Treating Progressive Optic Pathway Glioma With Tovorafenib
In this video, Ashley Plant-Fox, MD, reviews a case of a 16-year-old patient with progressive BRAF fusion–positive optic pathway glioma after multiple prior treatments. She explains her rationale for choosing tovorafenib as the next line of therapy and how she managed laboratory abnormalities during treatment. While on tovorafenib, the patient experienced approximately 40% tumor shrinkage and resolution of her headaches, with no further shunt revisions; her disease remained stable three years after treatment ended.
Transcript:
Hi, my name is Ashley Plant-Fox. I'm a neuro-oncologist at Lurie Children's Hospital in Chicago. I'm an associate professor at Northwestern Medicine as well. Today, I'm presenting a case of a 16-year-old female who initially was diagnosed with a low-grade glioma in the context of diencephalic syndrome when she was an infant. Her tumor was found based on her diagnosis of failure to thrive and not knowing why that was happening. Eventually, she got an MRI that showed the tumor, and she was treated for that with standard-of-care chemotherapy. With vincristine and carboplatin, she responded to that initially and was able to have stabilization of her tumor and was able to grow at that time. Unfortunately, years and years' worth of treatment for subsequent recurrences occurred before she came to our attention. She was referred to us when she was 16 years old, when her team felt that they had exhausted all treatment.
So during that time, the important background was that she had mostly just achieved stabilization of her tumor on any of her prior chemo regimens. So we were really looking for something that might do more than that for her. She had accumulated a lot of toxicities from her other treatments. Also, in the last month, she had had six revisions of her ventriculoperitoneal shunt, mostly because of the obstruction from the tumor and its bulky size. Surgery had been considered but was thought to be too risky. She was having chronic headaches and was really looking to potentially try something that could give her both a clinical and radiographic response, hoping that the obstruction from the tumor maybe could be alleviated in that setting. So while we had multiple ideas of other chemotherapies we could do, or even circling back to prior chemotherapies that she had had stabilization on, we were really looking to try something that might be targeted.
She did have a KIAA1549::BRAF fusion. She hadn't tried any of the targeted agents yet outside of a MEK inhibitor, and we had been hopeful about the responses we had seen on FIREFLY-1 in some of our patients, both from a clinical and radiographic perspective. So we chose tovorafenib at that point. It was generally well tolerated. We were very optimistic when her headaches, which had been occurring daily, resolved by two months into the treatment, and the family and patient were very excited about that benefit alone. The first MRI at three months did show about a 25% response in the tumor, which was great. And the best response was seen at six months, which was around 40% improvement from baseline. This also resulted in the first time in many months not having issues with the shunts. So she didn't have to have any revisions after starting tovorafenib, which was one of the most exciting things to the family, given she had been through so many surgeries for that.
So both a clinical and radiographic response. Around the time of the six-month MRI, we did note on routine labs that she had a CK elevation. This increased to a number in the thousands, at which point we did hold the drug for two weeks and monitor her labs. It quickly came down off of the drug, on the drug hold, and we were able to resume without any recurrence of the CK elevation. So we had worked up that CK elevation, checking her urine for myoglobin. She was asymptomatic. We had her drink lots of water just to ensure we were supporting her if there was anything brewing, but fortunately it was just a lab abnormality. She didn't subsequently develop any symptoms and was able to go back on the drug, no problem. We also followed her anemia that resulted from being on tovorafenib, but she never required a transfusion, and that kind of stabilized out as well.
She did have low phosphorus, for which we gave her supplementation. She only required twice-a-day supplementation at the max, and she was able to continue on with stable levels from there. Once she got to 26 cycles, which is what we had previously treated to on the FIREFLY-1 trial, we had talked about whether or not we would discontinue. At that point, she had had a year and a half of this 40% reduction being stable throughout, with resolution of her clinical symptoms that she had initially presented with. And of course, she kind of wanted to return to normal life at that point and stop taking therapy if she could. The family was very interested in the idea of weaning, given they had weaned the trametinib with success in the past. We did reach out to the company regarding the idea of weaning and had learned about some concerns about paradoxical activation at lower levels of the drug.
So we decided that, based on that, it wasn't safe to do a wean and just stopped it completely at that point after completion of 26 cycles. She had no rebound growth on subsequent MRIs and is now three years off treatment with continued stable disease and continued clinical improvement and no long-term toxicities from her therapy. So overall, we felt like this was a very successful treatment for her, and she was able to return back to her local doctors for further monitoring.
