STARGLO shines on first CD20xCD3 BsAb for DLBCL

The addition of glofitamab – a CD20xCD3 T-cell engaging bispecific antibody (BsAb) – to gemcitabine and oxaliplatin (GemOx) chemotherapy improves survival in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one prior line of systemic therapy and are ineligible for autologous stem cell transplant, findings from the phase III STARGLO trial have shown.

“Fixed-duration glofitamab added to GemOx demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit in [these patients],” said principal investigator Dr Jeremy Abramson from the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, US, at EHA 2024. “The prespecified, event-driven interim analysis was met at 11.3 months [primary analysis]. At which time, the primary endpoint [of OS] was met.”

The hazard ratio (HR) was 0.59 in favour of G-GemOx over rituximab and GemOx (R-GemOx). This translated to a 41-percent reduction in the risk of progression or death (p=0.011). [EHA 2024, abstract LB3438]

G-GemOx remained superior to R-GemOx in the updated analysis (median follow-up 20.7 months) when all patients had completed all study treatments (25.5 vs 12.9 months; HR, 0.62; p=0.006). The 24-month OS was 52.8 percent with G-GemOx and 33.5 percent with R-GemOx.

In the exploratory OS analysis in prespecified subgroups, results were generally directionally consistent in favour of G-GemOx over R-GemOx in most of the clinically relevant subgroups, Abramson noted.

“We did observe regional inconsistencies, particularly in the European and North American subgroups, but interpretation of these data is limited by extremely small patient numbers and very wide confidence intervals,” he pointed out. “Thus, we conducted a multivariable analysis including treatment arm, geographic region, and all clinically relevant covariates, and found no association between geographic region and OS. This confirmed the OS benefit of G-GemOx, with HR of 0.65.”

PFS, response rates

Progression-free survival (PFS) was also significantly improved with G-GemOx vs R-GemOx. The HR at the primary analysis (median follow-up 9.6 months) was 0.37, correlating with a 63-percent reduction in the risk of progression or death (p<0.000001).

In the updated analysis (median follow-up 16.1 months), median PFS was thrice longer with G-GemOx than R-GemOx (13.8 vs 3.6 months; HR, 0.40; p<0.000001). The 12-month PFS was twice as high with the former vs the latter (51.7 percent vs 25.2 percent).

Overall response (68.3 percent vs 40.7 percent) and complete response (CR; 58.5 percent vs 25.3 percent; p<0.0001) rates in the updated analysis also favoured G-GemOx over R-GemOx. “The CR rate was already statistically significant at the primary analysis, with increased difference between treatment arms at the updated analysis,” noted Abramson.

Safety profile

There was an increase in serious adverse events (AEs) in the G-GemOx vs R-GemOx arm (54.4 percent vs 17 percent), which largely represented the known toxicity profile of glofitamab, Abramson said. These events include cytokine release syndrome (CRS), cytopenias, and infection.

According to Abramson, this may have been driven by the difference in cumulative drug exposures between the G-GemOx and R-GemOx arms (median number of cycles 11 vs 4). “There was more treatment in the G-GemOx arm, thus more potential for cumulative toxicities and immune suppression.”

The rate of fatal AEs was higher with G-GemOx than R-GemOx (8.3 percent vs 4.5 percent), which was largely driven by COVID-19, as was the incidence of severe infections (23 percent vs 12.5 percent).

About 45 percent (n=76) of G-GemOx recipients had CRS, but these were predominantly grade 1–2 and most occurred during the step-up dosing in cycle 1. Half were given corticosteroids while over a third received tocilizumab for CRS management. Due to the successful risk mitigation strategy implemented, CRS became generally manageable and reversible, noted Abramson.

Neurologic events were also more frequent with G-GemOx than R-GemOx (58.3 percent vs 39.3 percent), the most common being primary sensory neuropathy attributable to oxaliplatin. There were four cases of ICANS* in the G-GemOx arm, but all were completely reversible.

Off-the-shelf BsAb

Participants (n=274; median age 68 years, 58 percent male, 51 percent Asian) were randomized 2:1 to receive eight 21-day cycles of G-GemOx or R-GemOx. Those on G-GemOx received four additional cycles of glofitamab monotherapy. About two-thirds of participants had received one prior line of therapy while the rest had ≥2 prior lines. More than half of the patients had had primary refractory disease and ~60 percent were refractory to their immediate prior line of therapy.

In the glofitamab arm, patients underwent obinutuzumab pretreatment for CRS mitigation followed by ramp up with dexamethasone pretreatment during cycle 1. Following which, glofitamab was administered as weekly step-up doses (2.5/10 mg) during cycle 1. The 30-mg target dose was then given every 21 days from day 1, cycle 2.

Glofitamab is an off-the-shelf BsAb targeting CD20 and CD3 designed to directly engage T cells and induce cell-mediated cytotoxicity. The deep and durable complete remissions observed in a phase I/II trial evaluating glofitamab as monotherapy in R/R DLBCL patients after ≥2 prior lines of therapy led to its regulatory approval for this population. [N Engl J Med 2022;387:2220-2231; https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-glofitamab-gxbm-selected-relapsed-or-refractory-large-b-cell, accessed August 17, 2024]

A number of firsts

“Glofitamab is the first CD20xCD3 BsAb to demonstrate a survival benefit in DLBCL in a randomized phase III trial,” Abramson said. “[G-GemOx] showed clinically significant improvement in OS, as well as key secondary endpoints, and the benefits were reinforced with an additional 11 months of follow-up.”

STARGLO is the first study to show the potential of a CD20xCD3 BsAb to “make a difference in second- or later-line DLBCL” in transplant-ineligible individuals with limited treatment alternatives, he said.

“This marks a first step in advancing glofitamab combinations in earlier settings to address the urgent need for the 40 percent of people who will relapse or have refractory disease and who have limited options,” commented Genentech chief medical officer Dr Levi Garraway, in a news release. “Moreover, patients do not have to wait to start treatment with glofitamab. This could be particularly important for patients with highly aggressive disease who are at risk of rapid disease progression.”