SUMMARY:The US Food and Drug Administration (FDA) approved XTANDI® (Enzalutamide), an oral agent, formerly known as MDV3100, for men with metastatic castration-resistant prostate cancer who had progressed on TAXOTERE® (Docetaxel) based chemotherapy regimen. The approval was based on the results from the AFFIRM clinical trial. XTANDI® is an androgen receptor antagonist with a significantly higher binding affinity for the androgen receptor (AR) compared to the antiandrogen bicalutamide and there by competitively inhibits the binding of androgens to the androgen receptor. Majority of the patients with advanced prostate cancer become refractory to hormone therapy because of increased production of androgen receptors by the tumors as well as mutated androgen receptors. The superiority of this novel agent, XTANDI®, is based on the fact that the expression of androgen receptor dependent genes are downregulated with XTANDI® leading to cell death or apoptosis, whereas with bicalutamide the expression of these genes are upregulated. Further XTANDI® continues to antagonize mutated androgen receptors on the prostate tumor cells in contrast to bicalutamide which behaves as an agonist. It is thus an androgen receptor signaling inhibitor (ARSI). The AFFIRM clinical trial is a randomized, multinational phase III study in which patients who had received prior docetaxel-based chemotherapy regimens were randomized 2:1 to receive either XTANDI®, 160 mg/day or placebo. Patients treated with XTANDI® had a median survival of 18.4 months, compared with 13.6 months for men treated with placebo, with a median OS advantage of 4.8 months and a reduction in the risk of death by 37%. Scher HI, Fizazi K, Saad F, et al. J Clin Oncol 30, 2012 (suppl 5; abstr LBA1)
Category: Hem/Onc Updates
Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer
SUMMARY: In this trial, neoadjuvant chemoradiation followed by surgery was compared with surgery alone, in patients with esophageal or GE junction tumors. Three hundred and sixty six (366) patients were randomized and chemoradiotherapy consisted of weekly PARAPLATIN® (Carboplatin) and TAXOL® (Paclitaxel) for 5 weeks with concurrent radiotherapy followed by surgery. Complete resection was feasible in 92% of the patients receiving chemoradiation compared to 69% in the surgery alone group (P<0.001). Overall survival was 49 months in the chemoradiation/surgery group compared to 24 months in the surgery alone group (HR=0.65, P<0.003). This benefit was seen regardless of histology and postoperative complications were similar in both treatment groups. This study has conclusively established that chemoradiation followed by surgery is superior to surgery alone, in patients with esophageal and GE junction tumors. van Hagen P, Hulshof MCCM, van Lanschot JJB, et al. for the CROSS Group. N Engl J Med 2012; 366:2074-2084
Prevention of Pegfilgrastim-Induced Bone Pain A Phase III Double-Blind Placebo-Controlled Randomized Clinical Trial of the University of Rochester Cancer Center Clinical Community Oncology Program Research Base
SUMMARY:Bone pain related to NEULASTA® (Pegfilgrastim) has been reported to 25%-60% of patients in various clinical trials. In this randomized placebo controlled clinical trial, 510 patients were randomly assigned to receive either Naproxen 500 mg PO BID or placebo, for 5-8 days following NEULASTA®. Naproxen reduced the proportion of pain, patients reported, by 10% (71% vs 61%, P=0.02) and severe pain was reduced by 8% (27% vs 19%, P=0.05). Naproxen also reduced the overall pain incidence (P=0.02) and duration of pain (P=0.009). The authors concluded that Naproxen 500mg PO BID is effective in modestly reducing the incidence and severity of NEULASTA® induced bone pain. The adverse effects of Naproxen, has to be taken into consideration before prescribing this agent for bone pain. Kirshner JJ, Heckler CE, Janelsins MC, et al. J Clin Oncol 2012;30:1974-1979.
