SUMMARY: Fulvestrant (FASOLODEX®) is an Estrogen Receptor (ER) antagonist and downregulates the cellular levels of ER in a dose-dependent manner. The CONFIRM trial is a phase III study in which postmenopausal women with estrogen receptor (ER) positive advanced breast cancer, who had progressed after prior endocrine therapy, were randomized to be treated with either FASLODEX® 500 mg (n=362) or FASLODEX® 250 mg (n=374) every 28 days. The primary end point for this study was Progression Free Survival (PFS). In the primary analysis, FASLODEX® 500 mg was associated with a statistically significant increase in PFS compared with FASLODEX® 250 mg. Even though there was a trend towards improved overall survival (OS) with the higher dose, this was not statistically significant. In the updated second survival analysis presented at this symposium, the median OS trend prevailed with FASLODEX® 500mg compared with FASLODEX® 250mg, given every 28 days (26.4 months vs 22.3 months, P=0.16). This translated into a 4 month increase in median overall survival and a 19% reduction in the risk of death. The authors concluded that the higher dose of FASLODEX® may indeed confer some survival benefit to this patient subsets. Di Leo A, Jerusalem G, Petruzelka L, et al. CTRC-AACR San Antonio Breast Cancer Symposium; 2012; Abstract S1-4.
Category: Meeting Updates
Neurocognitive impact in adjuvant chemotherapy for breast cancer linked to fatigue a prospective functional MRI study
SUMMARY: Cognitive impairment in patients with breast cancer has been frequently attributed to chemotherapy (Chemo Brain) without any data supporting this hypothesis. Utilizing functional magnetic resonance imaging, brain function was tested while the patients were performing a working memory task in the scanner, before adjuvant treatment and then one month after adjuvant treatment. Sixty six breast cancer patients with Stages 0-IIIA were studied and their cognitive function was compared with 32 healthy controls. Patients on treatment were receiving either an anthracyline-based adjuvant chemotherapy regimen (n = 29) or radiotherapy (n = 37). Patients self-reported on levels of cognitive functioning and fatigue after each imaging study. Pretreatment brain imaging revealed decreased functioning in the frontal lobe of the brain (responsible for memory and cognition), compared to the controls and this cognitive impairment was most severe in patients awaiting chemotherapy, whereas the radiotherapy group fell between the pre-chemotherapy and control group. Of Interest, the decreased functioning in the frontal lobe area before treatment predicted the severity of fatigue. Further, those with greater fatigue experienced greater cognitive impairment over time. The authors concluded that the cognitive problems are probably related to worry and fatigue prior to treatment intervention rather than the treatment itself. They recommend identifying patients at risk and early intervention. Cimprich B, Hayes DF, Askren MK, et al. CTRC-AACR San Antonio Breast Cancer Symposium, 2012; Abstract S6-3.
ATLAS 10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease effects on outcome in the first and in the second decade after diagnosis
SUMMARY: Historically, adjuvant treatment with tamoxifen beyond five years has not been recommended, as the benefit of tamoxifen beyond five years was unknown but there was an increased risk of endometrial cancer. (Tamoxifen Treatment for Breast Cancer and Risk of Endometrial Cancer: A Case-Control Study, J Natl Cancer Inst 2005; 97: 375-384). The ATLAS trial has now shed some light on the duration of tamoxifen treatment. In this study, 6846 women with ER positive breast cancer were enrolled between 1996 and 2005 and following five years of adjuvant tamoxifen were randomized to five additional years of tamoxifen or observation. Women who continued on tamoxifen had a 25% lower recurrence rate and 29% lower breast cancer mortality rate compared with women who stopped tamoxifen after five years. This significant benefit was seen in the second decade after diagnosis with little benefit seen in the 5-9 year period after diagnosis. There was a higher cumulative risk of death from endometrial cancer for those who continued tamoxifen beyond 5 years compared to those who did not (0.4% vs 0.2%). It appears that the reduction in breast cancer deaths outweigh the risk of endometrial cancer and other adverse events associated with longer duration of tamoxifen use. This new information will help physicians make appropriate treatment recommendations for those patients on adjuvant tamoxifen. Davis C, Hongchao P, Godwin J, et al. CTRC-AACR San Antonio Breast Cancer Symposium, 2012; Abstract S1-2.
Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer the CALOR trial (Chemotherapy as Adjuvant for Locally Recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02)
SUMMARY: Approximately 5% to 15% of all breast cancer patients present with local and/or regional recurrences. The role of adjuvant chemotherapy after resection of an isolated recurrence of breast cancer is unknown. To address this, in the CALOR trial, 162 patients with recurrent tumors underwent surgery and were then randomized to receive either four cycles of a multidrug chemotherapy regimen of investigator’s choice (n=85) or observation (n=77). The median age was 56 years. The treatment groups were well balanced and 68% and 58% of patients in the observation and treatment arms respectively received prior adjuvant chemotherapy. The median time to recurrence was 5 years in the treatment group and 6 years in the observation group. The primary end point was disease free survival (DFS). The 5-year DFS rate for the chemotherapy group and observation group was 69% vs 57% respectively. This translated into a relative risk reduction of 41% (hazard ratio [HR], 0.59; P = 0.045). The 5-year overall survival rate between the chemotherapy group and observation group was 88% vs 76% with a 59% reduction in the relative risk for death for patients treated with chemotherapy (HR, 0.41; P = 0.02). In patients with ER-negative tumors, the 5-year DFS was 67% in the treatment arm versus 35% in the control group (HR = 0.32; P = 0.007). This data supports the role of chemotherapy for patients with completely resected isolated locoregional recurrences of breast cancer. Aebi S, Gelber S, Láng I, et al. Presented at: CTRC-AACR San Antonio Breast Cancer Symposium, 2012. Abstract S3-2.
Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts) Results of S9346 (INT-0162), an international phase III trial
SUMMARY: Preclinical data had suggested that Intermittent Androgen Deprivation (IAD) could prolong response to therapy and alleviate side effects related to androgen deprivation. In this Phase III trial, 3040 enrolled patients with hormone sensitive metastatic prostate cancer, with PSA ≥ 5 ng/ml, were treated for 7 months with ZOLADEX® (Goserelin) plus CASODEX® (Bicalutamide). After 7 months of this combination therapy, 1535 eligible patients achieved a PSA of ≤4.0 ng/ml. These patients were then randomized to either continue ZOLADEX® plus CASODEX® (Continuous Androgen Deprivation -CAD) or receive this combination intermittently (Intermittent Androgen Deprivation – IAD). The primary endpoint was overall survival. The median Overall Survival from the time of randomization in the CAD group was 5.8 years versus 5.1 years for the IAD group. However, a subset analysis surprisingly revealed that patients with minimal metastatic disease had a statistically significant survival advantage with CAD whereas those with extensive metastatic disease had a better survival with IAD. Counter intuitive as it may be, this study has clearly suggested that the choice of CAD versus IAD should be based on the extent of metastatic disease, in patients with hormone sensitive prostate cancer. Hussain M, Tangen CM, Higano CS, et al. J Clin Oncol 2012; 30, 2012 (suppl; abstr 4)
Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC) Results of a randomized phase II study
SUMMARY: Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17. This agent, was approved by the FDA in April, 2011 for use in combination with prednisone, for the treatment of patients with metastatic CRPC (Castrate Resistant Prostate Cancer), who have received prior chemotherapy containing docetaxel (TAXOTERE®). Patients with high risk localized prostate cancer do poorly in spite of aggressive local therapies. To improve outcomes in this patient population, the authors conducted a neoadjuvant trial in which patients with localized prostate cancer with high risk features were divided into two groups. The first group (n = 28) was treated with the LHRH analog, LUPRON® (Leuprolide acetate) for 12 weeks, followed by 12 weeks of combination treatment with LUPRON® and ZYTIGA® . The second group (n = 30) received neoadjuvant LUPRON® plus ZYTIGA® for the entire 24 week period. Patients had radical prostatectomies following their neoadjuvant therapy. Fifty eight patients were enrolled and the eligibility criteria included either T3 disease, a Gleason score of ≥7, a prostate-specific antigen (PSA) level ≥20, or a PSA velocity >2 ng/mL/year. Post prostatectomy specimen analysis revealed that patients treated with the combination of LUPRON® plus ZYTIGA® for the entire 24 week period has a complete pathologic response (pCR) or near complete pCR (≤ 5mm residual tumor) rate amounting to 34%. This benefit was seen without significant systemic toxicities. The authors concluded that neoadjuvant androgen deprivation therapy may significantly improve outcomes in high risk patients with localized disease and will need to be studied further. Taplin ME, Montgomery RB, Logothetis C, et al. J Clin Oncol 30, 2012 (suppl; abstr 4521)
