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Antibodies for the brain. Discuss the clinical efficacy of the following antibody-based therapies: (i) Bevacizumab for glioblastomas, (ii) Erenumab for migraine.
Monoclonal antibodies (mAbs) are antibodies derived from a single B-lymphocyte clone of cells and consist of identical antibody molecules (Figure 1)(1). They can be designed to theoretically target any protein, and with the recent advances in biotechnologies they can now be mass produced(2). Pharmacologically speaking, they are large proteins, with often poor oral availability and long plasma half-life, and as such are often administered in injection form (intravenously or subcutaneously) at monthly intervals(3). mAbs have become an important approach as possible therapies to various neurological diseases where available treatments have been suboptimal. This essay will focus on the clinical efficacy of two examples: bevacizumab for the treatment of glioblastoma, and erenumab for the treatment of migraine. It should be noted that data on safety (adverse drug reactions etc.) and cost-effectiveness are both important factors to consider but are beyond the scope of this essay.
Figure 1. Diagram showing the basis of how monoclonal antibodies are derived(1). An animal (typically a mouse) is immunised with the selected antigen (the target protein) to stimulate the formation of antibody-forming immune cells. These immune cells are then isolated from the spleen of the animal and fused with myeloma cells to produce an immortal hybridoma. This is then screened for the antibody against the antigen of interest. These antibody-producing hybridoma cells can be isolated and grown in culture to mass produce a single population of monoclonal antibodies.
Part 1: Bevacizumab for glioblastomas
Glioblastoma is the most common and most aggressive form of primary malignant brain tumour in adults(4). It comprises 15% of all brain tumours, and arises specifically from the astrocyte cell type. They are fast-growing and likely to spread, and tend to occur in the elderly. The mainstay of treatment therefore remains palliative and involves maximal surgical resection, followed by a combination of radiotherapy and chemotherapy with DNA akylator temozolomide(5,6). Its prognosis remains poor, with a 5-year survival of approximately 10%(7). Little further improvements have been documented in terms of outcomes since the introduction of radiotherapy-temozolomide therapy in 2005.
Glioblastomas are characterised by overexpression of vascular endothelial growth factor A (VEGF-A), a protein involved in angiogenesis (the formation of new blood vessels)(8). Several approaches have been proposed to target this protein, one of which involves the use of mAbs. Preclinical models have shown anti-angiogenic therapies ‘normalise’ tumour-associated blood vessel structure and function, therefore improving blood flow(5,9). This in turn should improve delivery of oxygen and cytotoxic agents to the tumour, potentially enhancing the efficacy of both radiotherapy and chemotherapy(9,10). This essay will focus on bevacizumab, as an example of a recombinant humanised mAb that inhibits VEGF-A(8). It was first approved for patients with recurrent glioblastoma in 2009, but its efficacy in newly diagnosed glioblastoma still remains uncertain. This essay will therefore discuss the evidence available on both its efficacy in patients with newly diagnosed and recurrent glioblastoma.
Clinical Efficacy of Bevacizumab
.1 In Recurrent Glioblastoma
The FDA approval of bevacizumab for patients with recurrent glioblastoma came following the results from 2 phase II clinical trials(11,12). The main findings of these are summarised in Table 1.
Abbreviations: BEV = bevacizumab; IRI = irinotecan; LOM = lomustine; mono = monotherapy; OS = overall survival; OS6 = rate of OS at 6 months; OS9 = rate of OS at 9 months; PFS = period-free survival; PFS6 = rate of PFS at 6 months; 95%CI = 95% confidence intervals.
*Note that this table includes results for response rate, and PFS as reported by each trial (even if they were only assessed as secondary endpoints).
Table 1. Summary of the main findings obtained in the different trials evaluating the efficacy of bevacizumab in patients with recurrent glioblastoma.
The randomised phase II trial by Friedman et al.(11), studied the use of bevacizumab alone and in combination with irinotecan (a chemotherapy agent) in 167 patients with recurrent glioblastoma. It concluded both bevacizumab alone and in combination improved rates of progression-free survival (PFS) at 6 months compared to historical controls (42.6% with bevacizumab alone and 50.3% when in combination) and found encouraging response rates based on MRI imaging and the WHO Response Evaluation Criteria (28.2% bevacizumab alone and 37.8% in combination). However, it is important to note that this study was not designed to compare the outcomes between the two treatment groups and was only randomised to prevent indication bias. In the supporting, single-arm, phase II trial by Kreisl et al.(12), 48 patients were treated with bevacizumab after having recurrent glioblastoma following radiotherapy and temozolomide chemotherapy. They reported a rate of PFS at 6 months of 29% and again a good overall response rate of 35% based on MRI imaging and the Macdonald criteria(15). This study however should again be taken with caution. It only includes a single arm of <50 patients, so given the lack of a control group and therefore the absence of comparative data, the conclusions derived should not be taken as proof of efficacy.
