Roche today announced that an analysis of the phase II BRAIN study of bevacizumab (Avastin®) alone or in combination with irinotecan chemotherapy for the treatment of relapsed or progressive glioblastoma (GBM) demonstrated that in addition to increasing the chance of patients being alive without worsening of their disease at six months (progression free survival; PFS-6)[i], bevacizumab-based therapy may also lead to additional positive impact on neurocognitive function.[ii] Adverse events in the BRAIN study were consistent with those previously seen with bevacizumab and no new safety signals were reported.

The analysis presented today at Europe’s largest scientific meeting for cancer specialists, the joint 15th ECCO and 34th ESMO, showed that those patients who responded to bevacizumab-based therapy may also have a stabilisation or improvement in neurocognitive function and a reduction in their dose of steroids.2

“Stabilising neurocognitive function and reducing reliance on steroids can improve day to day life for patients with recurrent GBM which, given the poor prognosis, is a key aim of treatment,” said Professor James Vredenburgh, Medical Director, Adult Clinical Service, Duke University Medical Center, Durham, USA. “This analysis suggests that bevacizumab-based therapy which has already demonstrated PFS benefits may also have a positive impact on patients’ daily lives and should offer hope to physicians, patients and their caregivers alike.”

Neurocognitive function includes the ability to think and reason, to make judgements and remember things. A decline in this function, a common consequence of GBM, can be distressing for both patients and their families. Bevacizumab based treatment was also associated with lower use of steroids in some patients. Steroids are an important part of managing symptoms in many patients with GBM but they can lead to complications such as weight gain, insomnia and behavioural changes. Reduction in steroid dose means that physicians may be able to reduce the side effects of long term steroid use.

GBM is the most common and the most aggressive type of primary malignant brain tumour and most patients experience relapse or progression of their disease following initial treatment.[iii] When the disease returns, prognosis is particularly poor and improving day to day life for patients is a component of the treatment aim.

“Avastin continues to demonstrate its benefits as a treatment for an increasing variety of cancers,” said William M. Burns, CEO of Roche’s Pharmaceuticals Division. “Avastin based therapy has the potential to make a real difference for patients with glioblastoma.”

Bevacizumab (Avastin) precisely inhibits vascular endothelial growth factor (VEGF) a key mediator of angiogenesis, the growth of new blood vessels, which is essential for tumour growth and spread. GBM has very high VEGF expression. By controlling angiogenesis, bevacizumab controls tumour growth.

Bevacizumab has a well-established tolerability profile and the most frequently observed adverse drug reactions in clinical trials were hypertension, fatigue, neuropathy and proteinuria.[iv] The most common side effects are generally manageable, for example, hypertension can generally be managed with conventional antihypertensive treatment.

In May 2009, bevacizumab was granted accelerated approval for the treatment of GBM patients with progressive disease following prior therapy from the US Food and Drug Administration (FDA) based on data from the BRAIN study (AVF3708g) which was recently published in the Journal of Clinical Oncology1 and an NCI study (NCI 06-C-0064E). The data is currently being discussed with regulators in Europe and has led to approvals in Switzerland, Albania, Dominican Republic, India, Moldova and the Ukraine.

Bevacizumab is not licensed for the treatment of GBM in the UK.

A large, over 900 patient phase III study of bevacizumab, for the treatment of newly diagnosed GBM patients (AVAGLIO) is underway.[v]

About the BRAIN study

The BRAIN study was a US based open-label, multicentre, non-comparative phase II study including 167 patients with histologically confirmed GBM that had progressed following initial treatment with temozolomide and radiation. The primary endpoints of the BRAIN trial were progression free survival-6 (PFS-6), (defined as the percentage of patients who remained alive and progression free at 24 weeks) and objective response rate (ORR), (defined as a complete or partial response on two consecutive MRIs obtained 4 weeks apart). Secondary endpoints explored included OS, PFS, duration of response to treatment and safety. The BRAIN study evaluated bevacizumab at a dose of 10mg/kg every two weeks, as a single agent (BEV), or in combination with irinotecan chemotherapy (BEV-IRI).

