Regulatory Decision Summary for Columvi

The purpose of this Supplement to a New Drug Submission (SNDS) was to seek market authorization for Columvi (glofitamab for injection), in combination with gemcitabine and oxaliplatin, for the treatment of adult patients with relapsed or refractory Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS) who are not candidates for autologous stem cell transplant. Upon review of the submitted data package, Health Canada authorized Columvi as filed.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS) is an aggressive form of Non-Hodgkin Lymphoma (NHL) that occurs due to the transformation of mature B-cells. A significant proportion of DLBCL NOS patients can be cured with first line treatment; however, it is expected that 30 - 50% of patients will relapse after, or be refractory to, frontline treatment. Despite significant advances in the treatment of DLBCL NOS, there remains a need for additional treatment options.

The STARGLO study, which enrolled patients with relapsed/refractory (R/R) DLBCL NOS who were not candidates for autologous stem cell transplant (ASCT), was successful in demonstrating the superiority of Columvi (G), in combination with gemcitabine and oxaliplatin (GemOx), compared to rituximab in combination with GemOx (R-GemOx). G-GemOx was associated with a statistically significant and clinically meaningful improvement in overall survival (OS) with a hazard ratio (HR) of 0.59 (95% confidence interval [CI]: 0.40, 0.89) at the time of the primary analysis, an estimate that was consistent upon re-analysis with approximately 11 months of additional follow-up. The primary endpoint was supported by improvements in progression free survival (PFS; HR: 0.40, 95% CI: 0.28, 0.57) and in the complete response rate (CRR), reported to be 58.5% in G-GemOx treated patients compared to 25.3% in R-GemOx treated patients.

As a bi-specific T-cell engager, there are adverse reactions that are known to be associated with Columvi based on previous investigations and based on its mechanism of action. In particular, the adverse events of special interest are cytokine release syndrome (CRS), neurological toxicities, including immune effector cell-associated neurotoxicity (ICANS), as well as tumour lysis syndrome (TLS) and tumour flare. Emerging evidence suggests potential risks of pneumonitis and colitis, which have been added to the Product Monograph - Adverse Reactions section.

The most commonly reported adverse events in the G-GemOx arm (occurring in at least 20% of participants) were: nausea, anemia, platelet count decreased, CRS, diarrhea, aspartate amino transferase increased, alanine aminotransferase increased, neutrophil count decreased, decreased appetite, vomiting, fatigue, pyrexia, lymphocyte count decreased and white blood cell count decreased.

Serious adverse events occurred in 34.3% of G-GemOx participants compared to 5.7% of R-GemOx participants. The difference was driven, in large part, by the occurrence of CRS (20.3%), which is not an adverse drug reaction associated with rituximab. Fatal (grade 5) adverse events occurred in 7.0% of G-GemOx participants compared to 4.5% of R-GemOx participants.

Given a demonstrated improvement in OS in the setting of R/R DLBCL-NOS in patients who are not candidates for ASCT, which is supported by improvements in PFS and CRR, the benefit of Columvi, in combination with gemcitabine and oxaliplatin, is considered to outweigh the risks when it is administered according to the directions provided in the Product Monograph. Of note, the Product Monograph includes a serious warnings and precautions box for CRS and neurotoxicity, including ICANS, in addition to guidance on the monitoring and management of these and other potential risks.

An updated Risk Management Plan (RMP) for Columvi was reviewed by Health Canada and considered acceptable.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Columvi (2.5 mg / 2.5 mL, 10 mg / 10 mL) for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Columvi (glofitamab), please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.