Does This Star ‘GLO’? Taking Aim at Second-Line Diffuse Large B-Cell Lymphoma With Glofitamab Plus Gemcitabine and Oxaliplatin

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma worldwide (accounting for about 30% of cases), is an aggressive disease that warrants treatment at diagnosis.¹  Yet while DLBCL is curative in approximately two-thirds of patients, this number is dependent on stage, patient age, and other inherent tumor properties. For those who relapse (tumor returns at least one year after completion of therapy) or are primary refractory to standard frontline therapy (relapse within one year of treatment completion), the standard of care (SOC) for years has involved salvage chemoimmunotherapy (CIT),^2,3  followed by consolidative autologous stem cell transplantation (ASCT). This has been dependent on eligibility for ASCT, which is restricted based on age and fitness given the intensity of the most-used induction regimens — RICE (rituximab, ifosfamide, carboplatin, and etoposide) and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin). Those ineligible for ASCT often receive more palliative CIT regimens, such as R-GemOx (rituximab plus gemcitabine and oxaliplatin). In both situations, the treatment outcomes have left much to be desired, particularly among those with refractory disease whose poor outcomes are likely explained by DLBCL’s resistance to CIT.⁴ 

A major advancement in the management of patients in second-line DLBCL occurred with the introduction of chimeric antigen receptor T-cell (CAR-T) therapy. This autologous T-cell treatment first demonstrated its efficacy in patients with third-line or later (3L+) DLBCL, leading to the approval of three products — axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel — for DLBCL patients whose disease has failed to respond to at least two prior lines of therapy.^5-8  Given the efficacy of these agents, it was natural to evaluate whether these drugs could help even the most difficult-to-salvage patients — those with primary refractory DLBCL. In randomized studies, axi-cel and liso-cel both demonstrated superiority over salvage CIT followed by ASCT. Additionally, liso-cel was approved for use in relapsed patients deemed ineligible for ASCT.^9-13 

With increasing approval worldwide, CAR-T therapy has “moved the needle” in cases of primary refractory disease or frail patients with relapsed disease. However, this treatment option remains hampered by accessibility-related issues such as distance from CAR-T-approved sites, logistical concerns, or cost.

Bispecific antibodies hold appeal by functioning to a degree as “off-the-shelf” CAR-T products, with the results of two pivotal trials leading to the approval of epcoritamab and glofitamab in 3L+ DLBCL.^14,15  Bispecific antibodies can also be combined with a multitude of agents, in similar fashion to what has developed with monoclonal antibodies.^16,17  Given these potential benefits, this class of drugs has the potential for greater reach and improved outcomes in relapsed or refractory (R/R) DLBCL.

In the global, randomized, phrase III STARGLO trial,¹⁸  Jeremy S. Abramson, MD, and colleagues explored the combination of glofitamab with gemcitabine and oxaliplatin (Glofit-GemOx) versus R-GemOx in the treatment of 274 patients with R/R DLBCL who had failed one or more prior lines of therapy (2L+) and were ineligible for ASCT. At the interim analysis, the study met its primary endpoint. After a median follow-up of 11.3 months (95% CI 9.6-12.7), median investigator-assessed overall survival (OS) was significantly longer in the Glofit-GemOx group (non-estimable [NE]; 95% CI 13.8-NE) versus nine months (95% CI 7.3-14.4) in the R-GemOx group (hazard ratio [HR] = 0.59, 95% CI 0.40-0.89; p=0.011).

In the updated analysis, after a median follow-up of 20.7 months (95% CI 19.9-23.3), the median investigator-assessed OS was 25.5 months (95% CI 18.3-NE) with Glofit-GemOx versus 12.9 months (95% CI 7.9-18.5) with R-GemOx (HR=0.62, 95% CI 0.43-0.88). After a median progression-free survival (PFS) follow-up of 15.7 months (95% CI 13.4-17.0), the median independent review committee (IRC)-assessed PFS was 13.8 months (95% CI 8.7-20.5) with Glofit-GemOx versus 3.6 months (95% CI 2.5-7.1) with R-GemOx (HR=0.40, 95% CI 0.28-0.57). The IRC-assessed median duration of complete response for Glofit-GemOx compared to R-GemOx was NE (95% CI NE-NE) versus 24.2 months (95% CI 6.9-NE), respectively (HR=0.59, 95% CI 0.25-1.35), while the IRC-assessed median duration of objective response was NE (95% CI 17.6-NE) versus 10.3 months (95% CI 6.5-NE), respectively (HR=0.57, 0.30-1.10). A higher rate of IRC-assessed disease progression was observed with R-GemOx compared with Glofit-GemOx (39.6% [95% CI 29.5-50.4] vs. 18.6% [95% CI 13.2-25.0], respectively). Overall, 106 patients (58%) in the Glofit-GemOx group discontinued treatment compared with 65 patients (71%) in the R-GemOx group, with the most common reason for discontinuation in both groups being disease progression (41 patients [22%] vs. 38 patients [42%], respectively).