This latest analysis of the BRAIN study demonstrated that:2

Steroid Use

Of the patients not requiring corticosteroids at baseline, more than 75% bevacizumab and 65% bevacizumab plus chemotherapy patients did not use corticosteroids post-baseline.

The majority of patients with an objective response or who were alive and without progression at 24 weeks had sustained reduction in steroid dose when receiving bevacizumab based therapy.

– At baseline, over half of the patients (50.6% BEV and 52.4% BEV-IRI pts) took systemic corticosteroids. Of these patients receiving steroids at baseline:

- In patients that responded (complete or partial) to bevacizumab-based therapy, 57% and 64% of patients receiving bevacizumab and bevacizumab + chemotherapy, respectively had a sustained reduction in steroid use (defined as being able to at least halve their steroid dose for at least half the time they were on treatment )

- In patients who were alive and without progression of disease at 24 weeks 58% and 86% demonstrated a sustained reduction in steroid dose (defined as being able to at least halve steroid dose for at least half the time on treatment) when receiving bevacizumab or bevacizumab + chemotherapy, respectively.

Neurocognitive Function

The majority of patients with an objective response or alive and without progression at 24 weeks had improved or stable neurocognitive function compared to baseline.

– Of the patients with an objective response, 75% and 60.7% of patients receiving bevacizumab and bevacizumab + chemotherapy, respectively experienced stable or improved neurocognitive function at time of their response relative to baseline

– Of the patients with PFS greater than 6 months, 70.4% and 70% had stable or improved neurocognitive function at week 24 relative to baseline, when receiving bevacizumab or bevacizumab + chemotherapy, respectively.

The BRAIN study previously demonstrated:2

– When bevacizumab was evaluated as a single agent, the study showed that at six months almost half (42.6%) of patients lived without their disease advancing, as defined by progression-free survival (PFS). When bevacizumab was combined with irinotecan, this figure increased to 50.3%.

– In the study, nearly a third (28%) of patients responded to bevacizumab as a single agent, meaning tumours decreased in size by at least 50%. When bevacizumab was combined with irinotecan, 38% of patients responded to bevacizumab.

– Patients receiving bevacizumab alone had a median overall survival of 9.2 months compared to 8.7 months for those receiving bevacizumab in combination with irinotecan, which was a secondary endpoint in the study. Most adverse events related to bevacizumab in this trial appeared to be similar to those previously reported in other bevacizumab studies1.

About Glioblastoma

Brain cancer affects approximately 4,500 people per year in the UK and there are many different types[vi] including glioblastoma. Following initial treatment, glioblastoma tumours nearly always return.[vii] According to historical estimates, less than 10 percent of patients with recurrent GBM respond to treatment and approximately 15 percent will live six months without their disease getting worse.1 GBM is a compelling therapeutic target for bevacizumab as these tumours have among the highest levels of vascular endothelial growth factor (VEGF) of any solid tumour.

About bevacizumab

Bevacizumab is an antibody that specifically binds and blocks VEGF (vascular endothelial growth factor). VEGF is the key driver of tumour angiogenesis - an essential process of development and maintenance of blood vessels which is required for a tumour to grow and to spread (metastasize) to other parts of the body. Bevacizumab’s precise mode of action helps control tumour growth and metastases with only a limited impact on side effects of chemotherapy. Bevacizumab is approved in EU for the treatment of the advanced stages of four common cancer types: colorectal cancer, breast cancer, kidney cancer.

More than 500,000 patients have been treated with Avastin (bevacizumab) so far. A comprehensive clinical programme with over 450 clinical trials is investigating the use of bevacizumab in various tumour types (including colorectal, breast, non-small cell lung, brain, gastric, ovarian, prostate and others) and different settings (advanced or early stage disease).

References

[i] Friedman H et al. J Clin Oncol 2009; 31 August. Last accessed 1 September 2009 at http://jco.ascopubs.org/cgi/content/abstract/JCO.2008.19.8721v1.

