BRAF studies from ASCO...and: NEW study open for BRAF positive NED melanoma patients!!!!

Updated overall survival for BRF113220, a phase 1-2 study of dabrafenib alone versus combined dabrafenib and trametinib in patients with BRAF V600 positive metastatic melanoma
Abstract 9010, ASCO
Flaherty, Daud, Weber, Sosman, et al

BRAF V600E/K positive, metastatic melanoma patients who had never taken either drug were enrolled.  Some were given dabrafenib alone and others the dabrafenib and trametinib combo...both at various dosage rates.  Cross over after progression on dabrafenib alone was allowed.  Updated data shows overall survival at 18 months for dabrafenib alone = 56%, for the combo =67%.
(My thoughts will follow in red!) Bit of an update on an older study.  Bottom line: dabrafenib and trametinib combo = better than dabrafenib alone.


Phase II study of vemurafenib in patients with locally advanced, unresectable stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E
Abstract 9075, J Clin Oncol
Hallmeyer, Hamid, Sorof, Mun, et al

Study was designed to look at response and reaction of stage IIIC or IV melanoma patients (previously treated or not with other therapies) with measurable disease and NON V600E BRAF mutation.  As of October 2013, 10 US sites enrolled 29 patients - 12 with V600K, 17 with non-V600K mutations.  7% of patients had never had treatment, those who had been treated had experienced a median of 2 prior therapies.  At this interim point of analysis:  12/29 (41%) of patients had an unconfirmed response (5 V600K, 3 V600R and 4 other).  Confirmed response was noted in 3 (V600K, V600R, and D594G).  There were no complete responses.  Adverse events were what is known to be typical for drug. Conclusion: Preliminary results - objective responses were attained in patients with rarer non-V600E BRAF mutations.
Small numbers...but patients with mutations other than V600E did respond to vemurafenib.

On-demand Gamma Knife combined with BRAF inhibitors for the treatment of melanoma brain metastases.
Abstract 9083 J Clin Oncol
Marqueste, Carron, Delsanti, et al (out of France)

Cases of radiosensitization after conventional radiation therapy in BRAFi treated patients had caused concern about using this combo.  In this study, blind review by 2 independent observers of brain MRI f/u scans and survival assessment in all patients treated with Gamma knife and BRAFi at a single institution, was completed.  Gamma knife was done on 30 patients who had previously been given BRAFi, 24 patients were under BRAFi treatment (with only 4 of those interrupting the BRAFi for the gamma knife procedure) and 15 patients had Gamma knife before starting BRAFi.  Out of 263 brain mets treated, only 3 edemas and 3 hemorrhages were detected within 2 months of gamma knife and 4/7 were noted later.  No brain met radiation necrosis and no scalp radiation dermatitis occurred.  Neither the MRI features nor the incidence of the rare adverse events were deemed unexpected in such a population.  Conclusion:  This series does not show immediate radiotoxicity nor radiation-recall in BRAFi patients treated with Gamma knife.  Interrupting  BRAFi for stereotactic radiosurgery of brain mets seems useless.
So...the fears about combining BRAF therapy and radiotherapy seem unfounded...combo = good!

Brain mets in melanoma patients:  Associations with BRAF status and age.
Abstract e20037 J Clin Oncol
Marinoli, Cocorocchio, Pennacchioli, et al (out of Italy)

Advanced melanoma patients (271) were tested for BRAF mutations and retrospectively analyzed.  V600 BRAF mutations were found in 53% and were associated with younger age at diagnosis and primary tumor site and had higher incidence of brain, but not of other visceral mets.  In young patients, wild type and V600 BRAF had a comparable incidence of brain mets, but wild-type was associated with a shorter brain met free interval.  In older patients, V600 BRAF had a higher incidence of brain mets and a shorter brain met free interval.  BRAF mutation per se, had no clear impact on overall survival.
OK.  So this is a little convoluted...but - If you are young and BRAF positive, you are likely to have your first primary sooner and greater incidence of a brain met.  If you are young with wild type, your brain met free interval may be shorter.  Older BRAF positive patients flipped...and showed a higher incidence of brain mets and shorter brain met free interval.  Big question here..."young" and "older" = what????   We can use me as a sort of messed up (due to anti-PD1 therapy) test case, as I am BRAF positive, diagnosed initially at age 39, went 4 years before another dermal met with no treatment other than surgical resection of lesion, positive sentinel node, and subsequent complete lymphadenectomy.  Treatment after second met = same, except no positive node.  3 more years before brain and lung mets, treated with SRS and surgery respectively.  Then 4 months and a tonsilar met, surgically removed.  Then, 2 1/2 years of Nivo (anti-PD1) and still NED.  Hmmm.... What will happen next??? 

Survival, response duration, and activity by BRAF mutation status of nivolumab (anti-PD1, BMS-936588) and ipilimumab concurrent therapy in advanced melanoma
Abstract LBA9003

Sznol, Kluger, Kirkwood, Wolchok, et al

53 melanoma patients were enrolled from 2009-2012 and were given ipi and nivo concurrently, then followed by nivo alone (with a variety of dosing patterns). Patients with and without BRAF had similar response. 

NIVO (mg/kg) + IPI (mg/kg) [n]	1-Y OS rate, % [pts at risk]	Median OS, mo	ACAR, %	ACAR by BRAF MT status,* % [n]
				Pos	Neg	Unk
0.3 + 3 [14]	56 [7]	14.8	57	50 [4]	67 [3]	57 [7]
1 + 3 [17]	94 [13]	NR	65	50 [2]	50 [6]	78 [9]
3 + 1 [16]	89 [3]	NR	81	67 [3]	85 [13]	– [0]
3 + 3 [6]	100 [5]	NR	83	100 [1]	75 [4]	100 [1]
Concurrent [53]	82 [28]	39.7	70	60 [10]	73 [26]	71 [17]
Sequenced† [32]	Insufficient followup	13.0	44	44 [9]	47 [15]	38 [8]

 So with ipi and nivo, combo or alone, BRAF status doesn't seem to affect response.

BRIM8:  A phase II, randomized, double-blind, placebo controlled study of vermurafenib in adjuvant therapy in patients with sugically resected, cutaneous BRAF-mutant melanoma at high risk for recurrence (NCT01667419)
Abstract TPS9118, ASCO

Lewis, Maio, Mandala, et al (Aurora, Colorado; Bergamo, Italy; San Francisco, CA; Essen, Germany)

Study for:  Stage IIC, IIIA, IIIB, or IIIC melanoma patients, BRAF V600 positive, and COMPLETELY RESECTED. Must have sentinel lymph node biopsy, even if no clinical or radiological evidence of disease.  If evidence of regional or sentinel lymph node involvement must undergo complete regional lymphadenectomy.  NO prior systemic therapy allowed - including interferon, limb perfusion or radiation therapy.  As of May 2014...still actively recruiting.  Birmingham, AL, Multiple CA sites, CO, FL, Illinois, Indiana, Kentucky, NJ, Michigan, Missouri, NY, NC, PA, SC, TN, TX, WV...as well as other international locations. 
Still actively enrolling!!!!!!!  Before my brain and lung met scenario...I would have qualified and think I would have done this.  Seems to me that using some of these successful therapies when the least disease possible is present is the way to go!

If BRAF and the mutation business is still confusing....I broke it down before.  Check out the link below if interested.  Wishing you all my best.  More from ASCO to come! - c

Explanation of BRAF in melanoma