Overview of treatments for Melanoma Brain Metastases

Novel Treatments for Melanoma Brain Metastases
Kenchappa, Tran, Rao, Smalley, Gibney, Sondak, and Forsyth. October 2013.  Cancer Control.

Twenty years ago, treatment options for patients with melanoma brain metastases (MBMs) were limited, and patients would generally die of the disease within 2 months.  Because of today's rapid progress of effective surgical, radiation, and systemic therapies for metastatic melanoma, hope exists for these patients....trials are being specifically designed for patients with MBMs rather than "lumping" them together with all types of brain metastases.  We believe this approach will accelerate the discovery of effective...therapy.

...Incidence of metastatic brain tumors is 200,000 cases per year in the US, which is ten times higher than the incidence of primary brain tumors.  Melanoma is the third most common cancer that metastasizes to the brain (5-10%, compared with 20-30% of breast, and 40-50% of lung), with a reported survival of less than 9 months.  A total of 50-75% of patients diagnoses with melanoma revealed brain mets at autopsy....

The metastatic process, particularly as it applies to the brain, is complex and poorly understood. [But basically, it takes cancer cells escaping from the primary tumor site, then invading the blood stream, traveling into the brain, surviving, stimulating the growth of circulation develop to supply them, and then prospering - using the brain's microenvironment!] Each step is controlled by genes and signaling pathways. [Therefore, researchers have looked at every step in the process to see if they can find ways to stop continued brain met development at any point.]

Surgical Treatment:
....Per guidelines from the National Comprehensive Cancer Network, when possible, surgery is the first step for the management of MBM.... This rule should be heavily qualified.  For example, in patients with extensive extracranial mets, initial treatment with BRAF or other targeted treatments may take priority, with surgery for MBM reserved for salvage.  Resection eliminates tumor-associated edema and obviates the need for sustained corticosteroid therapy and associated adverse events, which represents an important consideration in melanoma mets because corticosteroids may impair the effectiveness of immunotherapeutic treatment regimens.  For small asymptomatic MBM lesions (<2cm i="" stereotactic="">radiation (SRS) may be considered as first-line treatment over surgery...

Radiotherapy:
Surgical treatment alone is not sufficient for prolonging survival.  Historically, whole brain  radiotherapy (WBRT) has been used to augment surgical resection....  However, SRS is the treatment of choice for patients who are not surgical candidates in an effort to "save the brain."  Melanomas are less sensitive to RT than, for example, lymphomas are, so the efficacy of WBRT is lower. Moreover, the long term cognitive "costs" are high.  Focused RT minimizes the neurocognitive deficits.  Hence, whenever possible, WBRT should be delayed or avoided if other treatment options are available.  The advent of effective systemic treatments (ipi, vermurafenib) to treat MBMs may further change the cost-benefit ratio in favor of SRS.  A new paradigm might include SRS to provide local control followed by systemic therapy to treat and prevent "micro"-brain mets.

Chemotherapy:
...standard chemotherapy for the treatment of MBMs [has been] disappointing.  This may be due to poorly understood factors such as inadequate BBB penetration, [etc].... Temozolomide and fotemustine, both of which do penetrate the BBB, have the best response rates among conventional chemotherapies; however, even they are associated with low response rates and short durations of response...

Novel Treatments:
The use of selective BRAF inhibitors or immunotherapies has indicated that these agents are safe, have significant activity in systemic melanoma, and are active in some patients with MBMs, raising the possibility of changing future treatment approaches for patients with MBMs.


Antiangiogenics:
Although antiangiogenics are commonly studied in systemic cancer, few clinical trials study them in MBMs because of their tendency to produce hemorrhage (up to 20% in some series). Although melanoma is a highly vascular tumor that secretes VEGF [a growth factor that helps vessels grow] and preclinical models show that angiogenesis is required for "dormant" MBMs to grow, a small phase II trial using bevacizumab did not show benefit in systemic melanoma (MBMs were excluded). No trial of antiangiogenics has been conducted for isolated MBMs...