Radical Prostatectomy versus Observation for Localized Prostate Cancer
SUMMARY: In this study, 731 men with localized prostate cancer, diagnosed based on PSA testing, were randomly assigned to Radical Prostatectomy (RP) or Observation. The median age was 67 years, median PSA was 7.8ng/ml and median follow up was 10 years. This study concluded that RP did not significantly reduce all cause mortality or mortality related to prostate cancer. However on subset analysis, RP slightly decreased mortality among men with PSA greater than 10ng/ml and among those with intermediate and high D’Amico tumor risk score. As only 10% of the patients were less than 60 years of age, these data may not be applicable to this patient subset. Based on this study, it may be reasonable to avoid RP for those prostate cancer patients with PSA levels of 10ng/ml or less and for those with low risk tumors. Wilt TJ, Brawer MK, Jones KM, et al., for the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. N Engl J Med 2012; 367:203-213
Adjuvant Therapy in the Treatment of Biliary Tract Cancer A Systematic Review and Meta-AnalysisAdjuvant Therapy in the Treatment of Biliary Tract Cancer A Systematic Review and Meta-Analysis
SUMMARY: The authors in this meta-analysis reviewed data on 6712 patients with biliary tract cancers, including gall bladder tumors. Ampullary tumors were excluded. These patients had resections done with a curative intent and this was defined as those with negative surgical margins (R0) or microscopic positive margins (R1). All these patients received adjuvant therapy, which included chemotherapy, radiation therapy or a combination of both, following surgery. There was an improvement in overall survival for those patients receiving adjuvant therapy. Patients who received chemotherapy or chemoradiation treatment derived greater benefit than those who received radiation therapy alone. The greatest statistically significant benefit was seen in those with lymph node positive disease and R1 disease. Based on this analysis, it may be reasonable to consider adjuvant therapy for patients with high risk biliary tract cancers. Horgan AM, Amir E, Walter T, et al. JCO 2012; 30:1934-1940
The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy
SUMMARY: Breakthrough Chemotherapy Induced Nausea and Vomiting (CINV) is encountered in 30-40% of patients, in spite of treatment with prophylactic antiemetics. ZYPREXA® (Olanzapine) is a FDA approved antipsychotic agent. In this double blind, randomized, phase III trial, chemotherapy naïve patients receiving highly emetogenic chemotherapy who had experienced breakthrough CINV were randomized to receive either ZYPREXA® 10 mg orally daily for three days or REGLAN® (Metoclopramide) 10mg orally TID for three days. They were then monitored for 72 hours. During this 72 hour observation period, 71% patients receiving ZYPREXA® had no emesis compared to 32% in the group receiving REGLAN® (P<0.01). With regards to nausea, 67% of patients in the ZYPREXA® group did not experience nausea, compared to 24% in the REGLAN® group (P<0.01). This new treatment option with ZYPREXA® may help a significant number of patients who experience breakthrough CINV. Navari RM, Nagy CK, Gray SE. J Clin Oncol. 2012; 30 (suppl; abstr 9064).
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)
Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma
SUMMARY:The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is an important signaling pathway which enables the cell to respond to external stimuli. There are a number of MAP kinase pathways, which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E site and is detected in approximately 50% of melanomas.The BREAK-3 trial is a randomized phase III trial, with the study design similar to that of the Vemurafenib BRIM-3 trial. Dabrafenib is a selective oral BRAF inhibitor. Patients with advanced BRAFV600E mutated melanoma were randomized to receive either Dabrafenib or Dacarbazine (DTIC). Primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and duration of response. The median PFS was 5.1 months for Dabrafenib and 2.7 months for DTIC (hazard ratio = 0.30; P< 0.0001). RR was 53% for Dabrafenib and 19% for DTIC. OS data was not mature for analysis. Squamous cell carcinomas were seen in 6% of the patients. Hauschild A, Grob JJ, Demidov LV, et al. J Clin Oncol. 2012:30(suppl; abstr LBA8500).