Roche’s Genentech Faces Setback as FDA Advisory Committee Rejects Columvi Expansion Proposal
The U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) delivered a significant blow to Genentech, a subsidiary of Roche, by voting overwhelmingly against the company’s attempt to broaden the approved use of its bispecific antibody, Columvi. The proposed expansion aimed to include transplant-ineligible patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), a critical segment of patients who urgently need more therapeutic options. However, concerns over the clinical trial data submitted to support the indication expansion ultimately led to the panel’s decisive rejection.
The Vote and Its Significance
On Tuesday, the FDA’s independent panel of cancer experts voted 8 to 1 against the recommendation to extend Columvi’s indication to cover transplant-ineligible R/R DLBCL patients when used in combination with gemcitabine and oxaliplatin. This rejection represents a notable setback for Genentech’s efforts to make the drug accessible to a broader patient population.
The advisory committee’s vote carries considerable weight in FDA’s regulatory decision-making process, often influencing the final approval or rejection of new drug indications. While the FDA is not bound to follow the committee’s recommendations, it typically aligns with their expert opinions.
Concerns Over Clinical Trial Population and Applicability
The primary reason for the committee’s disapproval centered on the patient population enrolled in Genentech’s pivotal Phase III clinical trial, STARGLO, which the company relied on to demonstrate the safety and efficacy of Columvi for this new indication. The panel highlighted that a substantial proportion of STARGLO participants—approximately 50%—were Asian patients. In stark contrast, only 25 patients enrolled were from North America.
This discrepancy raised significant concerns about whether the trial data could be reliably extrapolated to the broader U.S. population. Factors such as genetic differences, dietary habits, environmental exposures, and varying standards of care can affect how patients respond to therapies, prompting doubts about the applicability of the trial results to U.S. patients.
The FDA itself flagged this issue during its review presentation, emphasizing the challenges inherent in relying on foreign data to inform U.S. treatment decisions. Such concerns are particularly relevant in oncology, where subtle biological differences can impact both efficacy and safety outcomes.
Expert Commentary on Global Trial Data Use
Ravi Madan, head of Prostate Cancer Clinical Research at the National Cancer Institute and an ODAC panelist, articulated the nuanced challenge in balancing global drug development with the need for U.S.-specific data. Although he acknowledged that oncology research increasingly involves multinational trials, Madan stressed the importance of sponsors making “deliberate decisions” to ensure that clinical evidence truly reflects the population where the drug will be marketed.
Madan pointed out that this issue “is further accentuated when standards of care or practice patterns differ” between countries, underscoring the potential for regional disparities to influence trial outcomes. His comments highlight a broader regulatory and scientific challenge that sponsors face in designing clinical programs that adequately serve diverse populations.
About Columvi and Its Current Approval
Columvi (generic name: glofitamab) is a bispecific antibody designed to simultaneously target two key proteins: CD20 on B-cells and CD3 on T-cells. This dual targeting mechanism helps redirect the immune system to recognize and destroy malignant B-cells in patients suffering from B-cell lymphomas.
The drug received accelerated FDA approval in June 2023 for adults with relapsed or refractory diffuse large B-cell lymphoma who have previously undergone at least two lines of systemic therapy. This approval marked a promising new treatment option for patients with limited alternatives, offering a novel immunotherapeutic approach in a challenging disease setting.
Genentech’s Expansion Proposal
Following the initial approval, Genentech sought to expand Columvi’s use to a subgroup of patients with R/R DLBCL who are ineligible for autologous stem cell transplantation—a procedure often considered the standard of care for eligible patients. This group includes individuals with significant comorbidities or other factors precluding intensive treatment.
Genentech argued that these patients face “an urgent need for effective, immediately available therapies,” underscoring the unmet medical need in this population. The company submitted the STARGLO trial data to support this expansion, hoping to offer a new therapeutic option for a vulnerable patient group.
Contrasting FDA Advisory Committee Outcome for Johnson & Johnson
The same ODAC meeting provided a contrasting example in the form of Johnson & Johnson’s Darzalex Faspro (daratumumab and hyaluronidase-fihj), a well-established anti-CD38 monoclonal antibody approved for multiple myeloma. Johnson & Johnson sought to expand Darzalex Faspro’s label to include adult patients with high-risk smoldering multiple myeloma, an early form of the disease.
In this case, the FDA advisory committee voted 6 to 2 in favor of the expansion, finding that the benefits of Darzalex Faspro outweighed the risks as a single-agent therapy in this patient population. The decision reflects confidence in the supporting clinical data and suggests a positive benefit-risk profile.
Broader Implications for Oncology Drug Development
The divergent advisory committee votes on Columvi and Darzalex Faspro highlight several critical themes in oncology drug development and regulatory review:
- Data Representativeness: The importance of ensuring that clinical trial populations adequately reflect the intended treatment populations, especially when expanding indications to new subgroups.
- Global vs. Local Evidence: The challenge of balancing increasingly global clinical development programs with the regulatory requirement to demonstrate safety and efficacy in specific local populations.
- Unmet Medical Needs: While regulators recognize the urgency to provide therapies for underserved patient populations, the evidence must be robust and applicable.
- Regulatory Scrutiny: Advisory committees are rigorously evaluating not just the clinical efficacy of new therapies but also the relevance and quality of underlying data.
Next Steps for Genentech
Following the advisory committee’s vote, Genentech will likely need to reassess its clinical data and development strategy for Columvi’s expanded indication. The company might consider conducting additional trials with a patient population more representative of the U.S. demographic or providing supplementary data addressing the committee’s concerns.
The FDA’s final decision is still pending but will likely be influenced by the ODAC vote and the broader considerations discussed during the meeting.
The FDA’s Oncologic Drugs Advisory Committee has cast doubt on Genentech’s proposal to extend Columvi’s use to a wider group of diffuse large B-cell lymphoma patients ineligible for stem cell transplant, primarily due to concerns about the relevance of clinical trial data to the U.S. population. This decision underscores the critical importance of patient population diversity and data applicability in oncology drug approvals.
In contrast, Johnson & Johnson’s Darzalex Faspro secured favorable advisory committee backing for its own indication expansion in multiple myeloma, illustrating that strong, relevant clinical evidence remains the cornerstone of regulatory success.
As the FDA moves toward its final determinations, the outcomes of this advisory committee meeting will resonate within the oncology community, influencing how pharmaceutical companies design clinical trials and approach regulatory submissions for new and expanded cancer therapies.
