Glofitamab Plus Gemcitabine/Oxaliplatin Shows Survival Benefit in Transplant-Ineligible R/R DLBCL

The addition of fixed-duration glofitamab-gxbm (Columvi) to gemcitabine and oxaliplatin led to a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs rituximab (Rituxan) plus gemcitabine/oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who were not eligible for autologous stem cell transplant (ASCT), according to data from the updated analysis of the phase 3 STARGLO study (NCT04408638).¹

Data presented at the 2024 EHA Congress showed that at a median follow-up of 20.7 months, the median OS with the glofitamab regimen (n = 183) was 25.5 months (95% CI, 18.3-not evaluable [NE]) vs 12.9 months (95% CI, 7.9-18.5) with the rituximab regimen (n = 91), translating to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.43-0.88; P = .006). The 24-month OS rates in the glofitamab and rituximab arms were 52.8% (95% CI, 44.8%-60.7%) and 33.5% (95% CI, 22.2%-44.9%), respectively.

At a median follow-up of 16.1 months, the median PFS with glofitamab plus gemcitabine/oxaliplatin was 13.8 months (95% CI, 8.7-20.5) by independent review committee (IRC) assessment vs 3.6 months (95% CI, 2.5-7.1) with rituximab plus gemcitabine/oxaliplatin, translating to a 60% reduction in the risk of disease progression or death (HR, 0.40; 95% CI, 0.28-0.57; P < .000001). The respective 12-month PFS rates were 51.7% (95% CI, 44.0%-59.4%) and 25.2% (95% CI, 13.6%-36.9%).

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate a survival benefit in DLBCL in a randomized phase 3 trial,” Jeremy S. Abramson, MD, director of the Jon and Jo Ann Hagler Center for Lymphoma at the Massachusetts General Hospital Cancer Center, and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts, said in a presentation during the meeting. “These results support the use of glofitamab plus gemcitabine and oxaliplatin for the treatment of relapsed/refractory DLBCL.”

Glofitamab is an off-the-shelf, fixed-duration treatment that engages and redirects T cells to eradicate malignant B cells. Earlier data from phase 1/2 studies have established a step-up dosing schedule and target dose of 30 mg with the agent in patients with B-cell non-Hodgkin lymphoma. Glofitamab monotherapy has been shown to produce deep and durable complete remissions in patients with relapsed/refractory DLBCL following 2 or more prior lines of treatment. In June 2023, the FDA granted accelerated approval to glofitamab for use in this population.²

The randomized, phase 3 STARGLO study enrolled patients with relapsed/refractory DLBCL not otherwise specified following 1 or more prior systemic therapies who had an ECOG performance status ranging from 0 to 2.¹ Those who only received 1 prior line of treatment must have been ineligible for transplant.

Study participants were randomly assigned 2:1 to the glofitamab or rituximab arms. Those in the experimental arm received pre-treatment with obinutuzumab (Gazyva) on day 1, gemcitabine at 1000 mg/m2 plus oxaliplatin at 100 mg/m2 on day 2, followed by glofitamab at 2.5 mg on day 8 and at 10 mg on day 15. In cycles 2 to 8, glofitamab was given at 30 mg and gemcitabine/oxaliplatin was given on day 1. For cycles 9 to 12, glofitamab was administered at 30 mg on day 1 of each cycle. Those in the control arm received rituximab at 375 mg/m2 plus gemcitabine and oxaliplatin given on day 1 of each cycle.

Stratification factors were disease-related (relapsed vs refractory) and number of prior lines of therapy received (1 vs ≥2).

OS served as the trial’s primary end point, and key secondary end points included PFS by IRC assessment, complete response (CR) rate by IRC assessment, and duration of CR by IRC assessment­–all tested hierarchically. Safety end points focused on the incidence, nature, and severity of adverse effects (AEs) experienced with the regimen.

“The prespecified event-driven interim analysis was met at the time of 11.3 months, at which time the primary end point was met. And thus, the interim analysis was also the primary analysis. At that time, not all patients had even completed their study treatment, and so, [the updated analysis] was performed after 10 additional months of follow-up,” Abramson explained.

Data from the primary analysis showed that at a median follow-up of 11.3 months, the median OS with glofitamab was NE (95% CI, 13.8-NE) vs 9 months (95% CI, 7.3-14.4) with rituximab (HR, 0.59; 95% CI, 0.40-0.89; P = .011). At a median follow-up of 9.6 months, the median PFS with glofitamab was 12.1 months (95% CI, 6.8-18.3) vs 3.3 months (95% CI, 2.5-5.6) with rituximab (HR, 0.37; 95% CI, 0.25-0.55; P < .000001).