Nonetheless, these findings have now been supported by a recently published phase III randomised clinical trial: the EORTC 26101 study(14). This study compared 437 patients with recurrent glioblastoma receiving either bevacizumab or placebo on top of lomustine chemotherapy. It concluded that adding bevacizumab to lomustine chemotherapy significantly improves median PFS (4.2 vs 1.5 months, p<0.001) and reduces the number of patients needing to take corticosteroids (23% of patients were able to stop in the bevacizumab group vs 12% in the control group). In comparison with previous phase II trials, this trial is superior in terms of design, sample size and endpoints, and is therefore the best available data up to date in terms of assessing the clinical efficacy of bevacizumab in the context of recurrent glioblastoma. Nonetheless, its results suggest no overall survival (OS) benefit in the treatment group (median OS of 9.1 vs 8.6 months, p=0.65) which may likely influence current guidelines on the use of bevacizumab in recurrent glioblastoma.
.2 In Newly Diagnosed Glioblastoma
The benefit of bevacizumab in patients with newly diagnosed glioblastoma, however, is even less convincing. Table 2 displays the main findings of the studies conducted assessing mainly OS and/or PFS as their primary outcomes.
Abbreviations: BEV = bevacizumab; TMZ = temozolomide; IRI = irinotecan; mono = monotherapy; OS = overall survival, PFS = period-free survival; PFS6 = rate of PFS at 6 months; 95%CI = 95% confidence intervals; HR = hazard ratio.
*Note that this table includes results for both OS and PFS as reported by each trial (even if they were only assessed as secondary endpoints).
**Note that this study does not include a control arm (and therefore the reported n number of 70 is that of the ‘treatment group’). For statistical analysis, they compared their results to that of published available historical data from the EORTC-NCIC trial(7).
Table 2. Summary of the main findings obtained in the different trials evaluating the efficacy of bevacizumab in patients with newly diagnosed glioblastoma.
Chinot et al.(17)randomised 921 patients to receive either placebo or bevacizumab on top of standard glioblastoma treatment (radiotherapy-temozolomide chemotherapy combination). They assessed OS and PFS and concluded bevacizumab combined with standard treatment was associated with a significantly longer PFS (10.6 vs 6.2 months, p<0.001) but no overall benefit in survival (p=0.10). This 4.4 month improvement in PFS was accompanied by an improvement in health-related quality of life (QoL) as reported by the patients from well-established QLQ-C30 and BN20 questionnaires, but was associated with a higher risk of serious adverse events (38.8% bevacizumab vs 25.6% placebo). In comparison, Gilbert et al.(18) randomised 637 patients with newly diagnosed glioblastoma to again receive either placebo or bevacizumab on top of standard glioblastoma treatment. They reported a similar trend with a 3.4 month improvement in PFS (HR of progression=0.79), and even though this was reported as significant, it should be noted that it did not reach their pre-specified target (HR=0.70). They again observed no significant difference in overall survival between the two groups (median of 15.7 months bevacizumab vs 16.1 months placebo; p=0.21). This study also evaluated QoL, but this time not only from patient questionnaires, but also with objective tests of neurocognitive function (HVLT-R, TMT and COWA). They paradoxically concluded the 3.4 month improvement in PFS with bevacizumab use was associated with higher rates of deterioration in neurocognitive function, increased perceived severity of symptoms and a decline in health-related QoL, suggesting either neurotoxicity from bevacizumab use or unrecognised tumour progression.
Both of these trials are phase III randomised clinical trials, and provide the best evidence available in the literature with a reasonably big sample size and a good comparison against available standard treatment rather than placebo. They both however fail to show improvements in survival with bevacizumab treatment with inconsistent benefits in quality of life and therefore do not support the use of bevacizumab in newly diagnosed glioblastoma.
Concerning bevacizumab, newer evidence now suggests bevacizumab does prolong PFS, especially in the recurrent setting, but does not improve OS in neither recurrent or the primary setting. This may potentially lead to the withdrawal of its FDA approval. Reasons for this lack in survival benefit may be related to the involvement in malignancy of many aberrant pathways, other than angiogenesis. These include an increased expression of other growth factor receptors and dysregulation of p53, PI3K/Akt and Ras/MAPK pathways(20). Perhaps these contribute more to the pathogenesis of glioblastoma and are potentially better therapeutic targets when in combination with standard treatments available.
Part 2: Erenumab for migraine
Migraine is a common and debilitating condition of recurrent headache pain episodes that affects around 1 in 7 people worldwide(21). Each episode usually lasts between 4-72 hours and is often accompanied by nausea and/or vomiting and photophobia (extreme sensitivity to light) and phonophobia (extreme sensitivity to noise). Migraine is often classified based on the number of headache days per month into: episodic (<15 monthly headache days) and chronic (>15 monthly headache days, of which >8 are migraine days). The mainstay of treatment involves a combination of symptomatic relief with acute migraine-specific medications (eg. triptans) and preventive treatments to reduce frequency and severity of migraine attacks (eg. topiramate, propanolol and amitriptyline)(22). Preventive-therapies are only recommended for patients who are disabled by the frequency and/or severity of these attacks(23). The agents used for prevention however were developed for purposes other than migraine, and are commonly discontinued due to lack of efficacy or poor tolerability(24), reflecting the need for newer migraine-specific preventive agents.