[ii] J. Vredenburgh et al. ECCO 15 ESMO 34 2009; Abstract #8707.

[iii] Cancer Research UK. Statistics and outlook for brain tumours. http://www.cancerhelp.org.uk/help/default_printer_friend.asp page=5296#astro Last accessed 18 September 2009

[iv] Avastin Summary of Product Characteristics. Available from http://emc.medicines.org.uk/ Last accessed September 2009

[v] O. Chinot et al. ECCO 15 ESMO 34 2009; Poster #46. Addition of Bevacizumab to the multi-modailty standard of care in patients with newly diagnosed glioblastoma: A Phase III trial.

[vi] Cancer Research UK. Brain tumours at a glance. Available from http://info.cancerresearchuk.org/cancerandresearch/cancers/brain/ Last accessed 18 September 2009

[vii] Medscape. Recurrent Glioblastoma Multiforme: Definition of Recurrent GBM. Last accessed 10 August 2009 http://www.medscape.com/viewarticle/540150_2

Source
Roche

View drug information on Avastin.

Adjuvant whole-brain irradiation failed to improve survival compared with observation in patients with brain metastases from solid-tumors, Italian investigators reported.

On average, patients lived about 11 months after surgery or radiosurgery, regardless of whether they received adjuvant whole-brain radiation therapy, Riccardo Soffietti, MD, of the University of Turin, said at the ECCO/ESMO joint European cancer congress in Berlin.

Radiation therapy modestly improved time to progression and reduced the risk of relapse at the treatment site, new brain lesions, and death from intracranial progression.

• Explain to patients that adjuvant whole-brain irradiation did not improve survival after surgery or radiosurgery for brain metastases associated with solid tumors.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

“Although this treatment gives a modest advantage in progression-free survival, it cannot be considered as the standard treatment after surgery or radiosurgery for all patients with brain metastases because it does not prolong the period of functional independence or extend overall survival, which are the key outcomes,” Soffietti said in a statement.

“We are still analyzing whether or not the treatment improved quality of life in this study, but we also now need new studies to determine whether it could help some subgroups of patients, such as, for instance, those with breast cancer.”

Whole-brain irradiation has been considered standard therapy for patients with a single brain metastasis unsuitable for surgery or radiosurgery, for patients with multiple brain metastases, and for those with other metastatic sites in addition to the brain.

However, the role of adjuvant brain radiotherapy after surgery or radiosurgery has been controversial.

“It can slow the spread of cancer in the brain but can damage cognitive functions, sometimes leading to dementia, in long-surviving patients,” said Soffietti.

“Attitudes toward whole-brain radiotherapy are quite variable across cancer centers at the moment, but overall, the tendency is to use it in cancers that respond well to radiotherapy, such as breast and lung cancer, and to avoid it in cancers that don’t respond well to radiotherapy, such as melanoma, kidney, and colon cancer,” he said.

In an effort to determine whether adjuvant brain irradiation offered meaningful benefits, investigators enrolled 353 patients with nonprogressing primary tumors that had metastasized to the brain. For all patients, brain metastases were removed by surgery or radiosurgery, and they were then randomized to prophylactic whole-brain irradiation or observation.

The primary outcome was survival with functional independence, as determined by duration of survival with WHO performance status ≤2.

Median survival was 10 months with observation and 9.5 months with whole-brain irradiation.

Overall survival was 10.7 months with adjuvant radiotherapy and 10.9 months without it.

Median progression-free survival was 4.6 months with adjuvant whole-brain irradiation and 3.4 months with observation (P<0.002).

In the observation group, intracranial progression occurred in 39.7% at six months and 54.2% at 24 months compared with 15.2% and 31.2% in patients who received whole-brain irradiation.

Relapse at the initial site of treatment occurred in 31.3% of the observation group at 24 months versus 16.4% of the irradiated patients (P<0.0001).

In addition, new intracranial lesions appeared in 32.4% of the observation group and 17.6% of irradiated patients (P<0.0001).

Neurologic death occurred in 43% of the observation group and 25% of the irradiated patients.