primeLINES CLINICAL OPINION POLL

JANUARY 2011 Issue

PHARMA NEWS

FDA and EMA Have Contradictory Opinion About Bevacizumab for Metastatic Breast Cancer

On December 16, 2010, the US Food and Drug Administration (FDA) recommended that bevacizumab (Avastin^®) no longer be used to treat metastatic breast cancer (MBC). This is the first step toward revoking approval of bevacizumab for this indication after it received accelerated approval in 2008 based on evidence that it significantly prolonged progression-free survival (PFS) by approximately 6 months when added to paclitaxel in first-line treatment of MBC. This move by the FDA is in line with the recommendation of its Oncology Drug Advisory Committee, which voted 12-1 in July to revoke approval of bevacizumab for breast cancer based on new data showing that the PFS benefit of bevacizumab was less than previously estimated and that bevacizumab does not improve overall survival (OS). The committee weighed this new evidence of efficacy against the toxicity of bevacizumab and concluded that the benefits do not outweigh the risks. In contrast, the European Medicines Agency (EMA), which granted bevacizumab full approval for breast cancer in 2008, supports the indication of bevacizumab for use in MBC in combination with paclitaxel. The EMA stated that the benefits of bevacizumab outweigh the risks when it is used in combination with paclitaxel but not with docetaxel or capecitabine. Interestingly, the National Comprehensive Cancer Network (NCCN) Breast Cancer Treatment Panel, upon review of the same studies as the FDA and EMA, concluded similarly as EMA and reaffirmed paclitaxel and bevacizumab as a treatment option for women with metastatic breast cancer.

CONFERENCE NEWS

Highlights from the 33rd Annual CTRC-AACRSan Antonio Breast Cancer Symposium

The 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) was convened from December 8-12 and hosted approximately 8000 attendees from more than 90 countries. An international group of breast cancer physicians, research scientists, other healthcare professionals, and patients’ advocates come to San Antonio every year to learn about the latest state-of-the-art research on the experimental biology, etiology, prevention, diagnosis, and treatment of breast cancer and premalignant breast disease. Since 2007, SABCS has been jointly sponsored by the Cancer Therapy & Research Center (CTRC) at University of Texas Health Science Center San Antonio and the American Association for Cancer Research (AACR). Full-text meeting abstracts can be accessed at http://www.abstracts2view.com/sabcs10/index.php.

Dual Blockade of HER2: Promising Strategy in Neoadjuvant Treatment of HER2-Positive Breast Cancer

There are now several different agents that can interfere with the human epidermal growth factor receptor-2 (HER2) signaling. These include: trastuzumab (Herceptin^®); lapatinib (Tykerb^®/Tyverb^®), a HER2-specific tyrosine kinase inhibitor; and pertuzumab (Omnitarg^™), a HER2 dimerization inhibitor. Three neoadjuvant clinical trials investigating these agents both alone and in combination with each other or with standard chemotherapy regimens were presented at this year SABCS.

The neoALTTO phase III trial, conducted by the Breast InterGroup (BIG), randomized 455 patients with HER2-positive breast cancer to 3 arms—trastuzumab (2 mg/kg weekly); lapatinib (1500 mg/day); or the combination of both agents (2 mg/kg trastuzumab + 1000 mg/day lapatinib)—for 6 weeks. After 6 weeks of receiving anti-HER2 therapy, weekly paclitaxel (80 mg/m²) was added to each arm for an additional 12 weeks prior to surgery. The first preliminary analysis of this trial showed that the pathologic complete response (pCR) rate at completion of neoaduvant therapy (absence of invasive cancer in the breast at surgery) was significantly higher in the combination arm with dual HER2 blockade (lapatinib/trastuzumab/paclitaxel) compared to either the trastuzumab/paclitaxel arm or the lapatinib/paclitaxel arm (51.3% vs 29.5% and 24.7%, respectively; P<.01 for both comparisons). There was no difference in the rate of breast conserving surgery between the treatment arms. Response rates in all treatment arms were substantially higher in hormone receptor (HR)–negative tumors compared to HR-positive tumors. Overall response rates (ORR) at 6 weeks (anti HER2-therapy alone) were higher for both lapatinib-containing arms. There was an increased, but manageable, toxicity observed in both lapatinib-containing arms (diarrhea and liver enzyme alterations). These data suggest that dual blockade of HER2 is more effective than single-agent HER2-targeted therapy.

Cancer Res. 2010;70(24 Suppl): Abstract S3-3.