A major concern with implementation of bispecific antibodies is key adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurological syndrome (ICANS). In this study, CRS occurred in 76 (44%) of 172 glofitamab-exposed patients. Most CRS events were low-grade (grade 1: 54 patients [31%]; grade 2: 18 patients [10%]; grade 3: four patients [2%]), predominantly occurring after the initial 2.5 mg glofitamab dose. CRS occurred 13.6 hours (95% CI 10.4-22.1) after administration and resolved after 23 hours (95% CI 5.7-68.0). Among the 76 patients with CRS, tociluzimab was administered in 28 (36.8%). ICANS was reported in four Glofit-GemOx recipients (2%). Of these, most were grade 1 to 2 (three patients [2%]), with one patient (1%) experiencing a grade 3 event (delirium). All ICANS events were reported concurrently with CRS and resolved with CRS resolution.

The STARGLO trial is the first to explore the application of a bispecific antibody (glofitamab) in 2L+ DLBCL, comparing its combination with GemOx to its use with R-GemOx, a regimen with demonstrated efficacy in R/R DLBCL and commonly used in ASCT-ineligible patients.^19-21  This study met its primary endpoint in demonstrating an OS benefit of Glofit-GemOx or R-GemOx. Based on the study findings, these combinations are primed to be used in the treatment of 2L+ DLBCL.

However, some questions remain about this trial, the foremost being the currently limited uptake of bispecific antibodies due to a lack of institutional structure in dealing with treatment-specific adverse events such as CRS and ICANS. Specific to the STARGLO study, ASCT ineligibility no longer holds the same meaning as it did in the pre-CAR-T era, especially in the U.S. As this study enrolled approximately 67% of patients with refractory disease, most of whom were CAR-T naive, it is safe to assume that most would have been eligible for and would have received CAR-T in the U.S. This is especially true given that most of the current bispecific use is at centers approved to provide and capable of administering CAR-T. Additionally, of the study’s 274 enrolled patients, the vast majority were enrolled in Asia and Australia, with only 25 (9%) enrolled/treated at sites in the U.S. While the study authors provide no clear explanation for the discrepancy in regional enrollment, it is hard to ignore that most of the participating sites in the U.S. are academic centers with access to CAR-T, where the SOC would hold little appeal in most cases. Another issue of concern is the region-specific OS benefit of Glofit-GemOx, which shines in Asia and Australia, diminishes to a flicker in Europe, and is extinguished among the few U.S. patients enrolled. In addition, the time interval to new anti-lymphoma therapies or death for Glofit-GemOx is greatest in patients treated outside of Europe or North American (2.8 and 4.3 months, respectively).

Given these concerns, it’s not difficult to ascertain the true scope of this trial’s “GLO,” especially for U.S. providers. For those with refractory disease, the SOC within the U.S. should remain CAR-T, given its noted benefits in this patient population. Yet even in this space, given what is required to administer CAR-T from both an institutional and patient perspective, such treatment is not an option for all. As such, the STARGLO regimen allows for a potentially curative therapy to be administered at sites that are willing to provide and are capable of administering bispecific antibodies. For the minority of patients who have relapsed disease and are ineligible for ASCT, this regimen demonstrates significant benefit over GemOx alone, but was this the best comparative arm for these patients? Several other novel regimens have demonstrated impressive overall and complete responses in patients with relapsed disease.^22-27  How would Glofit-GemOx compare to regimens that are logistically as easy or easier to administer and have the benefit of not including chemotherapy?