SUMMARY: MDV3100 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, MDV3100, is based on the fact that the expression of androgen dependent genes are downregulated with MDV 3100 leading to cell death or apoptosis, whereas with bicalutamide the expression of these genes are upregulated. Further MDV3100 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 MDV3100, 160 mg/day or placebo. Patients treated with MDV3100 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
Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies
SUMMARY: In this phase III trial, patients with metastatic colorectal carcinoma who had progressed after approved standard therapies were randomly assigned in a 2:1 ratio to receive either Regorafenib, an oral multikinase inhibitor plus best supportive care or placebo plus best supportive care. Seven hundred and sixty patients were randomized. Patients receiving Regorafenib had a statistically significant improvement in the overall survival and progression free survival compared to placebo, without any unexpected toxicities. This important study gives a new option for individuals with advanced colorectal cancer who have progressed on all available standard therapies. Grothey A, F. Sobrero AF, Siena S, et al. J Clin Oncol 30, 2012 (suppl 4; abstr LBA385)
Risk Factors for Breast Cancer for Women Aged 40 to 49 Years
SUMMARY: There is presently no clear consensus regarding breast cancer screening for women in their 40’s. The risk/benefit ratio of screening mammography has not been properly defined in this age group. In this review, Nelson and colleagues identified the risk factors for breast cancer and concluded that there is a 2 fold increase in the risk for breast cancer in women 40-49 years of age, who have dense breast tissue and first degree relatives with breast cancer. This meta analysis has identified a subset of patients in their 40’s who would benefit from screening mammography. Nelson HD, Zakher B, Cantor A, et al. Ann Intern Med. 2012;156:635-648
Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT Results of a randomized phase III intergroup study (TML study)
SUMMARY:The ML18147 (TML) is a randomized phase III trial in which patients who received AVASTIN® (Bevacizumab) plus standard chemotherapy as initial treatment (first-line treatment) for their metastatic colorectal cancer were then randomized to either continue AVASTIN® with a different chemotherapy after their cancer progressed (second-line treatment) or receive the different chemotherapy regimen without AVASTIN®. Patient group continuing AVASTIN® as a part of second line treatment demonstrated an improved survival compared to those who received chemotherapy alone, as second line treatment. This study has demonstrated that continuing AVASTIN® with second line chemotherapy post progression, extends survival in patients with metastatic colorectal cancer. Arnold D, Andre T, Bennouna J, et al. J Clin Oncol 30, 2012 (suppl; abstr CRA3503)
Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer
SUMMARY: The CLEOPATRA trial is a phase III trial in which 808 HER positive metastatic breast cancer patients, for their first line treatment, were randomized to either HERCEPTIN® plus Docetaxel or the above two drug combination given along with PERJETA® (Pertuzumab). PERJETA® 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. The addition of PERJETA® to the combination of HERCEPTIN® and Docetaxel significantly prolonged progression-free survival compared to HERCEPTIN® plus Docetaxel alone (18.5 months vs 12.4 months, P<0.001). This benefit was seen without increase in cardiotoxicity. It appears that PERJETA® complements HERCEPTIN® in targeting HER-2 receptor. Baselga J, Cortés J, Kim S, et al. N Engl J Med 2012; 366:109-119
Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer
SUMMARY: In this phase III trial, 360 patients with muscle-invasive bladder cancer were randomized to receive radiation therapy with or without concurrent chemotherapy. The chemotherapy regimen consisted of 5-fluorouracil given on days 1-5 and days16-20 of radiotherapy and mitomycin C given on day 1. The primary end point of this study was locoregional disease free survival. Secondary end points included overall survival and toxicities. The locoregional disease–free survival at two years was 67% in the chemoradiation group and 54% in the radiation therapy only group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiation group was 0.68 (P=0.03). The overall survival at five years was 48% in the chemoradiation group and 35% in the radiation therapy only group with a hazard ratio of 0.82 (P=0.16). The authors concluded that for patients with muscle invasive bladder cancer, concurrent chemoradiation significantly improved locoregional disease free survival compared to radiation therapy only. James ND, Hussain SA, Hall E, et al. N Engl J Med 2012; 366:1477-1488
ZALTRAP® for second line treatment of metastatic CRC
ZALTRAP® (Aflibercept) is a soluble fusion protein that is capable of binding with high affinity to pro-angiogenic factors such as all VEGF-A isoforms, VEGF-B, and PlGF. This is unlike bevacizumab, which is a monoclonal antibody that only targets all isoforms of VEGF-A. In the VELOUR trial, second-line chemotherapy in combination with ZALTRAP® (Aflibercept) demonstrated significant improvement in the progression-free survival as well as overall survival compared to chemotherapy alone. This benefit was seen irrespective of prior bevacizumab therapy. This data was presented at the 13th ESMO world congress.
Regorafenib improves survival in advanced CRC
The CORRECT trial is a randomized phase III study which demonstrated improved survival with Regorafenib, an oral multikinase inhibitor when compared to placebo, in individuals with advanced colorectal cancer, who had progressed on all available standard therapies. This important study gives a new option for individuals with advanced colorectal cancer. Additional data will be presented at ASCO 2012 meeting.
Intravenous (IV) aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC) Results of a multinational phase 3 trial (EFC10262-VELOUR)
SUMMARY:ZALTRAP® (Aflibercept) is a soluble fusion protein that is capable of binding with high affinity to pro-angiogenic factors such as all VEGF-A isoforms, VEGF-B, and PlGF. This is unlike bevacizumab, which is a monoclonal antibody that only targets all isoforms of VEGF-A. VELOUR is a phase III trial in which 1,226 patients who had failed oxaliplatin-based therapy received second-line therapy and the comparison was FOLFIRI (leucovorin, fluorouracil, irinotecan) with or without ZALTRAP® (Aflibercept). With a median follow-up of 22.3 months, there was significant improvement in the progression-free survival noted in the ZALTRAP® (Aflibercept) group (6.9 vs 4.67 months; HR = 0.758;P = .00007) as well as overall survival (13.5 vs 12.06 months; HR = 0.817;P = .0032). This benefit was seen irrespective of prior bevacizumab therapy. The authors did point out that in the E3200 Intergroup trial, which tested second-line FOLFOX4 chemotherapy with or without bevacizumab, all of the patients were bevacizumab-naive, whereas 70% in the VELOUR trial were bevacizumab-naive.Van Cutsem E, Tabernero J, Lakomy R, et al. Results of a multinational phase 3 trial (EFC10262-VELOUR). 13th ESMO World Congress on Gastrointestinal Cancer. Abstract 0-0024.
CLEOPATRA Trial in Breast Cancer
In this Phase III trial involving first line treatment of patients with HER-2 positive metastatic breast cancer, the addition of Pertuzumab (an anti-HER-2 humanized monoclonal antibody that inhibits receptor dimerization) to a combination of Trastuzumab and Docetaxel significantly prolonged progression-free survival, without increase in cardiotoxicity when compared to Trastuzumab and Docetaxel alone. It appears that Pertuzumab complements Trastuzumab in targeting HER-2 receptor.
These findings from the CLEOPATRA trial have demonstrated that comprehensive HER-2 blockade may result in improved outcomes for patients with breast cancer over expressing HER-2.
The original article was published in the January 2012 issue of the NEJM.