofit) Plus R-CHOP Has a Favorable Safety Profile and Induces High Response Rates in Patients with Previously Untreated (1L) Large B-Cell. Lymphoma (LBCL) Defined As High Risk By Circulating Tumor DNA (ctDNA) Dynamics: Preliminary Safety and Efficacy Results” Presented at ASH 2023 (Abstract 858).