Drug shows ‘very promising’ activity in breast cancer brain metastases
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Sacituzumab govitecan-hziy exhibited efficacy as therapy for two traditionally difficult-to-treat populations, according to results of a window-of-opportunity trial.
Researchers enrolled 25 adults who either had recurrent glioblastoma or brain metastases resulting from breast cancer.
All study participants received a single dose of IV sacituzumab govitecan (Trodelvy, Gilead) — a Trop-2-directed antibody-drug conjugate approved for certain patients with breast cancer or urothelial cancer — a day before surgery. They received subsequent doses on days 1 and 8 of each 21-day cycle after recovery.
Among patients with breast cancer brain metastases, results showed median PFS of 8 months (range, 2-26.5) and median OS of 35.2 months (range, 2.7-37). Among those with recurrent glioblastoma, researchers reported median PFS of 2 months (range, 0.5-13.2) and median OS of 9.5 months (range, 1-28).
Results of an unplanned exploratory analysis showed intracranial objective response rates of 50% among those with breast cancer brain metastases and 28% for those with recurrent glioblastoma.
The ability of sacituzumab govitecan to achieve concentrations of inhibitors inside tumors sufficient to help patients — with minimal toxicity — is “very promising,” according to investigator Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research at Mays Cancer Center at UT Health San Antonio.
“This shows proof of concept that drug concentrations from antibody-drug conjugates can be in a therapeutic range,” Brenner told Healio. “This means we can be looking at antibody-drug conjugates as a means of treating cancer in the brain.”
Healio spoke with Brenner about the study and the potential implications of the findings.
Healio:: Can you describe the rationale for this study?
Brenner: We have had antibody therapies for a long time, but the recent trend is to load chemotherapy onto the antibodies. This enables us to turn those antibodies into a heat-seeking missile that carries chemotherapy directly to the cancer cell to kill it. However, antibodies are big. When we’re talking about delivering therapy to the brain, we have to account for the blood-brain barrier. These antibody-drug conjugates would seem to work well throughout the body but, the question is, do these large molecules get into the cancer in the brain?
Sacituzumab govitecan was developed for triple negative breast cancer, which has a lot of expression of the membrane protein TROP-2 on its surface. We wanted to know what happened to these patients who later developed brain metastases.
Healio: How did you conduct the study?
Brenner: First, we implanted tumors from triple-negative breast cancer into the brains of immunocompromised mice. We then gave half of the mice placebo and the other half sacituzumab govitecan. We saw significant inhibition of growth in the intervention group — the tumors actually shrunk. All animals that didn’t receive treatment died while animals in the treatment group remained alive.
We then decided to do a window-of-opportunity trial and with colleagues at UT Austin developed a method of testing for the payload, the chemotherapy that is attached to the antibody. Whenever we identified a patient who had a brain metastasis who needed to go to surgery to remove it, we approached them and offered to give them sacituzumab govitecan, which is known to work for breast cancer.
The day before surgery, all patients received a dose of this antibody-drug conjugate. We continued to provide patients with the medicine thereafter for any other brain lesions, or to prevent new ones. We enrolled 13 patients with breast cancer brain metastases and 12 patients with glioblastoma. We decided to include patients with brain tumors and not just brain metastases, because these patients are lacking options and the payload is the active component of a drug historically used for these patients.
Healio: What did you find?
Brenner: What’s relatively surprising is that the amount of drug we found in the tumor tissue was about 10-fold higher than the IC50 — the concentration of drug that will kill 50% of the cells. Basically, it’s an active concentration.
We also saw very impressive activity. In the breast cancer group, eight patients who had tumors in the brain following surgery responded to the drug. This means this is an active drug and we should continue evaluating it.
Healio: What are the next steps in research?
Brenner: The SWOG S2007 registration trial is ongoing for this drug for patients with HER2-negative breast cancer and brain metastases. We are halfway done.
Healio: What are the potential implications of this study?
Brenner: This provides preliminary evidence that we can potentially treat breast cancer brain metastases with sacituzumab govitecan. To a lesser extent, we showed that we should be looking at this drug in glioblastoma, an incurable primary brain tumor for which the 5-year survival is only 4%. We’re not making the claim that this is ready for use in clinical practice, but we’re saying these are very promising findings for both diseases. It also adds a significant piece to the data for antibody drug conjugates in treating cancer in the brain.
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For more information:
Andrew J. Brenner, MD, PhD, can be reached at brennera@uthscsa.edu.
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