The GeparQuinto phase III study is also directly comparing trastuzumab with lapatinib but does not have a combination arm. In this study, 620 patients with HER2-positive breast cancer were randomized to neoadjuvant therapy with either trastuzumab (6 mg every 3 weeks) or lapatinib (1000-1250 mg/day) in conjunction with neoadjuvant anthracycline/taxane-based chemotherapy (epirubicin/cyclophosphamide–docetaxel [EC-D] regimen; 3-week cycles).The primary endpoint of the study, pCR rate (defined as no invasive or noninvasive residual disease in the breast or nodes) was significantly higher in the trastuzumab/chemotherapy arm than in lapatinib/chemotherapy arm (31.3% vs 21.7%; P<.05). Pathologic complete response of no residual invasive carcinoma in the breast was also significantly higher for trastuzumab arm compared to lapatinib arm (50% vs 35%). More patients in the trastuzumab arm also received breast conserving surgery (66% vs 56%). There were 10% more discontinuations in the lapatinib arm. These data suggest that, at these doses and in combination with EC-D chemotherapy, trastuzumab is better tolerated and more effective than lapatinib. However, in the neoALTTO trial, which used a higher dose of lapatinib (1500 mg/day) in combination with weekly paclitaxel, there was no significant difference between the trastuzumab and lapatinib arms.

Cancer Res. 2010;70(24 Suppl): Abstract S3-1.

NeoSphere is a randomized phase II study comparing 4 neoadjuvant treatment regimens: docetaxel+trastuzumab (TH), docetaxel+pertuzumab (TP), docetaxel+trastuzumab+pertuzumab (THP), and trastuzumab+pertuzumab (HP). Notably, approximately 40% of 417 enrolled patients had locally advanced or inflammatory breast cancer. Similar to the neoALTTO study, the combination of chemotherapy with both antibodies was significantly superior to treatment with either monoclonal antibody/chemotherapy regimen alone. The THP regimen yielded a pCR rate in the breast of 46% compared to 29% with TH (P = .01) and 24% with TP (P = .003). However, there was no significant difference between the two antibodies. The pCR rate with a fourth arm that combined the two antibodies without chemotherapy (HP) was 18%, and this combination was extremely well tolerated. These results suggested that trastuzumab plus pertuzumab could be a valuable option for a not-yet identified subset of women and could spare them the toxicity of chemotherapy. The safety profile of THP was similar to TH and TP, and there was no increase in cardiac risk.

Cancer Res. 2010;70(24 Suppl): Abstract S3-2.

Taken together these results are very exciting. However, Eric Winer, MD of the Breast Oncology Center at Dana Farber Cancer Institute, Boston, United States, who discussed the presented neoadjuvant trials, pointed out that pCR have not always been associated with significant improvements in DFS and OS and thus should not yet be used as an “endpoint for drug approval or practice changing”.

CYP2D6 Genotype Did Not Effect Clinical Outcomes in BIG 1-98 and ATAC Trials

For years, there has been speculation that variation in the metabolism of tamoxifen by genetic variants of CYP2D6 in the population may have affected the outcomes of patients treated with tamoxifen. It has been hypothesized that patients with genetic variants associated with low or absent CYP2D6 activity do not efficiently metabolize tamoxifen to its active metabolite and, therefore, have worse clinical outcomes. Some have also proposed pharmacogenetic testing before treating women with adjuvant tamoxifen. This controversy has been compounded by conflicting evidence from recent clinical trials as to whether clinical outcomes are affected by the patient’s CYP2D6 genotype. This hypothesis was finally put to the test in post hoc analyses of the BIG 1-98 and ATAC trials. The conclusion, based on long-term follow-up data from the BIG 1-98 trial, is that CYP2D6 genotypes associated with poor or intermediate metabolism of tamoxifen were not associated with worse clinical outcomes when compared to extensive metabolizers. No significant differences in the hazard ratio for breast cancer–free interval were observed between the different CYP2D6 genotypes. Moreover, these genotypes were not associated with a reduced incidence of hot flushes. Therefore, the authors concluded that CYP2D6 pharmacogenetic testing is not recommended in patients considering tamoxifen therapy, and the presence or absence of hot flushes should not be used as a marker of tamoxifen efficacy. The analysis of the ATAC trial reached a similar conclusion, finding no significant correlation between CYP2D6 genotype and the primary endpoints of the trial. Furthermore use of CYP2D6 inhibitors such as selective serotonin reuptake inhibitors (SSRIs) did not affect outcomes.

Cancer Res. 2010;70(24 Suppl): Abstract S1-8.

Cancer Res. 2010;70(24 Suppl): Abstract S1-7.

