Good morning, I am Dr. Amanda Berhaupt, the Health Policy Director at the National Center for Health Research (NCHR). We are a nonprofit think tank that evaluates scientific evidence on the safety and efficacy of drugs, biologics, and medical devices. We do not accept funding from entities with a financial interest in our work, so we have no conflicts of interest. I am a proud FDA alumna and I appreciate the chance to share NCHR’s concerns about the STARGLO confirmatory trial at this important meeting.
In 2023, Glofitamab-gxbm received accelerated approval for patients with relapsed or refractory:
- diffuse large B-cell lymphoma, not otherwise specified, and
- large B-cell lymphoma arising from follicular lymphoma after at least 2 prior lines of systemic therapy.
The STARGLO trial aimed to confirm Glofitamab-gxbm for that use and to support its use in earlier therapy for the US patient population. STARGLO was a randomized, multiregional trial, with 274 patients residing in four regions; 25 patients in the US, 88 in Europe across eight countries, 30 patients in Australia, and 131 spanning China, Korea, and Taiwan.
- As you know, one group received a Glofitamab-gxbm, gemcitabine, and oxaliplatin (i.e., Glofit-GemOx) drug combination
- while the second group received a combination that substituted Glofitamab-gxbm with Rituximab, gemcitabine, and oxaliplatin (i.e., R-GemOx).
All patients had at least one unsuccessful prior line of systemic therapy and were ineligible for stem cell transplantation.
STARGLO results demonstrated a statistically significant improvement in Overall Survival, Progression-Free Survival, and Complete Response Rate in the group receiving the Glofitamab-gxbm drug combination compared to the other group.
However, the Overall Survival was lower for patients living in the US and Europe than in China, Korea, and Taiwan. White patients, regardless of where they live, were significantly less likely to survive than Asian patients. And the same was true for the secondary endpoints as well.
The FDA described these results as inconsistent, and raised concern about the ‘robustness of the efficacy and safety data and whether results could be generalized to US patients.’
The agency completed a subgroup analysis, merging patients into two groups: those residing in an “Asian region” and others in a “non-Asian region”.
While regrouping led to a balanced sample size to compare results for patients in the Asian and non-Asian regions, only 9% — 25 patients — in the study were based in the US…for a trial seeking drug approval for use in the US patient population…
This means there were only 15 US patients in the Glofitamab-gxbm drug combination group and 10 in the Rituximab group.
A key question is why patients in Asia benefitted from the Glofitamab-gxbm drug combination while patients in the US, Europe, and Australia did not. The US patients were older and were different in terms of their health and healthcare system.
- Most Asian patients were younger than 65 yo compared with non-Asians who were older
- Although the study intended to include patients who were ineligible for transplants, 65% of patients in the Asian region refused a transplant whereas in the US, 60% of ineligibility was due to age.
- There were regional differences in the type of therapies used by Asian patients vs others, as was the cell of origin
- More Asian patients also discontinued treatment due to progressive disease.
The bottom line is that patients studied in Asia benefited from the drug combination under consideration this morning, but the other patients did not.
NCHR applauds the FDA for completing the subgroup analyses. The agency’s main focus is to study treatments for US patients, and the STARGLO trial did not confirm the benefits identified during the accelerated approval of Glofitamab-gxbm. Moreover, there are potential safety concerns for cytokine release syndrome, infection, neurologic toxicity, and tumor flare. The study results are not merely inconsistent — they indicate a lack of benefit for US patients for the indication specified and therefore do not meet the standard for patients and the standard for oncological medical care in the US.