Baseline characteristics were well balanced across the glofitamab and rituximab arms. The median age in both arms was 68.0 years (range, 20-88), and more than half of patients were aged 65 years or older (63.4% vs 61.5%). Approximately half of patients were male (57.4% vs 58.2%). With regard to race in the glofitamab arm, 47.0% of patients were Asian, 1.1% were Black or African American, 44.8% were White, and in 7.1% this information was unknown; these respective rates in the rituximab arm were 56.0%, 1.1%, 36.3%, and 6.6%. With regard to ECOG performance status in the glofitamab arm, most patients had a status of 1 (49.4%), followed by a status of 0 (40.0%) and 2 (10.6%). In the rituximab arm, most patients had a status of 0 (50.0%), followed by 1 (40.9%), and 2 (9.1%). In both the glofitamab and rituximab arms, the majority of patients had Ann Arbor stage III to IV disease (67.2% vs 76.9%).

More than half of patients in the glofitamab and rituximab arms were primary refractory (57.9% vs 51.6%). In the glofitamab arm, 38.8% relapsed on their last therapy and 61.2% were refractory; in the rituximab arm, these respective rates were 40.7% and 59.3%, respectively. Bulky disease was present in 12.6% and 15.4% of patients, respectively, and 7.1% vs 8.8% of patients had prior exposure to a CAR T-cell therapy.

Additional data from the updated analysis showed that the objective response rate achieved with glofitamab plus gemcitabine/oxaliplatin was 68.3% vs 40.7% with rituximab plus gemcitabine/oxaliplatin. The CR rate in the glofitamab arm was 58.5% vs 25.3% in the rituximab arm, translating to a statistically significant 33.2% difference between the arms (95% CI, 19.7-44.5; P < .0001).

“Comparable results were observed in clinically relevant stratified subgroups, including relapsed vs refractory status and second-line vs third-line patients,” Abramson said. “Regional inconsistencies were observed, but interpretation was limited by a wide confidence interval and small patient numbers.”

Regarding safety, any-grade AEs occurred in all patients who received the glofitamab regimen vs 95.5% of those given the rituximab regimen; 82.8% vs 65.9% of these effects were related to glofitamab or rituximab. Serious AEs occurred in 54.4% vs 17.0% of patients, respectively, 34.4% vs 8.0% of which were related to glofitamab or rituximab. Grade 3 to 5 AEs were observed in 77.8% of those in the glofitamab arm vs 40.9% of those in the rituximab arm, and 47.2% vs 22.7% were related to glofitamab or rituximab. Fatal AEs were experienced by 8.3% of those in the glofitamab arm vs 4.5% of those in the rituximab arm; 2.8% vs 1.1% were associated with glofitamab or rituximab, respectively. Lastly, 26.7% of patients who received the glofitamab regimen discontinued treatment due to toxicity; this rate was 12.5% in those who received the rituximab combination.

“The safety profile of glofitamab plus gemcitabine/oxaliplatin is consistent with the known risk of the individual study drugs,” Abramson noted.

In the glofitamab arm, any-grade cytokine release syndrome (CRS) was experienced by 44.2% of patients; 31.4% of cases were grade 1, 10.5% were grade 2, and 2.3% were grade 3. The median time to onset of this toxicity was 13.5 hours (range, 4.4-134.9) with 2.5 mg of glofitamab and 32.4 hours (range, 7.4-564.3) with 10 mg of glofitamab. The median duration of CRS with 2.5 mg and 10 mg of glofitamab was 22.7 hours (range, 0.0-168.0) and 24.0 hours (range, 0.0-248.5), respectively. Tocilizumab (Actemra) was administered to 36.8% of patients and corticosteroids were given to 51.3% of patients to manage the toxicity.

“CRS mainly occurred in cycle 1 and was predominantly low grade,” Abramson said. “Other AEs of interest were consistent with the known risk of the individual study drugs.”

Neurological AEs occurred in 58.3% of those who received the glofitamab regimen (grade ≥3, 6.7%), immune effector cell–associated neurotoxicity syndrome occurred in 2.3% of patients (grade ≥3, 0.6%), tumor flare was reported in 0.6% of patients, infections occurred in 57.2% of patients (grade ≥3, 23.3%), neutropenia occurred in 42.2% of patients (grade ≥3, 33.9%), and febrile neutropenia occurred in 3.3% of patients.

Any-grade COVID-19 AEs occurred in 18.3% of those in the glofitamab arm vs 9.1% of those in the rituximab arm; these effects were grade 3 or higher for 6.1% and 2.3% of patients, respectively. This AE proved to be fatal for 7 patients in the glofitamab arm. Moreover, 12.2% of those in the glofitamab arm and 5.7% of those in the rituximab arm ended up discontinuing treatment due to this toxicity.

“The COVID-19–related AE profile should be contextualized considering the rapidly changing landscape of the COVID-19 pandemic and management during the STARGLO study,” Abramson concluded.

References

1. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (Glofit-GemOx) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): results of a global randomized phase III trial (STARGLO). Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract LB3438.
2. FDA approves Genentech’s Columvi, the first and only bispecific antibody with a fixed-duration treatment for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Genentech. June 15, 2023. Accessed June 15, 2024. https://www.gene.com/media/press-releases/14994/2023-06-15/fda-approves-genentechs-columvi-the-firs