Meningiomas to demonstrate effectiveness given the low 6PFS and

Meningiomas are primary central nervous system (CNS) tumors
that constitute more than 20 % of adult primary brain tumors. Complete surgical
resection offers the best chance of cure but unfortunately it is not safely
possible for all tumors. Histological grading is important because it helps to
predict the likelihood of recurrence with benign meningiomas (WHO grade 1) having
a recurrence risk of 7–20% after gross total resection and atypical meningiomas
(grade 2) having a 40% recurrence rate despite resection. Malignant meningiomas
(grade 3) represent 1–3% of meningiomas but recur in 50–80% of patients.
Despite maximal surgical resection and radiotherapy, a subset of these patients
will recur and require additional treatment. Treatment of these surgery and
radiation refractory recurrent meningiomas require systemic therapy but
unfortunately currently there is no effective systemic therapy that stands out
as standard of care despite a number of agents including chemotherapies,
hormonal and biologic therapies have been investigated.

Recently there has been increasing use of targeted therapies
directed at recognized mutations of meningioma oncogenesis, such as receptor
tyrosine kinases (RTK). The RTKs believed to be most relevant for meningioma
growth and proliferation are EGFR, PDGF, VEGF and recently FGFR. We would like
to summarize the findings of available prospective trials and infer its
significance in terms of present role of receptor tyrosine kinase inhibitors in
recurrent meningiomas. All these trials used six- month PFS as their primary
endpoint for evaluating outcomes with secondary outcome being overall survival
and radiological response. However there is paucity of data regarding the
natural history of untreated recurrent meningiomas making it hard to interpret
results of these trials.

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Trials involving imatinib and erlotinib/geftinib failed to
demonstrate effectiveness given the low 6PFS and lack of radiological response
however there were limitations of these studies which have been summarized in
the table below that could have contributed to the outcome. Along with the low
number of subjects recruited in both of these trails to draw statically robust
conclusions, receptor status evaluation was not done for all patients. Although
PDGFR is expressed in majority of meningiomas and EGFR in more than 60% of
meningiomas but subjects chosen may have had a different phenotype. In
addition, the subjects were heterogenous with regard to pretreatment. The 6PFS
in Imatinib trial in Grade 2/3 meningioma was 0 % whereas it was 29% in
geftinib/erlotinib trial. This could be because in the imatinib trial the
subjects were heavily pretreated as there was no limitation in the number of
prior therapies, which could already signify a more advanced disease resulting
in poorer outcome whereas in the geftinib/erlotinib trial patients having
greater than 2 recurrences were excluded resulting in less heavily pretreated
cohort selection. Another possible explanation could be the inhibition of PDGFR
or EGFR alone is insufficient to prevent growth of meningiomas and that other
tyrosine kinases such as VEGF/IGF/FGF, may play a greater role in maintaining
the transformed phenotype.

Kaley et al evaluated sunitinib in recurrent meningiomas and
it is the first prospective trial to demonstrate efficacy of a medical
treatment for patients with aggressive meningioma. Primary efficacy endpoint
was reached, with PFS6 of 42% in the primary study cohort of atypical and
anaplastic meningioma. Although subject were heterogenous with regard to
earlier trials with other tyrosine kinase inhibitors, sunitinib being a
multi-tyrosine kinase inhibitor (PDGFRa, PDGFRb, VEGFR2, and KIT) might
therefore have been more effective by blocking multiple pathways. However, considerable
toxicity to sunitinib was observed with 30 patients (60%) experiencing grade 3
or higher toxicity but overall toxicity was rather similar to the prior
literature on sunitinib with the exception of the CNS hemorrhages. Correlation
of receptor status with PFS and OS was also done. In 28 patients of meningiomas
( 3 grade 1 and 25 grade 2/3) VEGFR2 expression predicted median PFS of 1.4
months in VEGFR2-negative patients versus 6.4 months in VEGFR2- positive
patients (P ¼ .005). Similarly, VEGFR2 expression predicted median OS of 9.1
months in VEGFR2-negative patients versus 24.6 months in VEGFR2-positive
patients (P ¼ .002). Tumors were variably positive with a wide range for PDGFRa
and PDGFRb, but no significant correlation was noted of PDGFRa or PDGFRb
expression with outcome measures in meningioma. However, it can not be
concluded that VEGF+ is a good prognostic marker as VEGF+ patients who did not
receive sunitinib were not evaluated.

Another recent trial with PTK787 (Vatalanib) also shows anti-tumor
activity of this molecule in recurrent meningiomas with acceptable toxicity
profile. Wen et al. suggested that a positive trial for recurrent Grade II and
III meningiomas would demonstrate a PFS-6 greater or equal to 30%. The
PFS-6 for Grade II/III patients combined was 54.4 % suggesting PTK787 is an active agent
for high-grade meningiomas but this trial could not be concluded as positive
because pre-specified statistical analysis was powered for Grade I meningiomas
based on the assumption that most of the patients enrolled would be grade 1 but
22 out of 25 patients enrolled were grade 2/3.

In conclusion, there have been only a handful of studies
that met their predetermined statistical criteria in evaluating this promising
targeted therapy, although one is currently enrolling and utilizing bevacizumab
(NCT01125046) and would be completed by this year. But there are issues
regarding interpreting data on role of receptor tyrosine kinase inhibitors in
meningiomas due to paucity of trials published, heterogeneity of patients on
these various trials with respect to prior treatment, the variability of tumor
grade, the small numbers of patients treated on a trial, the lack of controls
to which to compare treatment, no standardized response criteria or
”benchmark” for activity (for example PFS-6, ORR or OS) and the absence of
prospective randomized clinical trials.  Also, response assessment is challenging in
this patient population. Macdonald criteria were used measuring the largest
cross-sectional area of the enhancing tumor but as many of these tumors have
irregular shapes, this measurement may be inaccurate. Improved response
assessment criteria for meningioma specifically are needed for more
standardized trial designs in the future. Sunitinib and Valatanib have shown
efficacy against high grade meningiomas and warrant further investigation in
randomized setting. Though, long term durable anti-tumor activity was not
present as all patients finally progressed highlighting that there may be activation
of other pathways, incomplete target suppression or the target not being the
sole driver of meningiomagenesis. Recently AKT and SMO mutations have also been
shown in meningioma so the need of the hour is to either come with a targeted
therapy that block at multiple levels the growth of tumor or try combination
therapy in randomized setting like combining PI3K inhibitor with an mTOR
inhibitor or an AKT inhibitor with an anti-angiogenic agent to more effectively
block alternate pathway activation and to improve the already grim prognosis in
this subgroup of patients.

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