Results of the Phase III ENRICH (RT-016) Study of Efaproxiral Administered Concurrently with Whole Brain Radiation Therapy (WBRT) in Women with Brain Metastases from Breast Cancer

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 23, 2008

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Presenter: J. H. Suh
Presenter's Affiliation: Cleveland Clinic, Cleveland, OH
Type of Session: Scientific

Background

  • Brain metastasis is a common and deadly complication of many cancers, including lung, breast, renal cell, melanoma, and others.
  • 170,000 individuals are diagnosed with new brain metastases annually in the United States.
  • Whole brain radiation therapy (WBRT) has been the principal treatment for patients with multiple metastases.
    • Local control rates with WBRT range from 50% to 75%, however survival in these patients remains dismal at 4-7 months.
  • Hypoxia has been known to be increased in brain tumors and is a well-established cause of resistance to cell damage caused by ionizing radiation.
  • Attempts to combat hypoxia may help improved survival in these patients treated with WBRT.
  • Efaproxiral (Efaproxyn, RSR13; Allos Therapeutics Inc, Westminster,CO) is an allosteric modifier of hemoglobin. It binds to hemoglobin and affects its conformational structure, leading to a reduction in its oxygen-binding affinity. This shifts the O2 binding curve to the right, and thereby results in enhanced tumor oxygenation.
  • It is hypothesized that the administration of this drug will therefore make tumors more sensitive to radiation and increase the effectiveness of WBRT.
  • A phase III study, RT-009, was published in JCO in 2006 by the current authors. In RT-009, they tested the hypothesis that adding efaproxiral to WBRT plus supplemental oxygen would improve survival better than WBRT with supplemental oxygen alone.
    • They found that there was no survival advantage associated with the addition of efaproxiral for all patients. However, on a subset analysis, the authors concluded that there was a demonstrated median survival advantage seen in patients with primary breast cancer (4.57 months vs. 8.67 months, with a statistically significant p-value).
    • On the basis of the study results of RT-009, a confirmatory trial of WBRT with or without efaproxiral (the Enhancing Whole Brain Radiation in Patients With Breast Cancer and Hypoxic Brain Metastases [ENRICH] trial) was initiated in patients with brain metastases from breast cancer.
  • The purpose of the ENRICH study was to determine if the addition of efaproxiral to WBRT prolongs survival and increases tumor response.

Materials and Methods

  • This is a phase III randomized, open-label study of WBRT with supplemental oxygen +/- concurrent efaproxiral in women with brain metastases secondary to metastatic breast cancer. 
  • It was a 1:1 randomization. 
  • The planned sample size was 360 patients, with 180 patients in each arm. 
  • Patients who were randomized to the Efaproxiral arm received the drug 30 minutes prior to the initiation of daily WBRT. 
  • Key inclusion criteria:
    • KPS> 70
    • No other active concurrent malignancy
    • Adequate PFTs
    • SpO2> 90% while breathing on room air
  • Key exclusion criteria:
    • Leptomeningeal disease
    • Planned concurrent systemic treatment
  • Patients were stratified by KPS 70-80 vs. 80-90 and presence or absence of liver metastases. 
  • The primary endpoint to be evaluated was overall survival (OS). Secondary endpoints included response rates, change in KPS and neurological symptoms. 

Results

  • Between February 2004 and September 2006, 368 patients with metastatic breast cancer to the brain were randomized at 78 sites in 15 countries. 3 patients were excluded since central review did not show brain metastases in these patients. 
  • Analyses were conducted on 365 patients; n=182 in drug arm and n=183 in control arm. 
  • Patient characteristics were well balanced between the control group and drug group. The vast majority of patients had >2 lesions. 
  • There was no statistically significant difference seen in overall survival between the 2 study arms using Kaplan-Meier analysis and log-rank test (HR=0.87, p=NS). 
    • Median survival time was 7.5 months for the control arm vs. 8.5 months for the drug arm; p=NS. 
    • The number of brain metastases did not influence survival.
  • Data for response rate in the brain at 3 months showed CR/PR rate of 27% in the control arm vs. CR/PR rate of 31% in the drug arm, p=NS. 
  • Change in KPS and neurological symptoms also did not differ significantly between the 2 arms. 

Author's Conclusions

  • The addition of the radiation sensitizer, efaproxiral, to WBRT in women with brain metastases from breast cancer failed to improve OS. 
  • It was predicted that survival for the control arm would be approximately 4.5 months, based on results of the previous RT-009 study. However, survival time for the control arm was greater than predicted at 7.5 months. 
  • No significant differences were observed for the secondary endpoints studied as well. 
  • This study was being done as confirmatory study to validate the results of a previous subset analysis from RT-009, and failed to confirm those results. 

Clinical/Scientific Implications

  • Brain metastases are a common and debilitating condition afflicting breast cancer patients. OS rates for patients treated with WBRT are dismal, and new methods to increase the effectiveness of current treatments are necessary.
  • One approach is to target hypoxia, which leads to radioresistance.
  • Efaproxiral is an allosteric modifier of hemoglobin which leads to enhanced tumor oxygenation. It has been proposed that the addition of this drug to WBRT may improve outcomes in this study patient population.
  • The authors conducted a very well-designed and large Phase III randomized trial to test this hypothesis. However, unfortunately, the study failed to achieve its primary endpoint of demonstrating a statistically significant improvement in overall survival for the control arm.
  • One question that must be raised is whether or not OS should be the primary endpoint of such studies, since historically, it has always been very difficult to show a survival benefit patients with brain metastases with such a poor prognosis.
    • The authors did note that they were hoping to improve survival by 30-40%, however the actual survival time for the control arm was much higher than predicted in this study.
    • There may need to be other endpoints evaluated if this drug is taken to future studies.
  • Based on these results and the results of this group’s previous trial RT-009, further studies of this drug, Efaproxyn, in patients with brain metastases are not warranted.
  • However, it may be interesting to test the use of this drug in combination with RT in other tumor sites which are known to be radioresistant, or in combination with SRS alone for patients with 1-3 brain metastases.



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