Phase III Stimulus-MDS2 Study of Sabatolimab and Azacitidine vs. Placebo and Azacitidine as Frontline Therapy for Patients with Higher Risk MDS or CMML-2
Dr. Amer Zeidan, MBBS, MHS, Yale Cancer Center
My name is Amer Zeidan. I'm an associate professor of medicine at Yale University and the chief of the Division of Hematologic Malignancies at Yale Cancer Center. I was in Madrid for the European Hematology Association meeting in June 2024 where I presented topline results from the Stimulus-MDS2 study.
This is a large, randomized phase 3 study in patients with high risk MDS in the frontline setting, where more than 500 patients with high risk MDS, around 530 to be specific, were randomized to receive Azacitidine with an anti-TIM-3 antibody called Sabatolimab versus Azacitidine with placebo.
As we all know, Azacitidine is the standard of care in the management of higher risk MDS patients. But we have been trying over the years to add additional therapies so that we can improve the outcomes of those patients. Earlier studies have suggested that Sabatolimab could increase the duration of response as well as increase the progression-free survival in patients with high risk MDS.
The idea of this study was to assess the benefit at the level of the overall survival, which was the primary endpoint of this study.
This was a large international, multicenter trial -- took place in more than 30 countries, more than 150 centers participated in this study. And patients were enrolled with an average age in the low 70s, which is a typical age for patients with MDS. Patients on the two arms were mostly balanced in terms of their characteristics, in terms of markers of their disease severity.
The primary outcome of the study was not statistically significant. However, the median overall survival with the combination arm was around 22.5 months compared to 18.5 months in the placebo arm. So, there was a three-and-a-half-month improvement in the outcome of, patients. However, the p-value was .08. So, it was slightly higher than statistical significance. But we did also observe favorable trends in other settings.
For example, the rate of the complete remission was higher in the Sabatolimab plus Azacitidine arm -- 19% compared to 14% in the Azacitidine and placebo arm. Also, the progression-free survival and the leukemia-free survival were in favor of the combination arm.
In terms of the adverse events, we did not see a significant, or something beyond what we have seen in previous studies. There was slightly higher incidence of grade three, hematologic adverse events, which is quite common in MDS studies. But there was no increase in the death rate or the early mortality.
This study also included a large number of patients with different mutations, including TP53 mutation. Around one quarter of the patients had TP53 mutation. And this is a subset where there was previous studies suggesting that they could be more prone to respond to immune-modifying drugs. However, there was no improvement here for those patients with TP53, which is a very high subset of patients with a significant, high unmet need.
So, in conclusion, there was a trend for improving overall survival with the combination. However, there was not a statistically significant improvement. And we are currently looking at the correlative laboratory assessment from the study to try to fully understand if there are biological subgroups that might have benefited more from this therapy.
Glofitamab plus Gemcitabine and Oxaliplatin (Glofit-GemOx) for Relapsed/Refractory Diffuse Large B-cell Lymphoma: Results of a Global Randomized Phase III Trial (STARGLO)
Jeremy Abramson, MD, Director, Jon and Jo Ann Hagler Center for Lymphoma, MGH, Associate Professor of Medicine, Harvard Medical School
I'm Jeremy Abramson. I'm director of the lymphoma program at the Massachusetts General Hospital Cancer Center and I'm an associate professor of medicine at Harvard Medical School.
At the most recent EHA meeting, we had the honor of presenting data from the STARGLO trial in the plenary session.
STARGLO is a randomized, controlled, phase 3 trial evaluating the bispecific antibody Glofitamab combined with Gemcitabine and Oxaliplatin versus Rituximab†plus Gemcitabine and Oxaliplatin, specifically as treatment of relapsed refractory diffuse large B-cell lymphoma after one or more prior lines of therapy.
The bispecific antibody Glofitamab has already been FDA approved based on the pivotal phase 1/2 trial evaluating Glofitamab monotherapy in patients with DLBCL after two or more prior lines of therapy, where it induced deep and durable rates of complete remission.
So, this randomized trial is evaluating whether we can move Glofitamab earlier in the line of therapy, combining it with chemotherapy with the goal of optimizing outcomes for patients with second line or later diffuse large B-cell lymphoma, and specifically patients who are considered transplant ineligible.
STARGLO was conducted across 13 countries in four continents, 274 patients were randomized 2 to 1 to receive Glofitamab-GemOX or R-GemOx. And we stratified patients whether they had relapsed or refractory disease and whether they had 1 or 2 or more prior lines of therapy.
And the primary endpoint of this trial was overall survival. Key secondary endpoints include progression free survival and complete response rate.
Among randomized patients the median age was 68 years old. The majority of patients had advanced stage disease, and 63% of patients had received one prior line of therapy, whereas 37% had received two or more prior lines of therapy.
Just over half of patients had primary refractory disease, and 60% of patients on both arms had disease that was refractory to their immediate prior line of therapy.
When we looked at our primary endpoint of overall survival, we found a statistically significant benefit for overall survival, favoring Glofitamab-GemOX in the primary analysis, with a hazard ratio of 0.59 And with 21 months of median follow up, we found that the median overall survival was 12.9 months for R-GemOx and 25.5 months for Glofitamab-GemOx.
We also saw an improvement in our secondary endpoint of progression-free survival, with a hazard ratio of 0.37, correlating with a 63% reduction in risk of progression or death favoring Glofitamab.
This correlated with a median progression-free survival of four months on R-GemOx compared to 14 months on Glofitamab-GemOx. Complete response rates also favored the Glofitamab-GemOx ARM at 58.5%, compared to 25%.
And in general, we saw that the toxicity profile in this study was consistent with the expected toxicities of the respective drugs.
We did see more serious adverse events on the Glofitamab-GemOx arm, but this largely reflected the expected toxicities Glofitamab, which were entirely manageable and generally reversible.
And this included a 44% rate of cytokine release syndrome. But this was almost entirely low grade and occurred predominantly during the first cycle of step-up dosing.
These results demonstrate that Glofitamab-GemOx substantially improves overall survival, progression-free survival, and complete response rate as second line or later therapy for diffuse large B-cell lymphoma.
This compares favorably with other options in the second line and later space presently, and it's an off-the-shelf, immediately available option unlike Car-T cells, which many patients do not have access to, or their disease kinetics prevent them from immediately proceeding to Car-T cell therapy. So, I think these data do support Glofitamab-GemOx as an exciting treatment option available to patients in the second line or later setting. And this is the first data to demonstrate second line activity of any bispecific antibody in a randomized trial for patients with non-transplant eligible DLBCL.