Obesity Associated with Worse Survival in Hormone Receptor–Positive Breast Cancer

Obesity has been associated with increased risk of recurrence and worse clinical outcomes in patients with breast cancer, but the reasons for this are not well understood. To investigate this, the authors of this study looked for correlations between body mass index (BMI) and disease-free survival (DFS) or OS in three Eastern Cooperative Oncology Group studies of adjuvant chemotherapy with or without endocrine therapy (E1199, E5188, and E3189). The analysis was done using multivariate Cox models adjusted for a variety of covariates such as age, tumor size, nodal status, race, surgery type, prior radiotherapy, menopausal status, and treatment. A rigorous analysis of study E1199, based on 3484 patients with BMI data, showed that patients with a BMI >30 kg/m² (38% of patients) had worse DFS and OS outcomes compared with non-obese patients, but the differences were not statistically significant. However, when the data were analyzed by breast cancer subtype, among the HR-positive, HER2-negative subgroup, obese patients had significantly worse DFS (HR = 1.23; P = .035) and OS (HR = 1.46; P = .002) compared with the non-obese population. In contrast, obese patients in other subgroups did not have worse outcomes. To further validate these findings, the authors performed a similar analysis using data from study E5188 in premenopausal, estrogen receptor (ER)–positive, node-positive patients (N = 1502) and study E3189 in ER-negative, node-positive patients (N = 613). As expected, the ER-positive obese patients in study E5188 had significantly worse DFS (HR = 1.41; P<.0001) and OS (HR = 1.51; P<.0001) compared with the non-obese population. In contrast, no difference in DFS or OS was observed for ER-negative obese patients in study E3189. These results suggest that the effect of obesity is primarily confined to the subset of patients with HR-positive breast cancer, and the authors conclude that further research is needed to identify the specific host factors responsible for the observed disparity in clinical outcomes.

Cancer Res. 2010;70(24 Suppl): Abstract S2-1.

AZURE Trial: Benefit of Adjuvant Zoledronic Acid Only in Subset of Postmenopausal Patients

Given the observed antitumor effects of zoledronic acid (Zometa^®) and synergy with chemotherapy agents, the AZURE trial (BIG 01/04) was designed to determine whether addition of zoledronic acid to standard adjuvant therapy could improve DFS and bone metastasis–free survival (BMFS) in patients with stage II/III breast cancer. The results of a second interim analysis of this trial were eagerly anticipated, particularly in light of recent evidence from the ABCSG-12 trial demonstrating that zoledronic acid reduced the risk of recurrence by 32% in premenopausal women receiving endocrine therapy (Gnant M, et al. N Engl J Med. 2009;360(7):679-691.). The AZURE trial randomized 3360 patients to receive neoadjuvant and/or adjuvant chemotherapy and/or endocrine therapy with or without zoledronic acid (4 mg every 3-4 weeks for 6 doses, then every 3 months for 2 years and every 6 months for 2.5 years to complete a total of 5 years of adjuvant therapy). At a median follow-up of 59 months, there was no significant improvement in either DFS (HR = 0.98; P = .79) or OS (HR = 0.85; P = .07) in patients receiving zoledronic acid. In contrast to the ABCSG-12 trial, there was no apparent benefit in the premenopausal HR-positive subgroup. However, it should be noted that all premenopausal patients enrolled in the ABCSG-12 trial had stage I disease, did not receive chemotherapy, had artificial menopause induced with goserelin, and were treated with either tamoxifen or anastrozole. Interestingly, in a preplanned subset analysis of the AZURE trial based on menopausal status, zoledronic acid showed a significant effect on OS in a subgroup of 1101 patients who were >5 years postmenopausal or >60 years of age, reducing the risk of death by 29% (HR = 0.71; P = .017). Although these results of the subgroup analysis were intriguing, the overall conclusion was that the results of AZURE trial do not support the routine use of adjuvant zoledronic acid in the management of early breast cancer.

Cancer Res. 2010;70(24 Suppl): Abstract S4-5.

What Is the Benefit of Adding Capecitabine to Standard Chemotherapy for High-Risk Early Breast Cancer?

Two studies (FinXX and the US Oncology study USON 01062) investigated the benefit of adding capecitabine (Xeloda^®) to different anthracycline and taxane-containing adjuvant chemotherapy regimens in patients with high-risk early breast cancer. The FinXX study defined high-risk disease as node-positive or node-negative with primary tumor >2 cm and progesterone receptor–negative. Patients were randomized to a sequential docetaxel→cyclophosphamide+epirubicin+5-fluorouracil (T-CEF) regimen (n = 747) or the capecitabine-containing regimen XT-CEX (n = 753). Although interim results showed that the 3-year DFS rate favored XT-CEX (HR = 0.66; P = .02), the final results at 5 years failed to demonstrate a significant DFS benefit associated with XT-CEX (87% vs 84%; HR = 0.79; P = .87) or an OS benefit. However, an exploratory analysis showed a significant improvement in breast cancer–specific survival at 5 years (94% vs 91%; HR = 0.64; P = .027) and suggested XT-CEX may benefit patients with more than 3 axillary nodes or those with triple negative breast cancer .

