Glofit-GemOx shows clinically meaningful benefit in relapsed/refractory diffuse large B-cell lymphoma

Dr Jeremy Abramson - Mass General Cancer Center, Boston, USA

At EHA in the plenary session we presented the results of the STARGLO trial which was a randomised phase III global trial evaluating the addition of glofitamab to gemcitabine and oxaliplatin compared to rituximab, gemcitabine and oxaliplatin in patients with relapsed or refractory diffuse large B-cell lymphoma who were considered transplant ineligible after one or more prior lines of therapy.

What was the study design?

The study was a randomised phase III trial, it was conducted with a 2:1 randomisation and patients were stratified by whether they had one or more than one prior line of therapy and whether they were relapsed or refractory to their prior line of treatment.

Patients on the glofitamab-GemOx arm received eight total cycles of glofitamab-GemOx followed by four cycles of glofitamab monotherapy to complete 12 total cycles, whereas patients randomised to R-GemOx received R-GemOx for eight total cycles. Importantly, patients on the glofitamab-GemOx arm did have a CRS mitigation strategy – they received a single obinutuzumab pre-treatment dose prior to the first dose of glofitamab and then had a ramp-up dosing of glofitamab with dexamethasone pre-treatment during cycle 1.

What were the results of this study?

The primary endpoint of this study was overall survival, key secondary endpoints included progression free survival and complete response rate. We enrolled 274 patients, the median age was 68 years old, most patients had advanced stage disease. 63% of patients had one prior line of therapy and 37% had two or more prior lines of therapy and 60% of patients were refractory to their immediate line of treatment.

In evaluating the overall survival we found a statistically significant overall survival benefit favouring glofitamab-GemOx over R-GemOx with a hazard ratio of 0.59. At a median follow-up of 21 months the median overall survival was 12.9 months on R-GemOx and 25.5 months on glofitamab-GemOx.

Looking at progression free survival we also found a superior progression free survival favouring glofitamab-GemOx with a hazard ratio of 0.37 which accounts for a 63% reduction in risk of progression or death. At 16 months of median follow-up the progression free survival was 3.6 months for R-GemOx and 13.8 months for glofitamab-GemOx.

We also saw improvement in the complete response rate which was 58.5% on glofitamab- GemOx and 25% on R-GemOx. We did see increased toxicity in the glofitamab-GemOx arm and that largely reflected the expected toxicity profile of glofitamab, including cytokine release syndrome, cytopenias and infections. Importantly, the incidence of cytokine release syndrome was 44% but it was almost entirely low grade and occurred predominantly during the first cycle with step-up dosing and was really quite manageable. ICANS occurred in only four patients and was considered grade 3 and only a single patient with grade 3 delirium and all cases of ICANS were entirely reversible.

So we concluded that glofitamab-GemOx substantially improved overall survival, progression free survival and complete response rate over R-GemOx in patients with one or more prior lines of therapy for relapsed DLBCL and that the toxicity profile was entirely manageable and consistent with the known toxicities of the study drugs.

What is the clinical significance of these results?

This is the first randomised trial to show a benefit for a bispecific antibody in second-line or later diffuse large B-cell lymphoma. There are currently no bispecific antibodies FDA approved in the second-line setting for DLBCL, they are only approved in the third line or later setting as monotherapy.

What this trial shows is that glofitamab can combine well with chemotherapy and provide substantial improvements in outcome in second-line patients who are considered transplant ineligible. Now, in this context we see this data compares favourably with other available options and unlike CAR T-cells, which are not as broadly accessible and which many patients may not be able to obtain due to either geography or to rapidly kinetic disease that precludes CAR T-cell manufacturing, glofitamab is an off-the-shelf bispecific antibody that should be more readily accessible to patients across the globe.