Bispecific Antibody Columvi Offering Option in Diffuse Large B-cell Lymphoma Treatment

Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy worldwide, making up approximately 3% of all cancer diagnoses and deaths.¹ In the United States, NHL accounts for 4% of US cancer diagnoses, making it the seventh most prevalent cancer with the sixth highest mortality.¹ It is estimated that there are 80,620 new cases of NHL per year and 20,140 deaths in the United States.² NHL diagnoses are staged, with later stages being more severe. Most patients (54%) have either stage III or stage IV disease.² Overall, 5-year relative survival for these patients is 74.3%, with survival decreasing by stage; patients with stage I disease have a 5-year relative survival of 87.0% whereas survival in those with stage IV drops to 64.2%.²

NHL is a highly heterogeneous disease, with many different histology types. They may be differentiated based on their origins, which may be from either precursors or mature B or T cells.³ B-cell lymphomas may include diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphomas (MCLs) while T-cell diseases may include adult T-cell lymphoma or mycosis fungoides.³ Risk factors associated with each of these subtypes do differ, but there are some similarities. Organic chemicals, radiation, and some chemotherapies increase the risk of NHL.³ Age and gender also play a role; NHL is more often diagnosed after 65 years of age, and men have more than double the lifetime risk of developing NHL relative to women.¹ Prior radiation, obesity, and smoking are highly associated with DLBCL, while immune disorders such as Sjögren’s syndrome and Hashimoto’s thyroiditis are associated with marginal zone lymphoma.¹

Treatment of NHL is specific to subtype and stage. In general, chemotherapy, radiotherapy, immunotherapy, and stem cell transplantation may be utilized.³ For DLBCL, combination chemotherapy utilizing R-CHOP is utilized in earlier treatment stages.³ Relapsed and refractory (R/R) DLBCL may opt for a salvage therapy followed by bone marrow transplant or CAR T-cell therapy.³ Mycosis fungoides, which is primarily skin related, is a highly indolent cancer.³ As such, the treatment of this disease is milder, utilizing topical steroids, topical retinoids, and skin irradiation.³ Later stages of mycosis fungoides may require systemic biologic therapies if a patient experiences treatment failure.³

Treatment options in NHL, particularly in the R/R population, are limited in number and in novel mechanisms of action. It is only recently that novel mechanisms of action such as CAR T cell have been approved in R/R DLBCL treatment, but salvage chemotherapy followed by consolidation with high-dose chemotherapy and autologous stem-cell transplantation is still the preferred regimen.⁴ Of all patients with DLBCL, 10% to 15% of all DLBCL patients will fail R-CHOP—one of the most utilized combination therapies—within 1 year from diagnosis.⁵ Furthermore, the efficacy of R/R DLBCL treatments has wide variations. Median overall survival (OS) for patients eligible for transplantation ranged from 9.9 to 44.0 months, while those ineligible for transplantation ranged from 3.4 to 9.0 months.⁶ OS also decreases as line of therapy increases, with third-line salvage therapy OS ranging from 5.9 to 8.0 months compared with second-line salvage therapy OS (11-17.2 months).⁶ The lack of efficacious treatments and novel mechanisms of action represent a high unmet need in this population.

Glofitamab Current Approval

On June 15, 2023, the FDA granted accelerated approval to glofitamab-gxbm (Columvi; Genentech, Inc) for the treatment of R/R DLBCL, not otherwise specified or large B-cell lymphoma arising from follicular lymphoma, after ≥2 lines of systemic therapy.⁷ This approval is based on the response rate and durability of the response demonstrated in the NP30179 (NCT03075696) study.⁸ The overall response rate (ORR) for the efficacy population (n=155) was 52% (95% confidence interval [CI], 43-60) and the median duration of response (DOR) was 18.4 months (95% CI, 13.7-not estimable).⁹

Mechanism of Action

Glofitamab-gxbm is a bispecific antibody that binds to CD20 expressed on the surface of B cells and the CD3 receptor expressed on the surface of T cells.⁸ This causes T-cell activation, secretion of cytokines, and the lysis of CD20-expressing B cells.⁸

Ongoing Clinical Trials

Currently, Columvi is only indicated for 2 forms of NHL in a pretreated setting. However, Genentech is currently conducting multiple trials to evaluate the efficacy of glofitamab-gxbm in other forms of NHL as well as other populations.

