Hi, I write again seeking advice. I have very much appreciated comments/advice over the years and the expertise of those on this blog. Unfortunately, for some weird reason I cannot respond to responses, but am very appreciative!
My 26 y/o son has had another recurrence of his IDH1+ secondary GBM in L frontal lobe..
To summarize his past history, he had an AA3 diagnosed when he was 18 y/o treated with GTR and proton therapy only (clinical study) and had 5 good years where he graduated from college (with honors), worked and started medical school. His tumor recurred his 1st year of med school as a very small area of IDH1+ low mutation GBM (unmethylated) treated with aggressive GTR and then started on BGB-290 and TMZ study. He was on study from 4/18 thru 7/19. He completed a year of med school successfully while on chemo, but pretty low doses of TMZ used due to anemia (needed a few transfusions). A 3 mm "scar" seen on 5/19 scan grew into a large tumor by 7/19. So, since not great options, we opted for immunotherapy given his hematologic issues with preceding therapy--he was enrolled in IL-12 + Veledimex +PD1. His recurrent tumor was found to be hypermutated and now methylated (?)--so thought it turned out to be an appropriate choice. He had another GTR 8/19 with excellent neuro recovery. His MRI showed a strong inflammatory response around meninges/spinal cord, which study group felt was due to treatment (and they were correct). Anyway, MRI at 2 months after surgery showed a large L frontal lobe mass--thought was that it could be pseudoprogression, but surgical path showed all tumor (don't have final path yet).
So...he had another GTR (fabulous neurosurgeon) and has no obvious cognitive deficits (he is tutoring Latin grammar at the moment). He starts radiation next week (has been 7 years since proton) and will likely still have immunotherapy and ...something else. (Immunotherapy--likely Keytruda which is FDA-approved for mismatch repair deficient tumors?)
His current neuro-oncologist seems excellent, but the question is what else?
Options that have been considered--olaparib--radiosensitizing and might work with IDH1
--CCNU--old standby--don't know how long will tolerate
--regorafenib--superior to CCNU in one study--fewer blood probs?
Interestingly, his tumor did not grow at all in the 2 weeks before surgery, so wonder if immunotherapy was starting to kick in, though I was told that tumor growth is not always linear.
I know that this history is long and somewhat technical, but also that there are some very knowledgeable people on this blog. Any insights of those on immunotherapy, CCNU or regorafenib would be appreciated. I would also be curious if anyone has been on olaparib--it was tolerated well with radiation in elderly patients in British study.
Thank you so much for any help you can give....Anne
Thats fantastic that your son has been able to have such a great QOL during all of this.
ReplyDeleteIt certainly is a complicated case at this point. I'm currently on olaparib (150mg daily 3 out of 7 days a week) and TMZ daily (75mg/m2). I'm not thrilled about the combo because studies have shown that it doesn't get into the brain terribly well except in regions with higher BBB disruption (high contrast enhancment on mri). So I have some doubts about the overall efficacy of adding Olaparib. On the other hand though Olaparib is one of the 'gentler' parp inhibitors in terms of blood counts. BGB-290 on the other hand has been showing some pretty high rates of blood issues. But considering he had significant progression on BGB it seems questionable to continue TMZ. CCNU may be more effective but is also notably harder on blood counts and isn't used in combo with radiation.
So doing a metabolic approach combined with immunotherapy during radiation could be an option. Metabolic could be metformin, or full care oncology clinic protocol, and or keto diet (which may be challenging to do on such short notice). Plus as you noted immunotherapy takes some time to build efficacy. Doing more chemo would do damage to immune system and be a setback in that axis of treatment. As you noted Regorafenib has much lower impact on blood counts and so could possibly be a better option, though combining with immuno-therapy may be uncharted waters. Regorafenib during RT would also add toxicity and would need evaluated for safety.
Finding the optimum combo might not be feasible on short notice, so getting any reasonable synergistic treatment setup for RT might be the main goal.
If the tumor is now indeed hypermutated (which company did the testing?), I would stay away from TMZ. The best chemo option for such a tumor is probably lomustine.
ReplyDeleteMy friend had a recurrence of a secondary IDHmut GBM a couple years ago, which was also found to be hypermutated. She was treated with 5 rounds of lomustine (after this her blood counts went too low and she discontinued) along with some Avastin, and this combo seemed to be very helpful. I suspect the lomustine was more important than the Avastin for this particular tumor type.
Given that he progressed on a trial that included another PD-1 inhibitor, I wonder whether you would have trouble getting pembrolizumab approved for him.
Regorafenib was found to be helpful in a trial of recurrent GBM (most would have been IDH wild type). Be aware IDH-mutant tumors tend to have a different profile of pro-angiogenic genes and growth factors, so we can't necesssarily extrapolate that it would work just as well for IDH-mutants.
Given my friend's experience, with a hypermutated IDH-mutant secondary GBM, I think lomustine (with or without Avastin, with or without pembrolizumab) would be my choice, at least as long as it is tolerable. He would probably start after the completion of radiation.