Calcitonin gene-related peptide (CGRP) has been shown to play an important role in migraine pathogenesis. Its complete involvement still remains unknown, but theories suggest it is implicated in both peripheral and central sensitisations underlying migraine pain(25-27). Studies with small molecule CGRP receptor antagonists have provided the initial clinical evidence of the benefit seen by targeting this pathway in the acute treatment of migraine(28,29). This essay will focus on erenumab, as the first available fully human mAb to inhibit the CGRP receptor. It is formulated as a subcutaneous injection to provide long-term relief, and has recently been approved by the FDA for prevention of migraine in April 2018. This essay will discuss the evidence behind its clinical efficacy in this setting.
Clinical Efficacy of Erenumab in Migraine
Two phase II trials (one for episodic migraine and one for chronic migraine) and three phase III trials (all for episodic migraine) have been published demonstrating the efficacy (and safety) of erenumab in the prevention of migraine. The main findings of these studies have been summarised in Table 3.
Table 3. Summary of the main findings obtained in the different trials evaluating the efficacy of erenumab in patients with migraine.
The phase II trial by Sun et al.(30) assessed the efficacy of 3 erenumab doses (7mg, 21mg and 70mg) in 483 patients with episodic migraine and only found a significant benefit in the 70mg treatment group in reduction of monthly migraine days (-3.4 days vs -2.3 days placebo, p=0.21). It was on the basis of these findings, that future trials assessed the efficacy of erenumab at a minimum dose of 70mg. Similar improvements in reduction of monthly migraine days were reported in the phase III ARISE trial(33) (-2.9 days on 70mg erenumab vs -1.8 days placebo; p<0.001) and STRIVE trial(32) (-3.2 days on 70mg and -3.7 days on 140mg vs -1.8 days placebo; p<0.001). The STRIVE trial provides the longest follow-up period out of all these studies (6 months), but this should still be considered too short to assess other endpoints like durability of treatment effects.
It is important to note that completion rates within these studies were very high (ARISE trial reported almost 95% completion rate(33), Sun et al. reported discontinuation of 2% of patients(30)). These rates are considerably higher to those observed in studies involving other preventive migraine treatments like topiramate, where withdrawal rates have been reported to range between 17% to 27% for the 50mg and 100mg doses respectively(35). This is especially important when considering one of the main problems with available migraine treatments is tolerability and adherence.
Most of the evidence available also excluded patients who had failed to respond to >2 previous preventive treatments, except the recently published LIBERTY trial(34). This trial assessed 246 patients in whom previous preventive treatment had been unsuccessful, and found a significant improvement in the percentage of patients achieving >50% change in monthly migraine days (30% on 140mg dose vs 14% placebo; p=0.002). Similar beneficial results have been found in trials where other mAbs targeting the CGRP system (such as galcanezumab) have been assessed for use in migraine patients in whom previous treatments had failed(36). This further supports the idea of CGRP as a good target for even difficult-to-treat patients in whom previous available medications did not work or were not tolerated. Note however that this trial only assessed a 140mg dose of erenumab, and therefore other studies are needed to study whether 70mg is enough in this difficult-to-treat subgroup of patients.
The only available evidence for the subgroup of patients with chronic migraine is the study by Tepper et al.(31). They followed 667 patients for 3 months and again found significant benefits with erenumab treatment (-6.6 days reduction in monthly migraine days in both 70mg and 140mg treatment groups vs -4.2 days in placebo; p<0.0001). This study however excludes patients with comorbidities such as fibromyalgia and poorly controlled hypertension, which limits the generalisability of theirs results. Note that this is also the case in the LIBERTY trial(34).
Another important finding reported in all of these trials is the percentage of patients developing anti-erenumab antibodies. Only a few patients develop these (4.3% participants of those exposed in the ARISE trial(33), 5.6% in the STRIVE trial(32)). However, due to their infrequency and the relatively small sample sizes of these studies, the potential impact of developing anti-erenumab antibodies cannot be assessed. This should be assessed in future reviews from the pooling of data from all the different studies (potentially including studies with longer follow-up periods, since anti-drug antibodies could develop later in due course).
Current available evidence supports the use of erenumab in the treatment of both episodic and chronic migraine at a minimum dose of 70mg. The average reduction of monthly migraine days is similar across all studies for the same duration of treatment and same dose of erenumab, 70mg. Some slightly better outcomes have been reported with the higher dose of 140mg, but the cost-benefit ratio of increasing the dose still needs to be assessed in future studies, especially when considering longer-term treatments. Longer studies are also needed to assess not only safety profiles, but durability of treatment effects and adherence rates.
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