ASCO 2017: Melanoma brain mets

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 randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).

2017 ASCO. J Clin Oncol 35, 2017. Long, Atkinson, Menzies, et al.

Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. [No SHIT!!!  And how many times have I yelled about this??????]   Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets. Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) greater than/= to wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:  Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. 

	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)

So....in this report (using only treatment naive and asymptomatic patients)...not surprisingly...the ipi/nivo combo did best in treating folks with melanoma brain mets...as it does in melanoma patients' mets located elsewhere!

Remember the ASCO 2015 link above?  Here are the results of THAT ipi/nivo study:

Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.

ASCO 2017. J Clin Oncol 35, 2017. Tawbi, Forsyth, Algazi, Hamid, Hodi, ...Postow, ….et al.

Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial, MEL pts with greater than/ = to 1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] for greater than or = to 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months. The IC objective response rate (ORR) was 56%; 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. 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. 

	global	intracranial	extracranial
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): 

Outcomes of melanoma brain metastases treated with stereotactic radiosurgery with and without concurrent immune checkpoint therapy.

ASCO 2017. J Clin Oncol 35, 2017. Yang, Cercle, Yaeh, et al.  

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.  

These were not your pristine, 'Oops I have a brain met, who knew?', ratties. Most of these had already been in the trenches with prior neurosurgery and systemic therapy.  That being said, there was no difference in local control when radiation was given alone as compared to when it was given with immunotherapy.  However, overall survival median was not yet reached in those who got immunotherapy WITH radiation, but was only 16.6 months for those with radiation alone. The last sentence may well speak volumes. 

Finally, there's the BRAF/MEK inhibitors...which work on brain mets, too!!!

COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant (mut) melanoma brain metastases (MBM).

ASCO 2017. J Clin Oncol 35, 2017. Davies, Robert, Long, ….Flaherty, et al.

Background: CNS metastases are common and associated with very poor prognosis in pts with metastatic melanoma (MM). In the phase II BREAK-MB trial, D had clinical activity in BRAF V600–mut MBM. D + T has shown superiority over D alone in pts with BRAF V600–mut mm without MBM; however, efficacy of this regimen on MBM has not been characterized. Here, we report results from a phase II trial of D + T in BRAFV600–mut MBM (COMBI-MB). Methods: This open-label, phase II study evaluated D 150 mg BID + T 2 mg QD (Dabrafenib and trametinib) in 4 MBM cohorts: (A) BRAFV600E, asymptomatic MBM, no prior local treatment (Tx); (B) BRAFV600E, asymptomatic MBM, prior local Tx; (C) BRAFV600D/K/R, asymptomatic MBM, with or without prior local Tx; and (D) BRAFV600D/E/K/R, symptomatic MBM, with or without prior local Tx. The primary objective was intracranial response rate (IRR) in cohort A (null hypothesis, IRR less than/= to 35%). Secondary endpoints included IRR in cohorts B, C, and D; extracranial (ERR) and overall (ORR) response rates; intracranial (IDCR), extracranial (EDCR), and overall (ODCR) disease control rates; duration of IR, ER, and OR; PFS; OS; and safety. Results: 125 pts were enrolled (A, n = 76; B, n = 16; C, n = 16; D, n = 17). In cohort A, median age was 52, 53% were male, and 37% had LDH greater than ULN. At data cutoff (28 Nov 2016; median f/u, 9.0 mo), in cohort A, investigator-assessed IRR was 58% (IDCR, 78%), ERR was 55% (EDCR, 80%), and ORR was 58% (ODCR, 80%). Median duration of IR, ER, and OR was 6.5 mo, 10.2 mo, and 6.5 mo, respectively. Median PFS was 5.6 mo. Independent review supported these results. 6-mo OS was 79%; with 31 pts (41%) still in f/u, preliminary median OS was 10.8 mo. Efficacy in cohorts B, C, and D will be reported. AEs across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior D + T studies; 10% of pts (8% in cohort A) discontinued due to AEs. Conclusions: In this first report of a phase II trial evaluating a BRAF and MEK inhibitor combination in BRAFV600–mut MBM, the primary endpoint was met. Promising IRR and IDCR were seen with D + T, but responses appear less durable than reported for mm without MBMs. No unexpected safety issues were observed. 

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