A Phase II multicenter, randomized trial to compare anastrazole plus gefitinib with anastrazole plus placebo in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (MBC)

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2008

Presenter: M. Cristofanilli
Presenter's Affiliation: MD Anderson Cancer Center
Type of Session: Scientific


  • It is well known that hormonal receptor status is an important prognostic factor in metastatic breast cancer patients and has clinical implications for hormonal therapies.
  • 55% of metastatic breast cancer patients are estrogen receptor (ER)-positive, and are therefore candidates for selective estrogen receptor modulators (SERMS) or aromatase inhibitors (AI), such as Anastrazole. AIs are the standard treatment for post-menopausal women who are hormone receptor-positive. Objective response rates for Anastrazole are only 15-20%, corresponding to a clinical benefit of 40%. Not all breast cancers respond to AIs, and many develop resistance despite initial benefit.
  • Preclinical studies have suggested that breast cancers which overexpress membrane tyrosine kinase receptors of the c-erb-B (HER) family may be less responsive to SERMS. It has been shown that there is an inverse relationship between overexpression of EGFR and the nuclear effect of estrogen in breast cancer. 
  • The mechanism for this may involve cross-talk between the 2 pathways leading to downstream tyrosine kinase signaling. This signaling in turn may activate ER coactivator complexes, thereby increasing the estrogen agonist effects of hormonal therapies. It is hypothesized that blocking tyrosine kinase activation using the epidermal growth factor receptor (EGFR)-inhibitor, gefitinib (a tyrosine kinase inhibitor or TKI), could inhibit this unwanted cross-talk and thus lead to decreased resistance to and increased efficacy of AIs. 
  • Massarweh et. al. presented data at SABCS 2008 showing that EGFR may mediate resistance to ER receptor antagonists in preclinical studies examining mouse models. 
  • A recent trial by Osborne et. al. presented at SABCS 2007 showed a modest improvement in PFS in patients with hormone-naive disease when treated with Tamoxifen and Gefitinib, compared to Tamoxifen and placebo.  However, this drug has not been tested in combination with aromatase inhibitors in post-menopausal women.
  • This phase II multicenter, randomized trial was undertaken to address this issue and evaluate efficacy and tolerability of Anastrazole + Gefitinib compared to Anastrazole + placebo for postmenopausal women with hormone receptor-positive MBC.

Materials and Methods

  • Post-menopausal women with HR+ metastatic breast cancer were randomized to Anastrazole + Gefitinib (A+G) vs. Anastrazole + Placebo (A+P). 
    • The dose of Anastrazole was 1 mg/day and Gefitinib was given as 250 mg/day. 
    • Eligibility criteria included women aged >18 years, newly diagnosed ER + (reviewed at a central labaratory) metastatic breast cancer, and no prior hormonal therapy. 
  • The primary objective was to examine progression-free survival (PFS). Secondary objectives included objective response rate (ORR) measured by RECIST criteria; clinical benefit rate (CBR) defined as objective response or stable disease >24 weeks; overall survival (OS); and safety and toxicity data. EGFR receptor data was also collected but will not be reported today. 
  • The study was powered to have a probability of 0.90 of observing a 5% improvement in PFS for gefitinib group. 
  • However, the trial closed early due to poor accrual, and hence limited statistical analyses could be performed. Hazard ratios were presented, however p values could not be obtained since the study was not powered to do so.


  • A total of 94 patients were randomized to the 2 groups. There were no differences seen in patient characteristics between the 2 groups. 


  • Median PFS, ORR and CBR data: 

A+G (n=43)
A+P (n=50)
Hazard Ratio
Not reported
14.5 months
8.2 months
0.55 (0.32,0.94)
Not reported
Not reported

P-values were not produced because the study was not powered to do so. 
  • In terms of treatment-related adverse events (AE), toxicities of diarrhea, fatigue, rash, and pruritis were increased in the gefitinib group compared to the placebo group. 21% of patients in the gefitinib group discontinued treatment compared to 4% of patients in the placebo group. Although more toxicities were seen in the A+G group, they were mostly mild and < grade 3. Two patients in the A+G arm and 1 patient in the A+P arm experienced an AE causing death; however these were deemed to be unrelated to treatment. 

Author's Conclusions

  • Gefitinib + Anastrazole demonstrated an improvement in PFS despite the early termination of accrual of patients. 
    • The overall survival data is too immature to report and may be reported in 2 years.
  • The results of this study are promising, and show that Gefitinib may prevent ER resistance and increase response rates in patients treated with combination therapy.
  • These data support the need to perform a phase III trial to prospectively examine these results in a larger patient population. 

Clinical/Scientific Implications

  • As drug resistance to standard breast cancer treatment increases, the need for combination therapies to target multiple pathways are strongly needed, especially in patients with metastatic disease. This phase II randomized trial provides valuable information about the combination of molecular targeted agents such as TKIs together with estrogen deprivation in an effort to overcome hormonal therapy resistance. It also supports the rationale that gefitinib decreases the development of drug resistance.
  • Osborne et. al. demonstrated a significant improvement in PFS in patients treated with tamoxifen and gefitinib. The current study was able to show similar results. As the authors note, this study found that the PFS improvement also holds for patients who are treated with Anastrazole and gefitinib. This is important because Anastrazole is the standard of care for most post-menopausal patients, especially those who have a contraindication to Tamoxifen use. 
  • Although the data seem promising, one must be aware that this is an underpowered phase II trial. To determine its clinical relevance, this hypothesis should optimally be tested in a Phase III randomized trial.  One important question to be considered when designing the future phase III trial will be patient selection. Certain patient populations have been shown to be better responders to EGFR inhibitors in previous lung cancer studies, and it will be important to determine how to select the optimal patient population for the next trial. 
  • In addition, overall survival data with longer follow up will be necessary to determine the clinical relevance of this treatment regimen and to potentially change the standard of care. It will also be useful to examine differences in response rates, clinical benefit rate, and EGFR and ER receptor expression in future studies.
  • The combination of molecularly targeted agents with current standard therapies for breast cancer is an exciting field and warrants continued investigation with multiple combinations.