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)
Author: RR
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).
Proton Versus Intensity-Modulated Radiotherapy for Prostate Cancer Patterns of Care and Early Toxicit
SUMMARY: Proton Radiotherapy (PRT) unlike external beam radiotherapy uses energy from positively charged particles called protons and has the ability to precisely localize the radiation dose to the tumor site, minimizing collateral damage. In this retrospective analysis, data on 27,647 Medicare beneficiaries who received PRT or IMRT (Intensity-Modulated RadioTherapy) for prostate cancer, was reviewed, during 2008 and/or 2009. At 12 months post-treatment, there was no statistical difference in genitourinary and gastrointestinal toxicity for patients who had received PRT compared to those who were treated with IMRT. With PRT almost twice as expensive as IMRT, it remains to be seen if PRT will be reimbursed by third party payors. It is interesting to note that in this study, patients receiving PRT were relatively younger, healthier, and lived in more affluent areas than patients receiving IMRT. Yu JB, Soulos PR, Herrin J, et al. J. Natl. Cancer Inst. 2013;105:25-32
Vitamin D deficiency and Bladder Cancer
The active metabolite of Vitamin D is Vitamin D3. In a recent study published in the JNCI, September 2012 issue, the authors noted a statistically significant increase in the risk of Bladder Cancer in individuals with low plasma concentrations of Vitamin D3. It is felt that Vitamin D3 favorably upregulates Fibroblast Growth Factor Receptor 3 (FGFR3). Mutations in FGFR3 are known to be associated with urothelial carcinoma. Urine samples evaluating for FGFR3 mutations, to diagnose urothelial carcinoma, has a positive predictive value of 95% when detected in patients with no history of Bladder Cancer. It appears that patients with aggressive bladder cancer have low expression of wild- type FGFR3 in association with low plasma concentrations of Vitamin D3. Therefore, it is possible that low plasma concentrations of Vitamin D3 may predict increased risk for bladder cancer, with more aggressive types of bladder cancer manifesting in those with significantly low Vitamin D3 levels.
POMALYST® (Pomalidomide)
The FDA on February 8, 2013 granted accelerated approval to POMALYST® for the treatment of patients with multiple myeloma who have received at least two prior therapies, including REVLIMID® (Lenalidomide) and VELCADE® (Bortezomib), and have demonstrated disease progression on or within 60 days of completion of the last therapy. POMALYST® capsules are a product of Celgene Corporation.
PROTON BEAM RADIATION THERAPY (PBRT) for Prostate Cancer
PBRT is a type of external beam radiation therapy in which a beam of Proton particles are used to irradiate cancer tissue. It has been claimed that the main advantage of proton therapy is its ability to more precisely localize the radiation dosage to the tumor tissue and thereby improve tumor control, without causing significant damage to the surrounding tissues. This theoretical consideration was however disproved in a study published in the Jan 2, 2013 issue of the JNCI. In this study, data was gathered following prostate cancer treatment of over 22,000 medicare beneficiaries, with either IMRT (Intensity Modulated Radiation Therapy) or PBRT. The authors noted that PBRT was not superior to IMRT with regards to efficacy or toxicity, after one year. PBRT was however twice as expensive as IMRT. It therefore remains to be seen if third party payors will warm up to PBRT, with the expansion of PBRT centers across the country.
AVASTIN® (Bevacizumab)
The FDA on January 23, 2013 approved AVASTIN® for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy, for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line AVASTIN® – containing regimen. The FDA initially approved AVASTIN® in 2004 for the first-line treatment of patients with metastatic carcinoma of the colon and rectum (in combination with intravenous 5-fluorouracil-based chemotherapy). AVASTIN® is a product of Genentech U.S., Inc.
Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening
SUMMARY: The National Lung Screening Trial (NLST) enrolled 53,454 individuals at high risk for lung cancer and randomly assigned them to undergo three annual screenings with either non-contrast, low-dose CT scan (LDCT) or single-view posteroanterior chest X-ray. This study demonstrated a 20% reduction in the risk of death from lung cancer in the group of people who were screened with LDCT compared to those who were screened with chest X-ray (P=0.004). Based on this study and data, the American Cancer Society has recommended lung cancer screening for individuals 55 to 74 years of age who are in fairly good health, have at least a 30 pack-year smoking history and are either still smoking or have quit smoking within the past 15 years. If a person remains in good health, annual LDCT is continued until the age of 74. Smokers should be counseled to quit smoking. Further more, people with abnormal scans should receive appropriate care and follow up. Lung cancer screening with LDCT is presently not covered by most insurance plans. The National Lung Screening Trial Research Team. N Engl J Med 2011; 365:395-409
Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation
SUMMARY: FLT3-ITD (FMS-like tyrosine kinase 3 – Internal Tandem Duplications) mutations are seen in approximately a third of the patients with AML and are associated with early relapse and poor survival. Quizartinib is an oral tyrosine kinase inhibitor, which has demonstrated activity in patients with both wild type FLT3 as well as those with FLT3 mutations. In this phase II trial, 333 patients were enrolled and divided into 2 cohorts – patients older than 60 years and those between 18 and 60 years of age. The data presented here relates to cohort 2 (younger cohort) which included 137 patients with AML, who either relapsed or were refractory to second line chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT). Of these patients, 99 were FLT3 -ITD mutation positive and 38 were FLT3 wild type. The dose of Quizartinib was 90 mg/day for women and 135 mg/day for men and was given continuously in 28-day cycles. This dosing schedule was chosen because of the risk for QT interval prolongation, based on gender. The primary end point was a composite complete remission rate (CRc), which included complete remission, complete remission with incomplete platelet recovery (CRp) and complete remission with incomplete hematologic recovery (CRi). Patients with FLT3 mutations had a CRc of 44% with 4% CR and 40% CRi. The median duration of response was 11.3 weeks and the median overall survival was 23.1 weeks. This compared to a CRc of 34% for those with wild type FLT3. Thirty four percent (34%) of the patients were able to undergo HSCT following response to Quizartinib. The most common side effects included nausea, vomiting, QT prolongation, cytopenia, diarrhea and fatigue. The authors concluded that Quizartinib has significant activity in patients with resistant and refractory AML and can facilitate HCST in about a third of the treated patients. Levis MJ, Perl AE, Dombret H, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 673
Pomalidomide in Combination with Low-Dose Dexamethasone Demonstrates a Significant Progression Free Survival and Overall Survival Advantage, in Relapsed/Refractory MM A Phase 3, Multicenter, Randomized, Open-Label Study
SUMMARY: Pomalidomide (POM) is a novel, oral, immunomodulatory drug which is far more potent than Thalidomide (THALOMID® and Lenalidomide (REVLIMID®) and has been shown to be active in REVLIMID® and Bortezomib (VELCADE®) refractory patients. In this phase III trial, the efficacy and safety of POM given along with low-dose dexamethasone (LoDEX) (n=302) was compared with high-dose dexamethasone (HiDEX) (n=153) in patients who were refractory to both REVLIMID® and VELCADE®. The primary endpoint was Progression Free Survival (PFS). The Overall Survival (OS) was only evaluated if PFS was statistically significant. With a median follow up of 18 weeks, the PFS was significantly longer in the POM + LoDEX group compared to the HiDEX group (15.7 vs 8.0 weeks; hazard ratio [HR], 0.45; P < .001). Following interim analysis, the OS was significantly longer in the POM + LoDEX group compared to HiDEX group (median not reached vs 34 weeks; HR, 0.53; P< .001). The authors concluded that this oral treatment regimen should be the new standard of care for patients who have disease refractory to REVLIMID® and VELCADE®. Carfilzomib (KYPROLIS®), a new parenteral proteasome inhibitor is another option for patients with resistant and refractory multiple myeloma. Dimopoulos MA, Lacy MQ, Moreau P, et al. 54th ASH Annual Meeting and Exposition 2012, LBA-6