Melanoma sucks great big green hairy wizard balls! And when you add brain mets, you really have a pair!!!! I have been yelling about treatments for brain mets for so long that I feel like Paula Poundstone, "I started writing because banging my head against the wall was starting to chip the paint!" I wrote this post in 2014: Should melanoma brain met patients be allowed in clinical trials?
Along with this one: Anti-PD1 in melanoma: T-cells, the brain, and EVERYWHERE ELSE!!!!
And this in 2015: Yep! Immunotherapy can work in the brain
For far too long, folks with brain mets (and don't even think about leptomeningeal disease) have been EXCLUDED from participation in clinical trials!!! Why???? You can keep them in their own arms... Pharma CEO Person!!!
Finally this study opened: ASCO 2015: New trial for melanoma brain mets!!! Ipi and Nivo, followed by Nivo alone (CheckMate 204) (Wait til you see what's below!!!)
First up: Nivo alone vs ipi/nivo in folks with brain mets.... (hmmmmm...let me think.....):
|A, ipi/nivo (n=25)||B, nivo (n=25)||C, nivo (n=16)|
|ICR %||44 (24, 65)||20 (7, 41)||6 (0, 30)|
|ICR (complete response)||16 (24, 65)||12 (7, 41)||0|
|ECR %||38 (18, 62)||26 (10, 48)||21 (5, 50)|
|6 Month PFS %||50 (33, 75)||29 (15, 50)||0|
|6 Month OS %||76 (59, 97)||59 (41, 86)||44 (25, 76)|
Remember the ASCO 2015 link above? Here are the results of THAT ipi/nivo study:
|Best overall response,
n (%, 95% CI)
|CR||2 (3, 0-9)||14 (19, 11-29)||4 (5, 1-13)|
|PR||40 (53, 41-65)||28 (36, 26-49)||33 (44, 33-56)|
|SD greater than 6 mo||5 (7, 2015)||6 (8, 3-17)||2 (3, 0-9)|
|ORR, n (%, 95% CI)||42 (56, 44-68)||42 (56, 44-68)||37 (49, 38-61)|
Again we are looking at the results of the cream of the melanoma brain met crop: folks who are asymptomatic. Nevertheless, the report above makes it very clear that immunotherapy (specifically ipi/nivo in this case) works in the brain and the body, with 56% of patients attaining an intracranial objective response, 19% of patients attaining a complete response, with responses to head and body being proportional. Side effects were sadly as expected. And while response was attained using immunotherapy only (ie with NO radiation), I'm not sure that, "The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT" is a conclusion that can be so readily drawn. (Especially since they just randomly throw in "whole brain RT"...something we KNOW provides no real benefit in melanoma and is used only in the most extreme cases.)
I am an odd duck in many ways. However, I (and my brain mets) have sat on both sides of this fence. I had one brain met treated with SRS (stereotactic radiation) in April of 2010. Before I could gain access to treatment, I developed another. Still, I was accepted into my Nivo trial, getting my first dose in December of 2010. By the next set of scans, three months later, the met was gone...and this was without additional radiation and nivo only, at a dose of 1mg/kg. Still....given the preponderance of the evidence, I would be hard pressed to choose to forego SRS should I develop another brain met.....
Here are just a few reports:
2015 - Why immunotherapy is good for lots of folks...not just those with melanoma and how radiotherapy may make it even better!
2016 - Nivo (Opdivo) with radiation = better for melanoma patients with brain mets
2016 - One more time....better responses when radiation is combined with immunotherapy
2016 - Brain mets in melanoma: Don't wait to add anti-PD1 to SRS!!! And....TILs correlates with extent of brain edema and survival time in patients with brain mets
2016 - Radiation and ipi = better responses than either alone!!! (AGAIN!!!)
2017 - SRS (radiation) better WITH ipi (immunotherapy) rather than AFTER in melanoma generally, and brain mets specifically
2017 - Efficacy of Pembro (Keytruda) in melanoma brain mets
2017 - Immunotherapy with SRS does NOT increase risk of radiation necrosis in melanoma brain mets!!!
Not to beat a "dead brain met" or anything... I believe in moving with the times and evidence based practice. IF we can attain an equivalent response by treating brain mets with ONLY immunotherapy as we can when immunotherapy is combined with radiotherapy...then I am all for it!!!! However, the links above provide a great deal of data comparing results when we treat melanoma mets with and without radiation be it SRS or gamma knife.
Now, here's this (GKRS is gamma knife radiation and is basically equivalent to SRS, stereotactic radiation):
Background: Evidence supports a synergistic effect between immunotherapy and radiotherapy. [Yep!!!] In this single-institution study, we compared outcomes of patients (pts) with melanoma brain metastases (BMs) who received Gamma Knife Radiosurgery (GKRS) with and without concurrent immune checkpoint blockade (ICB). Methods: Using an IRB-approved protocol, we identified pts with melanoma BMs who received GKRS from 5/2000 to 8/2016. Treatment was deemed concurrent if patients had GKRS within 4 weeks of ICB. Irradiated lesion control, tumor growth rate (TGR; percent change in product diameters per month), distant brain control, overall response rate (ORR) by modified WHO criteria, best response, and overall survival (OS) were compared. Results: 28 pts were identified: 17 (34 BMs total) received GKRS alone; 11 (23 BMs total) received concurrent GKRS/ICB. ICB included: ipilimumab (n = 3), anti-programmed death-1 (anti-PD-1) therapy (n = 4), and combined ipilimumab + nivolumab (n = 4). In comparing baseline characteristics between the GKRS alone and GKRS/ICB groups: median age was 65 v. 59 years, proportion of males was 53% v. 73%, 41% v. 45% had prior neurosurgery, and median number of prior systemic therapies was 1 v. 0. There was no difference in irradiated lesion control (6-month control rate 86% v. 96%; n = 57, median TGR (-14% [range -100% to +61%] v. -20% [range -71% to 0%]; n = 42 lesions), or distant brain control (6-month control rate 68% v. 60%; median follow-up 8.6 months v. 8.0 months) with GKRS/ICB v. GKRS alone. The ORR with GKRS alone v. GKRS/ICB was 61% v. 47%, and the median maximum reduction in BM bidimensional measurement was -69% v. -45%. Median OS from the date of GKRS was not reached for the GKRS/ICB group and was 16.6 months for the GKRS alone group. Conclusions: There was no difference in local lesion control, TGR, or distant brain control with concurrent GKRS/ICB compared to GKRS alone, but the study was limited by small patient numbers and biased by closer follow-up in the GKRS/ICB group. OS was longer with concurrent ICB, likely reflecting the survival improvement with immune checkpoint inhibitors.
Again, no real news here. BRAF/MEK inibitor combo's work in brain mets...much like they work in the body of those who are BRAF +, but responses are not durable. However, when utilized strategically, they are an important part of our arsenal against melanoma.
I hope I have been able to share some needed information and made what is hard to wrap ones head around (I crack myself up!!!), a little more comprehensible. However, at this point, my holy head is tired. I think I'll go make a cute pink Polly top!!! That should get a girl back on track!
Love and thanks to all the ratties. We would know even less if it were not for you! - c
LATE NOTE: The Edster found this video interview in which Dr. Long breaks down some of the data above: Dr. Long talks brain mets as well as Dabrafenib and trametinib
Thanks, Ed! You can look back to a discussion of dabrafenib and trametinib outcomes in a post from December 2016 if you're interested. For what it's worth! - c