The first efficacy results from the multicenter, phase III, USON 01062 trial were also mixed. In this study, high-risk patients (defined as node-positive, node-negative with a primary tumor >2 cm, or node-negative with a primary >1 cm and negative for both estrogen and progesterone receptors) were randomized to doxorubicin plus cyclophosphamide followed by docetaxel (AC-T) with or without capecitabine (X). At a median follow-up of 5 years, the event rates were low in both arms, and there was no significant DFS benefit associated with AC-XT (89% vs 87%; HR = 0.84; P = .125). However, there was a significant OS benefit in favor or AC-XT (94% vs 92%; HR = 0.68; P = .011). As expected, hand-foot syndrome and stomatitis were higher in the capecitabine arm. The authors concluded that these results should be interpreted with caution given the low event rates; a follow-up analysis is planned for August 2012. Taken together, these studies both show a similar trend in favor of the capecitabine-containing regimen, but the benefit appears marginal.

Cancer Res. 2010;70(24 Suppl): Abstract S4-1.

Cancer Res. 2010;70(24 Suppl): Abstract S4-2.

Fulvestrant (500 mg) Superior to Anastrozole as First-Line Therapy for Metastatic Breast Cancer

The primary analysis of the randomized phase II study known as The FIRST (Faslodex fIRst line Study comparing endocrine Treatments) trial (N = 205), comparing fulvestrant (Faslodex^®) given as a once monthly intramuscular injection at a dose of 500 mg with 1 mg/day anastrozole (Arimidex^®) as first-line therapy for ER-positive advanced breast cancer in postmenopausal women, suggested a significant improvement in median time to progression (TTP) in favor of fulvestrant (HR = 0.63; P = .049). The current presentation reported longer follow-up data for TTP and time to treatment failure (TTF). Median TTP was 23.4 months with fulvestrant vs 13.1 months with anastrozole (HR = 0.66; P = .01). A similar benefit in TTF was also observed, and both regimens were well tolerated. Moreover, patients who progressed on either fulvestrant or anastrozole remain sensitive to subsequent endocrine treatments (41% vs 42%, respectively). These updated results of the FIRST trial confirm that fulvestrant, at dose of 500 mg, has significant TTP benefit over anastrozole in first-line endocrine therapy for endocrine-responsive advanced breast cancer.

Cancer Res. 2010;70(24 Suppl): Abstract S1-3.

Everolimus May Overcome Resistance to Endocrine Therapy in HR-Positive Metastatic Breast Cancer

It has been hypothesized that resistance to endocrine therapy may occur via activation of the PI3K/Akt/mTOR pathway. This hypothesis is supported by preclinical data showing that everolimus (Afinitor^®), an mTOR inhibitor, can reverse resistance to tamoxifen in breast cancer cell lines. TAMRAD is a randomized, phase II study designed to test whether everolimus can overcome resistance to endocrine therapy in patients with breast cancer previously exposed to an aromatase inhibitor (AI) either in the adjuvant or metastatic setting. In total, 111 patients with HR-positive/HER2-negative metastatic breast cancer were randomized to tamoxifen alone (20 mg/day) or tamoxifen plus everolimus (10 mg/day). The primary endpoint was clinical benefit (defined as complete response [CR], partial response [PR], or stable disease [SD] at 6 months). The clinical benefit rate was 61% in the everolimus arms versus 42% in the tamoxifen-alone arm. Even more impressive were the outcomes of secondary endpoints. Time to progression was improved by nearly 50% (HR = 0.53; P = .0026) and OS was improved by nearly 70% (HR = 0.32; P = .0019). Analysis of stratification groups also showed that patients with secondary resistance (defined as late relapse ≥6 months after adjuvant AI therapy or prior response to an AI in the metastatic setting) had the greatest improvement in TTP (HR = 0.38). The incidence of fatigue, stomatitis, rash, anorexia, and diarrhea were substantially higher in the everolimus arm. These results suggest that an mTOR inhibitor may overcome resistance to endocrine therapy, particularly secondary resistance, and this strategy clearly warrants further study.

Cancer Res. 2010;70(24 Suppl): Abstract S1-6.