SUMMARY: PERJETA® (Pertuzumab) is a recombinant, humanized, monoclonal antibody that binds to the HER2 dimerization domain and prevents the dimerization of HER2 with other HER receptors, ie. HER3, HER1 and HER4. HERCEPTIN® (Trastuzumab) is a monoclonal antibody that specifically targets the HER2 receptor and blocks the downstream signalling pathways. The accelerated approval of PERJETA® for the neoadjuvant treatment of breast cancer was based on a randomized, multicenter, open-label, phase II trial, in which 417 patients with HER2-positive, operable, locally advanced or inflammatory breast cancer (T2-4d), were randomly assigned to receive preoperative therapy with either HERCEPTIN® plus TAXOTERE® (Docetaxel), PERJETA® plus HERCEPTIN® and TAXOTERE®, PERJETA® plus HERCEPTIN® or PERJETA® plus TAXOTERE®. Patients in the three drug group received preoperative therapy with PERJETA®, HERCEPTIN® and TAXOTERE® every 3 weeks for a total of 4 cycles and following surgery, all patients received 3 cycles of Fluorouracil, ELLENCE® (Epirubicin), and CYTOXAN® (Cyclophosphamide) – (FEC) IV every 3 weeks and HERCEPTIN® was continued every 3 weeks for a total of one year of therapy. The primary endpoint was pathological Complete Response (pCR) rate defined as the absence of invasive cancer in the breast. The FDA definition of pCR is the absence of invasive cancer in the breast and lymph nodes. All treatment groups were well balanced. Seven percent of patients had inflammatory breast cancer, 32% had locally advanced cancer and 70% had clinically node-positive breast cancer. Forty-seven percent of the patients had hormone receptor-positive disease. The FDA defined pCR rates were 39.3% in the PERJETA® plus HERCEPTIN® and TAXOTERE® group and 21.5% in the HERCEPTIN® plus TAXOTERE® group P=0.0063). Of Interest, the pCR rates in the three drug group were lower in patients with hormone receptor positive tumors compared to patients with hormone receptor negative tumors. The most common adverse events in the three drug group were alopecia, diarrhea, nausea and neutropenia. The accelerated approval by the FDA was based solely on the improved pCR rate with the three drug combination with no demonstrable improvement in event-free survival or overall survival. A confirmatory phase III trial is underway, with results expected in 2016. Gianni L, Pienkowski T, Im YH, et al. Lancet Oncol. 2012;13:25-32
Tag: Breast Cancer
PERJETA® (Pertuzumab) The FDA on September 30, 2013 approved PERJETA® for use in combination with HERCEPTIN® (Trastuzumab) and TAXOTERE® (Docetaxel) for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This combination was approved by the FDA in June 2012, for the treatment of patients with HER2-positive metastatic breast cancer
The FDA on September 30, 2013 approved PERJETA® for use in combination with HERCEPTIN® (Trastuzumab) and TAXOTERE® (Docetaxel) for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This combination was approved by the FDA in June 2012, for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. PERJETA® is an injection and is a product of Genentech, Inc.
KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1):
The FDA on February 22, 2013 approved KADCYLA® for the treatment of patients with HER2-positive metastatic breast cancer who have received prior treatment with HERCEPTIN® (Trastuzumab) and a Taxane chemotherapy. KADCYLA® is marketed by Genentech U.S., Inc.
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 HER1,HER2,HER3 and HER4. Overexpression of HER2 in breast cancer has been associated with higher risk for relapse as well as overall survival. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. It binds to the extracellular domain of the receptor and blocks the downstream cell signaling pathways. KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an antibody-drug conjugate (ADC) comprised of the antibody Trastuzumab and the chemotherapy agent Emtansine, linked together. It inhibits HER2 signaling and destroys the HER2-positive tumor cells by delivering the chemotherapy agent Emtansine which binds to tubulin, directly inside the tumor cells. The EMILIA trial is a phase III study in which 991 patients with HER2-positive locally advanced or metastatic breast cancer who had previously received treatment with HERCEPTIN® and a Taxane chemotherapy, were enrolled. Patient received either KADCYLA® or XELODA® (Capecitabine) and TYKERB® (Lapatinib) doublet. The primary endpoints were Progression Free Survival (PFS), Overall Survival (OS) and safety. Patients receiving KADCYLA® had an improved PFS compared to XELODA® and TYKERB® (9.6 months vs 6.4 months, HR=0.65, P <0.0001). The median overall survival was 30.9 months in the KADCYLA® group and 25.1 months with the XELODA® and TYKERB® doublet. KADCYLA® is the fourth drug approved by the FDA, that targets the HER2 oncogene. The other FDA-approved drugs used to treat HER2-positive breast cancer include HERCEPTIN® (1998), TYKERB® (2007) and PERJETA® (Pertuzumab) (2012). Blackwell KL, Miles D, Gianni L, et al. J Clin Oncol 30, 2012 (suppl; abstr LBA1)
KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) now approved
The FDA today approved KADCYLA® for the treatment of patients with HER2-positive metastatic breast cancer who have received prior treatment with HERCEPTIN® (Trastuzumab) and a taxane chemotherapy. In a large Phase III trial, KADCYLA® improved Progression Free Survival as well as Overall Survival compared to XELODA® (Capecitabine) and TYKERB® (Lapatinib). KADCYLA® is the fourth drug approved by the FDA, that targets the HER2 oncogene. The other FDA-approved drugs used to treat HER2-positive breast cancer include HERCEPTIN® (1998), TYKERB® (2007) and PERJETA® (Pertuzumab) (2012).
Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC)
SUMMARY: PD 0332991 is an oral, selective inhibitor of CDK4/6 kinases. This agent interrupts cellular DNA synthesis by inhibiting the progression of the cell cycle from G1 to S phase and thus prevents tumor cell growth. The results presented, includes the pooled data from the study of 2 cohorts of patients. Both groups included postmenopausal women with advanced breast cancer and ER positive, HER2 negative tumors. Patients were randomized 1:1 to receive either letrozole (FEMARA®) along with PD 0332991 or FEMARA® alone. Group 1 enrolled 66 patients and Group 2 enrolled 99 patients. Group 2 patient tumors were also evaluated for the biomarkers cyclinD1 amplification and/or loss of p16, by FISH analysis. For both these study groups, the primary endpoint was Progression Free Survival (PFS). Secondary endpoints included response rates, overall survival, safety, and biomarker correlates. Data from the pooled analysis which included 165 women from both the groups demonstrated a median PFS of 26.1 months for the combination compared to 7.5 months with FEMARA® alone. This represented a 63% reduction in risk of progression (hazard ratio =0.37; P < 001). The most common adverse events noted in the combination group included uncomplicated neutropenia, anemia, and fatigue. Biomarkers expression (cyclinD1 amplification and/or loss of p16) had no impact on outcomes suggesting that the biomarker for PD0332991 may be the estrogen receptor itself rather than CDK4/6 kinases. Finn RS, Crown JP, Lang I, et al. CTRC-AACR San Antonio Breast Cancer Symposium 2012; Abstract S1-6.
Prospective study of treatment pattern, effectiveness, and safety of zoledronic acid (ZOL) therapy beyond 24 months subgroup analysis of patients (pts) with metastatic bone disease (MBD) from breast cancer (BC)
SUMMARY:There is not much data on the effectiveness and safety of Zoledronic acid (ZOMETA®) beyond 2 years. Two studies one from Belgium and the other from Japan shed some light on this issue. In the prospective multicenter Belgian trial, 108 women with breast cancer prior to enrollment had received at least 24 months of therapy with ZOMETA® infusions given every 3 to 4 weeks and 21% had received at least 48 months of therapy. They were followed for 18 months and monitored for Skeletal Related Events (SRE’s), Osteo Necrosis of the Jaw bone (ONJ), renal failure and hypocalcemia. During this follow up period, SRE’s were low and 83% of the women were free of SRE’s. ONJ was seen in 7 patients (4.5%). The rate of ONJ however rose to 11% after any invasive dental procedure. The risk of renal failure was low but increased to 12%when the dose of ZOMETA® was not adjusted for renal function. The Japanese study was a retrospective analysis of 83 patients who had been treated with ZOMETA® for at least 24 months (median 33 months). SRE’s were low and the frequency of ONJ was 3.6% compared to 2.4% for those patients who had been ZOMETA® for shorter periods. Both these studies demonstrated that longer duration of therapy with ZOMETA® resulted in increased rate of ONJ. Therefore, particular attention should be paid to prevent this complication by adhering to proper dental hygiene and avoiding dental trauma and extractions. Van den Wyngaert T, Delforge M, Doyen C, et al. and Suzuki Y, Saito Y, Ogiya R, et al. CTRC-AACR San Antonio Breast Cancer Symposium 2012; Poster P3-13-01 and P3-13-02.
Final analysis of overall survival for the phase III CONFIRM trial fulvestrant 500 mg versus 250 mg
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.
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.