BRAF Pathway inhibitors:
....Dabrafenib was studied in a small cohort of patients with untreated MBMs. Nine of the 10 patients with MBM responded...  ...a phase II study of dabrafenib was conducted...a total of 172 patients with between 1 - 4 active MBMs were stratified...:  no prior brain therapy (cohort A) or prior brain therapy (cohort B).  The overall intracranial response rates in patients with BRAF V600E-mutant melanoma were 39% and 31% in ... A and B respectively.  Median progression free survival rates were 33.1 and 31.4 months, respectively. A lower response rate was seen in BRAF V600K-mutant melanoma....  Patients with BRAF V60E-mutant melanoma may develop brain mets while taking BRAF inhibitor therapy, with the central nervous system as the only site of disease progression in 19% of patients. It will be important to investigate the underlying mechanisms involved in this paradoxical phenomenon and the potential strategies to prevent it....  Currently, patients who develop MBMs while experiencing control of their extracranial disease on BRAF inhibitor therapy can be managed with RT or surgery while temporarily withholding the drug.  An intact BBB may also protect small micrometastases from the effects of systemic BRAF inhibitors until these micromets grow large enough to damage or destroy the barrier, in which case some MBMs that develop while patients are on BRAF inhibitor therapy may retain a degree of sensitivity of the drug.

Immunotherapies
High-Dose Interleukin:
Reports exist of complete response in patients with MBMs who were treated the HD IL-2. A retrospective analysis of 1,069 patients either with metastatic melanoma or renal cell carcinoma found that 7 patients had untreated brain mets and 2 had a brain response. Another...review of  15 patients with MBMs treated with HD IL-2 reported that 2 had a complete response.  Given the nature of this treatment, it is unlikely to be used routinely for this indication...


Adoptive Cell Therapy:
...retrospective analysis...[of] 26 patients with untreated MBM's discovered incidentally in a cohort undergoing immunodepletion (with chemo or total body irradiation) followed by autologous tumor-infiltrating lymphocytes (TILs) or autologous peripheral lymphocytes transduced with a T-cell receptor (TCR)....[showed]....of the 17 patients...[given] TILs, 7 had a complete response in the brain and 6 achieved an overall partial response.  Two of the 9 patients [given] TCR had a complete response in the brain.  Therefore, aggressive immunotherapy used in patients with small asymptomatic MBMs may produce CRs.  These results also suggest that activated T cells traffic into MBMs in the CNS.


Ipilimumab:
Another strategy that has changed the treatment of melanoma is the use of drugs to upregulate T-cell function using antibodies to block the cytotoxic T-lymphocyte antigen (CTLA)4, which potentiates antitumor immune responses.  Ipi, the anti-CTLA-4 monoclonal antibody, prolonged overall survival rates in patients with metastatic mel in two phase III studies. Although traditional radiographic responses were seen in a small percentage of patients (10-15%), many of these responses lasted months to years.  These first pivotal studies excluded patients with MBMs. [Later studies using ipi in brain mets showed that patients with asymptomatic brain mets and NOT on corticosteroids had a 25% rate of disease control, while symptomatic patients with MBMs currently taking corticosteroids had a 10% rate of control.]  ...this study revealed that ipi has activity in MBMs...it is unknown whether the treatment was more effective in larger MBMs in which the highly permeable BBB may allow a greater ingress of activated cytotoxic T cells.

     ...Patience...[in monitoring clinical benefit] is required when using immunotherapies.  Early in the course of treatment, lesions may grow and become symptomatic, which is a pattern seen in systemic melanoma lesions treated with ipi, even though significant clinical response will ultimately occur.  In general, we attempt to wait until the end of the induction phase of ipi before concluding the presence of progressive disease.
      One retrospective review sought to answer whether combination therapy with CTLA-4 antibodies was effective. Control rates using SRS combined ipi were reported and favorable survival and response rates were seen.  In this context, SRS may synergistically work with ipi by lysing tumor cells and presenting a broader antigen repertoire to primed T cells.....

Programmed Death 1 Inhibitors:
Programmed death (PD) 1 is an inhibitory co-receptor on antigen-activated T-cells.  Activated T cells may be suppressed by ligands PD-L1 and PD-L2...Inhibiting the PD-1 receptor with a blocking antibody enhances T-cell responses and antitumor activity. Response rates have been reported in melanoma and in non-small-cell lung cancer.  Patients with radiographically stable (>/= 8 weeks) brain mets were enrolled in these trials, but results in MBMs were not separately reported...

Special challenges:
The use of immune modulators (CTLA-4, PD-1 antibodies) poses...challenges...in treating brain mets...  Although T cells pass through an intact BBB, which is disrupted in MBMs, the brain remains "immunoprivileged"....  This suggests that strategies to increase BBB penetration may increase the efficacy of immune-based approaches...  The concept of delayed response - for example, with ipi - is important to avoid discontinuing the drug too early because of changes in volume enhancement unrelated to tumor growth....

So...not such terribly new information.  But, I thought this presented a nice overview of treatments so far.  I think it is good that they are looking at the fact that when radiation (in the form of SRS) is combined with immunotherapies patients show better responses.  Also glad they are looking at ways to make the T-cell action even better in the brain and in MBMs in particular.

To all my MBM buddies, I wish you my very best. - c