Thursday, July 24, 2014

Cytotoxic T cells and BRAFi work on melanoma brain mets! One more time....

...and this is OLD, y'all!

Melanoma brain metastasis:  overview of current management and emerging targeted therapies.
Expert Rev, Neurother. 2012.  Fonhem, Uhlmann, Floyd, et al.

“While ipilimumab cannot cross the blood–brain barrier, activated T cells can migrate into the brain and exert an anti-tumor effect. However, data on its efficacy against melanoma brain metastases are limited.  Only one prior trial enrolled patients with known brain metastases and the inclusion criteria required them to be treated and to have achieved radiologic stability prior to enrollment. Nevertheless, anecdotal reports have indicated that ipilimumab may have efficacy against metastatic melanoma in the brain and the spinal cord. Hodi et al. reported a case of a woman with melanoma that had metastasized to the brain and spinal cord from an unknown primary. After initial treatment with neurosurgical resection of a symptomatic metastasis, adjuvant radiosurgery to other brain metastases, external beam irradiation to spinal metastases and adjuvant temozolomide, she received ipilimumab at the time of disease progression in the brain. Although a new brain metastasis was found during the maintenance phase of ipilimumab treatment, surgical removal of the metastasis demonstrated predominantly CD8+ cytotoxic T cells but few FoxP3+ Tregs, suggesting a fulminant immune response against this brain metastasis rather than tumor progression.”  

And there's this on the BRAFi:    

"The efficacy of vemurafenib against brain metastasis from melanoma is unknown. This is because past clinical trials excluded patients with active brain metastases. However, the physio-chemical property of vemurafenib suggests that it may have difficulty crossing the blood–brain barrier. This is because drug penetrance into the CNS depends on its size...and lipid solubility. Vemurafenib has a molecular weight of 489.9 and its large size makes it difficult to passively diffuse across the blood–brain barrier.

Despite these unfavorable chemical properties, there have been anecdotal reports of vemurafenib efficacy against melanoma brain metastases… A case report described the use of vemurafenib in a 16-year-old woman with rapidly progressive and hemorrhagic CNS metastases from BRAFV600E mutation-positive melanoma despite prior high-dose IL-2, ipilimumab and stereotactic radiosurgery. At baseline she was receiving dexamethasone as the largest of several lesions was 5cm with associated vasogenic edema. She had an excellent response while being dosed at 960mg twice daily, and after 6 months an MRI showed reduction in all brain metastases. 

Dabrafenib (GSK2118436) is another orally bioavailable and specific inhibitor of mutated BRAFV600E protein currently in development. It has the lowest IC against BRAFV600E among its competitors and may have a more favorable chemical profile for penetrating the CNS compared with vemurafenib. In a Phase I/II trial presented at the ESMO 2010 meeting in Milan (Italy), dabrafenib shrank the previously untreated brain metastases in seven out of ten patients. The overall reductions ranged from 20 to 100% of brain metastases that were 3mm or larger in diameter before treatment."

 The final note:

“Five years from now, there will most likely be additional targeted therapies and immunotherapies for metastatic melanoma. Because of the high rate of metastasis to the CNS, the treatment of brain, spinal cord and leptomeningeal metastases will become an even more pressing issue in the management of patients with advanced melanoma. The critical issues will include the design of small molecule inhibitors that have a high penetrance across the blood–brain barrier as well as immunotherapies that can drive more anti-melanoma cytotoxic T cells into the CNS.”

There is not much info included re: anti-PD1 as there was limited data available at the time of this publication.  Additionally, the caveat for most all recently developed drugs is that clinical trials denied access to patients with brain mets or any sort of CNS disease.  I can only hope that folks will start listening to the data and the researchers who have been pressing for a change in the way those issues are managed.  Don't forget this quote, also back in 2012...

Melanoma Brain Metastases: Is it time to reassess the bias? By: Flanigan, Sznol, et al. July 2012. These authors note that melanoma brain met patients are typically excluded from trials. They conducted a chart review of 251 metastatic melanoma patients diagnosed after 2005 to evaluate them in the context of eligibility for treatment with novel agents. And "found median survival of malignant effusion (mets in the pleural cavity) patients was significantly shorter than brain met patients (2 vs 8 months)." Therefore, "exclusion of melanoma brain met patients from clinical research programs is no longer justified and alternate investigational approaches, possibly combining local and systemic therapies, are greatly needed for these individuals." melanoma movers and shakers....GET WITH THE PROGRAM!!!!  Are you listening over there on your forum???? And to all my little ratties....keep on pushing!  Much love - c

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