Transparency Submission

FDA Clearance: Glofitamab-GemOx is not approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma. Currently, glofitamab-gxbm (Columvi™) monotherapy has been granted accelerated approval for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy. Please refer to the product prescribing information for the full FDA-approved indication and safety information, available at: https://www.gene.com/download/pdf/columvi_prescribing.pdf

Rationale for Requested Change: Please consider the enclosed information on use of glofitamab in combination with gemcitabine and oxaliplatin (Glofitamab-GemOx) in patients with relapsed/refractory diffuse large B-cell lymphoma for your guideline updating needs. Please note that data from the randomized Phase 3 STARGLO study have been submitted to a peer-reviewed journal. Genentech plans to submit the STARGLO publication to the B-Cell Lymphomas Panel for review once published. Approximately 40% of diffuse large B-cell lymphoma (DLBCL) patients do not respond to or relapse after first-line chemoimmunotherapy. While chimeric antigen receptor (CAR) T-cell therapy has advanced the treatment of relapsed/refractory (R/R) DLBCL and with some patients potentially being cured with autologous stem cell transplant (ASCT), not all patients have access to CAR T-cell therapy or are eligible for ASCT due to comorbidities or logistical limitations. There continues to be a high unmet need for effective new therapies to improve clinical outcomes for these patients. The Phase 3 STARGLO trial comparing Glofitamab-GemOx versus rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) in ASCT-ineligible patients with R/R DLBCL met its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in overall survival (OS) (hazard ratio [HR] 0.59; 95% CI: 0.40–0.89; p=0.011). Results from the STARGLO primary analysis (median follow-up of 11.3 months) and updated follow-up analysis (median follow-up of 20.7 months) are summarized below. STARGLO is a Phase 3, open-label, randomized study designed to evaluate the efficacy and safety of Glofitamab-GemOx versus R-GemOx in patients with R/R DLBCL after =1 prior line of therapy. Patients who failed only 1 prior line of therapy were considered ineligible for ASCT based on age =70 years, organ dysfunction, ECOG performance status =2, patient refusal for ASCT, or other investigator-assessed comorbidities. Randomization was stratified by the number of prior lines of therapy (1 vs =2) and outcome of last systemic therapy (relapsed vs refractory). The primary endpoint was OS. Key secondary endpoints included independent review committee (IRC)-assessed progression-free survival (PFS) and complete remission (CR) rate. In total, 274 patients were enrolled (Glofitamab-GemOx, n=183; R-GemOx, n=91), including 172 (62.8%) after 1 prior therapy and 102 (37.2%) after =2 prior therapies. Overall, 153 (55.8%) patients had primary refractory disease and 166 (60.6%) were refractory to last therapy. Efficacy: Glofitamab-GemOx demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of OS compared with R-GemOx at the primary analysis and continued to be observed at the updated follow-up analysis. - OS at the primary analysis: HR=0.59 (95% CI: 0.40–0.89; p=0.011); median OS: NE (95% CI: 13.8–NE) vs 9 months (95% CI: 7.3–14.4) - OS at the updated follow-up analysis: HR=0.62 (95% CI: 0.43–0.88); median OS: 25.5 months (95% CI: 18.3–NE) vs 12.9 months (95% CI: 7.9–18.5) A statistically significant improvement in IRC-assessed PFS and CR rate was also demonstrated with Glofitamab-GemOx at the primary analysis and continued to be observed at the updated follow-up analysis. - PFS by IRC at the primary analysis: HR=0.37 (95% CI: 0.25–0.55; p<0.000001); median PFS: 12.1 months (95% CI: 6.8–18.3) vs 3.3 months (95% CI: 2.5–5.6) - PFS by IRC at the updated follow-up analysis: HR=0.40 (95% CI: 0.28–0.57); median PFS: 13.8 months (95% CI: 8.7–20.5) vs 3.6 months (95% CI: 2.5–7.1) - Best CR rate by IRC at the primary analysis: 50.3% vs 22.0% (?28.3%; 95% CI: 16.3–40.3; p<0.0001) - Best CR rate by IRC at the updated follow-up analysis: 58.5% vs 25.3% (?33.2%; 95% CI: 19.7–44.5) In exploratory subgroup analyses of overall survival, comparable results were observed in clinically relevant stratified subgroups (relapsed vs refractory disease and 2L vs 3L+). Regional inconsistencies were observed, but interpretation was limited by wide confidence intervals and small patient numbers. Safety: Glofitamab-GemOx was well tolerated with a safety profile consistent with the known risk of each individual drug. The rates of serious adverse events (AEs) (54.4% vs 17.0%), Grade =3 AEs (77.8% vs 40.9%), Grade 5 AEs (8.3% vs 4.5%), and AEs leading to any treatment discontinuation (26.7% vs 12.5%) were higher with Glofitamab-GemOx compared to R-GemOx, noting higher median number of cycles received with Glofitamab-GemOx compared to R-GemOx (11 vs 4). Cytokine release syndrome (CRS) was the most common AE reported in patients treated with glofitamab, mainly occurring in Cycle 1 and was predominantly low grade (any grade: 44.2% [Grade 1: 31.4%; Grade 2: 10.5%; Grade 3: 2.3%; no Grade 4 or 5]). Neurological AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 4 (2.3%) patients treated with glofitamab, all of which were concurrent with CRS and were mostly low grade. References: 1. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus Gemcitabine and Oxaliplatin (Glofit-GemOx) for Relapsed/Refractory Diffuse Large B-cell Lymphoma: Results of a Global Randomized Phase III Trial (STARGLO). Presented at the European Hematology Association (EHA) Annual Meeting; June 13-16, 2024; Madrid, Spain. [oral presentation: https://medically.gene.com/global/en/unrestricted/haematology/EHA-2024/eha-2024-presentation-abramson-glofitamab-plus-gemcitab.html] 2. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus Gemcitabine and Oxaliplatin (Glofit-GemOx) for Relapsed/Refractory Diffuse Large B-cell Lymphoma: Results of a Global Randomized Phase III Trial (STARGLO). Presented at the European Hematology Association (EHA) Annual Meeting; June 13-16, 2024; Madrid, Spain. [abstract: https://library.ehaweb.org/eha/2024/eha2024-congress/4136516] Any references supplied to you are protected under U.S. Copyright Law (Title 17, U.S. Code). No further reproduction or distribution is permitted. Thank you for your consideration of this request. If you have any questions, please contact me at the phone number or email provided above. Respectfully submitted, Raymond La, PharmD