ODAC Summary Report – COLUMVI (Glofitamab)
Background & Clinical Data
COLUMVI (glofitamab-gxbm) is a CD20 × CD3 bispecific T-cell engager, initially approved in June
2023 via accelerated approval as monotherapy for relapsed/refractory diffuse large B-cell
lymphoma (DLBCL) after ≥2 lines of therapy.
The sBLA under review proposed using COLUMVI in combination with GemOx chemotherapy for
adults with relapsed/refractory DLBCL ineligible for autologous stem cell transplant (ASCT), with
the confirmatory Phase III STARGLO trial as the basis.
STARGLO trial (n=274) randomized 2:1 glofitamab + GemOx vs rituximab + GemOx. Results
showed:
- OS HR=0.59 (p=0.011),
- PFS HR=0.37 (p < 0.000001),
- Complete response: 50.3% vs 22.0%.
Updated OS: 25.5 vs 12.9 months (HR=0.62) after ≥20 months follow-up.
ODAC Discussion Highlights
Main concern: Region-specific efficacy variance. Only ~9% of participants came from North
America; nearly 50% were from Asia.
In non-Asian subgroups (North America + Europe + Australia), no OS benefit was observed (HR ≈
1.06).
ODAC voted 8–1 against the applicability of STARGLO to the U.S. population.
Concerns centered on generalizability: ethnic, biological, and healthcare system differences
could drive uneven outcomes.
Panel members emphasized the importance of adequate accrual of U.S. patients in confirmatory
trials for FDA review.
Safety & exposure concerns: Adverse events (CRS, infections, hematological toxicities) were
consistent with known profiles; no new safety signals.
Public & sponsor views: Patient advocates and Roche emphasized the significant OS benefit and
COLUMVI’s inclusion in NCCN guidelines as a Category 1 regimen.
Final ODAC vote: The committee unanimously recommended against approval, citing insufficient
evidence for efficacy in the U.S. clinical setting.
Personal Perspective & Regulatory Insights
Clinical impact: COLUMVI + GemOx showed substantial survival benefits in STARGLO’s global
population—doubling median OS and substantially improving PFS.
However, regional heterogeneity in results raises crucial questions about the transferability of
global trial data to U.S. patients.
Regulatory considerations:
1. Multiregional trial design must ensure adequate representation of the target regulatory
population.
2. The accelerated approval pathway continues to rely on OS endpoints in randomized studies.
The lack of robust, regionally consistent OS data weakened the submission.
3. FDA’s stance reflects a broader emphasis on diversity, equity, and inclusion in trials.
4. ODAC reinforced that label expansion requires not only global efficacy but predictable,
interpretable results within the U.S.
Strategic takeaways:
- Pharma sponsors should aim for balanced enrollment strategies.
- Regulatory guidance is trending toward explicit expectations on regional heterogeneity.
- Pipeline planning must include mitigation strategies, such as U.S. expansion cohorts.
Conclusion
While COLUMVI + GemOx holds compelling clinical promise, the ODAC sensitively highlighted
concerns around external validity, heterogeneity in treatment effect, and insufficient U.S.-
centric evidence. In the current regulatory climate—where multiregional trial consistency and
ethical representativeness are paramount—companies must anticipate and address regional
data variability proactively. Moving forward, GNE/Genentech might consider a dedicated U.S.
cohort or bridging study to meet FDA expectations and fully realize COLUMVI’s potential for
DLBCL patients in America.
