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).
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)
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)
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 â€¨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)
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).
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. Vemurafenib is a novel oral inhibitor of mutated BRAF. However, Vemurafenib may increase the risk of developing a secondary malignancy (squamous cell carcinoma). Trametinib is a very potent and selective inhibitor of MEK gene and by seeking out this mechanism of action, there is probably a lower risk of another activated event ie. secondary malignancies. This is because MEK is downstream from RAF in the MAP Kinase pathway. In a phase III trial, patients with advanced melanoma with BRAF V600E/K mutations and without brain metastases were randomized to receive Trametinib or chemotherapy (either dacarbazine or paclitaxel). Patients receiving chemotherapy were allowed to crossover to receive Trametinib if they had documented progression. Primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and safety. The outcomes were in favor of Trametinib with a PFS of 4.8 months vs 1.4 months (HR =0.44; P<0.0001), RR of 24% vs 7%, with a 47% reduction in the risk of death compared to chemotherapy. Robert C, Flaherty KT, Hersey P, et al. J Clin Oncol. 2012:30(suppl; abstr LBA8509).
SUMMARY:Regorafenib is an oral multikinase inhibitor. In this randomized trial, patients with advanced GIST who had progressed on both GLEEVEC® (Imatinib) and SUTENT® (Sunitinib) were randomized to receive either Regorafenib or Placebo. The primary endpoint was progression-free survival (PFS). Patients in the Regorafenib group had a statistically significant 3.9 month improvement in progression-free survival (PFS) compared to placebo (4.8 months vs 0.9 months; Hazard Ratio = 0.27; P<.0001). Demetri GD, Reichardt P, Kang YK, et al. J Clin Oncol. 2012; 30 (suppl; abstr LBA10008).
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).
SUMMARY: AURELIA is a multicenter, randomized, open-label, two-arm Phase III study in which 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer were enrolled. These patients had disease progression within six months of their platinum based chemotherapy. Patients were randomly assigned to receive AVASTIN® (Bevacizumab) in combination with chemotherapy which included weekly paclitaxel, topotecan or pegylated liposomal doxorubicin or chemotherapy alone. The primary end point was Progression Free Survival. There was a 52% reduction in the risk of progression in those who received AVASTIN® plus chemotherapy compared to those who received chemotherapy alone (HR=0.48, P<0.001). Further, there was a significantly higher objective response rate in the AVASTIN® group compared to those who received chemotherapy alone (30.9 percent vs. 12.6 percent, p=0.001). Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol 30, 2012 (suppl; abstr LBA5002)
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.