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL) Updated results from the StiL NHL1 study
SUMMARY: This is an updated analysis of a study initially presented at ASH 2009 meeting. TREANDA® (Bendamustine) is an alkylating agent presently indicated for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) as well as Indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during 
or within six months of treatment with RITUXAN® (Rituximab) or a RITUXAN® containing regimen. In this randomized phase III trial, TREANDA® plus RITUXAN® (B-R)was compared to R-CHOP as first line treatment for patients with indolent or MCL. The primary endpoint was Progression Free Survival (PFS). With a median follow up of 45 months, patients on B-R had a PFS of 69.5 months vs 31.2 months for R-CHOP (HR =0.58; P<0.001). This benefit was seen in all age groups and all histological subtypes except marginal zone lymphoma. B-R was better tolerated than R-CHOP. There was no difference in the overall survival between the two groups. It should be noted however that close to 50% of the patients on R-CHOP whose disease progressed, were permitted to cross over to B-R and this could have impacted the overall survival results. Rummel MJ, Niederle N, Maschmeyer G, et al. J Clin Oncol 30, 2012 (suppl; abstr 3)
LUX-Lung 3 A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations
SUMMARY: Afatinib is an oral tyrosine kinase inhibitor that irreversibly inhibits EGFR (ErbB1), HER2 (ErbB2), and ErbB4. In this study, chemo naïve patients with advanced stage adenocarcinoma of the lung (stage IIIB/IV) with EGFR mutations, were randomly assigned to receive either Afatinib or a combination of Pemetrexed and Cisplatin. Primary endpoint was progression-free survival (PFS). Treatment with Afatinib resulted in a significantly prolonged PFS compared to combination chemotherapy (median 11.1 vs 6.9 months; HR 0.58; P=0.0004). Further, patients in the Afatinib group had a higher objective response rate ((56% vs 23%; p<0.0001), as well as significant delay in symptom progression, compared to the combination chemotherapy group. Yang JC-H, Schuler MH, Yamamoto N, et al. J Clin Oncol. 2012;30(suppl; abstr LBA7500).
Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer
SUMMARY:Durable tumor responses have been demonstrated in previous clinical studies using high dose interleukin 2 and anti-CTLA 4 antibody YERVOY® (Ipilimumab), for advanced malignancies such as metastatic melanoma. The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. It has two known ligands, PD-L1 and PD-L2 which can turn off the immune system when they combine with the PD-1 receptor. BMS-936558 is an anti-PD-1 targeted, fully human, monoclonal antibody which acts similar to the anti CTLA 4 antibody YERVOY®, thereby unleashing the T cell response against cancer cells. Results from a Phase 1 study in which 296 patients were enrolled demonstrated a durable response rate of 18% among patients with advanced non- small cell lung cancer, 28% among patients with advanced melanoma and 27% among patients with advanced renal cell carcinoma. PD-L1 was identified as a potential biomarker for response, with no responses seen in PD-L1 negative tumors. Topalian SL, Hodi S, Brahmer JR, et al. NEJM June 2, 2012.
Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane
SUMMARY:The HER or erbB family of receptors consist of HER 1,HER 2,HER 3 and HER 4. Overexpression of HER 2 in breast cancer has been associated with higher risk for relapse as well as overall survival. Trastuzumab is a humanized monoclonal antibody targeting HER 2. It binds to the extracellular domain of the receptor and blocks the downstream cell signaling pathways. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) comprised of the antibody trastuzumab and the chemotherapy agent DM1 linked together and inhibits HER2 signaling and destroys the HER2-positive tumor cells by delivering the chemotherapy agent DM1 directly inside the tumor cells. The EMILIA trial is a phase III study in which 978 patients with HER2-positive locally advanced or metastatic breast cancer who had previously received treatment with HERCEPTIN® (Trastuzumab) and a taxane chemotherapy, were enrolled. Patient received either trastuzumab emtansine (T-DM1) or XELODA® (Capecitabine) and TYKERB® (Lapatinib) doublet. The primary endpoints were Progression Free Survival (PFS), Overall Survival (OS) and safety. Patients receiving T-DM1 had an improved PFS compared to XELODA® and TYKERB® (9.6 months vs 6.4 months, HR=0.65, P <0.0001). A final OS analysis will be available at a later date. Blackwell KL, Miles D, Gianni L, et al. J Clin Oncol 30, 2012 (suppl; abstr LBA1)