Currently, there are 3 different active or recruiting phase 3 trials exploring glofitamab-gxbm use in NHL.¹⁰ GLOBRYTE (NCT06084936) is an open-label, multicenter randomized study evaluating the efficacy of glofitamab-gxbm monotherapy versus an investigator’s choice of bendamustine + rituximab, or lenalidomide + rituximab in patients with R/R MCL.¹¹ Key inclusion criteria for the study include having histologically confirmed MCL with documentation of either overexpression of cyclin D1 or the presence of t(11;14) and having at least 1 line of prior systemic therapy that includes a Bruton tyrosine kinase inhibitor.¹¹ The primary endpoint of this trial is progression-free survival (PFS), and secondary endpoints include OS, ORR, DOR, and health-related quality of life.¹¹

SKYGLO (NCT06047080) is a recently initiated multicenter, open-label, phase 3 study evaluating the efficacy and safety of glofitamab-gxbm in combination with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) versus Pola-R-CHP alone in untreated patients with CD20-positive large B-cell lymphoma.¹² This study was initiated after the Pola-R-CHP arm of the phase 1b NP40126 study demonstrated that 91.7% of patients had a complete response with no progression observed with a 12-month PFS of 91.5%.¹³ Inclusion criteria for this trial include having an International Prognostic Index (IPI) score of 2-5, an ECOG Performance Status of 0-2, and a left ventricular ejection fraction ≥50% on cardiac multiple-gated acquisition scan or cardiac echocardiogram.¹³ Patients who have any contraindication to any of the individual components of Pola-R-CHP, have had a prior solid organ transplantation, or received any form of systemic immunotherapy were excluded from the study.¹⁴ The study was initiated in September 2023, and the primary completion date is expected to be June 2026.¹⁴

STARGLO (NCT04408638) is a phase 3, multicenter, open-label study evaluating the efficacy and safety of glofitamab-gxbm in combination with gemcitabine and oxaliplatin (Glofit-GemOx) versus rituximab in combination with gemcitabine and oxaliplatin (R-GemOX) in patients with R/R DLBCL.¹⁵ In this study, patients with R/R DLBCL must have received at least 1 prior line of therapy and not be a candidate for high-dose chemotherapy followed by autologous stem cell transplant.¹⁶ The primary endpoint of this trial was OS, and secondary endpoints included PFS, ORR, DOR, and time to deterioration.¹⁶ Recent data from this study were featured at the 2024 European Hematology Association Congress as a late-breaking oral presentation. The primary analysis at this time included 274 patients with a median follow-up time of 11.3 months.¹⁷ A significant benefit in OS was seen with Glofit-GemOx versus R-GemOx (hazard ratio [HR], 0.59; 95% CI, 0.40-0.89).¹⁷ Significant PFS benefit was also seen for Glofit-GemOx (HR, 0.37; 95% CI, 0.25-0.55).¹⁷ Adverse events (AEs) for Glofit-GemOx were higher than the comparator group (grade 3-4 AEs; Glofit-GemOx vs R-GemOx: 69.4% vs 36.4%).¹⁷

Glofitamab-gxbm has its share of early-phase development trials as well. iMATRIX-GLO (NCT05533775) is a phase 1/2, open-label, single-arm, 2-part trial that is evaluating safety, tolerability, and antitumor activity of glofitamab-gxbm in patients with R/R mature B-cell NHL.¹⁸ This trial is evaluating 2 different treatment regimens: glofitamab-gxbm as monotherapy and in combination with rituximab, ifosfamide, carboplatin, and etoposide.¹⁸ The trial is divided into 2 separate cohorts, the first of which allows patients between the ages of 6 months and 30 years who have received at least 1 previous treatment for their disease, and the second that allows patients who are between the ages of 6 months and 18 years and have received ≥2 prior treatments for their disease.¹⁹ Primary endpoints include achievement of a complete response, incidence of AEs, and serum concentration of the agents being utilized in both arms.¹⁴ Secondary outcomes for iMATRIX GLO are ORR, OS, PFS, and duration of complete response.¹⁹

Glofitamab-gxbm also has an active phase 2, open-label, multicenter study (NCT04980222) evaluating the safety and efficacy of glofitamab-gxbm in combination with R-CHOP in untreated patients with circulating tumor DNA (ctDNA) high-risk DLBCL.²⁰ Key inclusion criteria for this study include having an ECOG Performance Status of 0-2, an IPI of 2-5, and a confirmation of high risk as defined by ctDNA.²⁰ The primary endpoint for this study is the end-of-treatment (EOT) complete response rate, and secondary endpoints include ORR, PFS, and OS.¹⁹ Data for this study showcasing the safety profile and response rates were featured at the 2023 American Society of Hematology Congress. At the time of data cutoff, 121 patients were screened, of which 24 were defined as high risk.²¹ The EOT complete response was 80.0% (95% CI, 51.9-95.7); the interim and EOT ORR were both 93.3% (95% CI, 68.1-99.8).²¹

Conclusions

As a heterogenous disease state, NHL has a myriad of treatment options available. Yet, of the treatment options currently utilized, the survival benefit being offered is minimal, highlighting an important unmet need in the NHL population. Glofitamab-gxbm is an agent that has shown early efficacy in the pretreated B-cell population. However, the agent is also being evaluated in different NHL subtypes and populations, and may soon become a viable treatment option for many other people suffering from NHL.

References

1. Thandra KC, Barsouk A, Saginala K, et al. Epidemiology of non-Hodgkin’s lymphoma. Med Sci (Basel). 2021;9:5.
2. National Cancer Institute. Cancer Stat Facts: non-Hodgkin lymphoma. Accessed July 26, 2024. https://seer.cancer.gov/statfacts/html/nhl.html
3. Sapkota S, Shaikh H. Non-Hodgkin lymphoma [Updated 2023 Feb 24]. Treasure Island, FL: StatPearls; 2024. Accessed November 7, 2024. https://www.ncbi.nlm.nih.gov/books/NBK559328/
4. Ip A, Mutebi A, Wang T, et al. Treatment outcomes with standard of care in relapsed/refractory diffuse large B-cell lymphoma: real-world data analysis. Adv Ther. 2024;41:1226-1244.
5. Sarkozy C, Sehn LH. Management of relapsed/refractory DLBCL. Best Pract Res Clin Haematol. 2018;31:209-216.
6. Lenz G, Rutherford SC, Davies A, et al. The burden of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): a systematic literature review (SLR). Blood. 2018;132(suppl 1):2241-2241.
7. FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refractory large B-cell lymphomas. Press release. June 15, 2023. Accessed August 26, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-glofitamab-gxbm-selected-relapsed-or-refractory-large-b-cell
8. Genentech. Columvi (glofitamab-gxbm) [package insert]. Accessed August 26, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761309s000lbl.pdf
9. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387:2220-2231.
10. Genentech. Genentech Clinical Trials. Accessed August 26, 2024. https://genentech-clinicaltrials.com/en/new-solr-search.html?phase=Phase%203&query=glofitamab&enter=true
11. ClinicalTrials.gov. A study to evaluate glofitamab as a single agent vs. investigator’s choice in participants with relapsed/refractory mantle cell lymphoma (GLOBRYTE). Accessed August 26, 2024. https://clinicaltrials.gov/study/NCT06084936?term=NCT06084936&rank=1
12. Genentech. A clinical trial to compare glofitamab plus Pola-R-CHP with Pola-R-CHP alone in people with untreated large B‑cell lymphoma. Accessed August 26, 2024. https://genentech-clinicaltrials.com/en/trials/cancer/non-hodgkins-lymphoma/an-open-label-study-comparing-glofitamab-and-polatuzuma-51322.html#forpatients
13. Genentech. New data for Genentech’s Columvi and Lunsumio. Presented at: ASH Annual Meeting; December 9-12, 2023. Accessed August 26, 2024. https://www.gene.com/media/press-releases/15015/2023-12-10/new-data-for-genentechs-columvi-and-luns
14. ClinicalTrials.gov. An open-label study comparing glofitamab and polatuzumab vedotin + rituximab, cyclophosphamide, doxorubicin, and prednisone versus pola-R-CHP in previously untreated patients with large B-cell lymphoma. Accessed August 26, 2024. https://clinicaltrials.gov/study/NCT06047080?term=NCT06047080&rank=1
15. Genentech. A clinical trial to compare glofitamab plus Pola-R-CHP with Pola-RCHP alone in people with untreated large B-cell lymphoma. Accessed August 26, 2024. https://genentech-clinicaltrials.com/en/trials/cancer/non-hodgkins-lymphoma/an-open-label-study-comparing-glofitamab-and-polatuzuma-51322.html
16. ClinicalTrials.gov. A phase III study evaluating glofitamab in combination with gemcitabine + oxaliplatin vs rituximab in combination with gemcitabine + oxaliplatin in participants with relapsed/refractory diffuse large B-cell lymphoma. Accessed August 26, 2024. https://clinicaltrials.gov/study/NCT04408638
17. Abramson J, Ku M, Hertzberg H, et al. Glofitamab plus gemcitabine and oxaliplatin (GLOFIT-GEMOX) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Presented at: European Hematology Association 2024; June 14, 2024. Madrid, Spain. Abstract LB3438.
18. ClinicalTrials.gov. A study to evaluate glofitamab monotherapy and glofitamab + chemoimmunotherapy in pediatric and young adult participants with relapsed/refractory mature B-cell non-Hodgkin lymphoma (iMATRIX GLO). Accessed August 26, 2024. https://clinicaltrials.gov/study/NCT05533775?tab=results
19. Genentech. A clinical trial to look at how well glofitamab works on its own, and in combination with standard cancer chemotherapy plus immunotherapy in children and young adults with B-cell non-Hodgkin lymphoma (B-NHL) after one or multiple standard therapies have not worked. Accessed August 26, 2024. https://forpatients.roche.com/bin/medically/download-clinical-trial?id=NCT05533775--CO43810
20. ClinicalTrials.gov. A study to evaluate the safety and efficacy of glofitamab in combination with rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in circulating tumor (ct)DNA high-risk patients with untreated diffuse large B-cell lymphoma. Accessed August 26, 2024. https://clinicaltrials.gov/study/NCT04980222?term=NCT04980222&rank=1
21. Falchi L, Jardin F, Haloun C, et al. Glofitamab (Glofit) plus R-CHOP has a favorable safety profile and induces high response rates in patients with previously untreated (1 L) large B-cell lymphoma (LBCL) defined as high risk by circulating tumor DNA (ctDNA) dynamics: preliminary safety and efficacy results. Presented at: ASH Annual Meeting; December 11, 2023; San Diego, CA. Oral session 626.