SUMMARY: It is common practice to combine anti-EGFR agent ERBITUX® (Cetuximab) or anti-VEGF agent AVASTIN® (Bevacizumab) with chemotherapy, in the initial management of patients with metastatic colorectal cancer. There is however a higher likelihood for patients with tumors expressing wild type KRAS (non-mutated KRAS), to respond to ERBITUX®. In this randomized multicenter study, a CAMPTOSAR® (Irinotecan) based backbone, FOLFIRI (folinic acid, fluorouracil and Irinotecan) given along with ERBITUX® (Group A) was compared with FOLFIRI plus AVASTIN® (Group B), in treatment naïve patients with metastatic ColoRectal Cancer (mCRC). Of the 592 patients with wild type KRAS mCRC, 297 patients were randomized to Group A and 295 patients to Group B. The median age was 64 years. The median duration of treatment was 4.7 months and 5.3 months in Group A and Group B respectively. The primary endpoint was Objective Response Rate (ORR). Even though the ORR was comparable in Groups A and B (62% vs 57%), there was a significant improvement in the overall survival (OS) favoring Group A (28.8 vs 25.0 months, HR= 0.77, P=0.0164). The comparable response rates and surprising improvement in OS in the ERBITUX® group suggests that either ERBITUX® or AVASTIN® can be added to FOLFIRI, in the first-line treatment of wild type KRAS mCRC patients. It is however clear that in wild type KRAS mCRC patients, it may be harmful to combine ERBITUX® with FOLFOX chemotherapy regimen, as was seen in the EPOCH trial and based on MRC COIN trial, NORDIC-VII trial and N0147 trial, ERBITUX® should not be combined with FOLFOX chemotherapy regimen as there is no added benefit. It is now well established that mCRC that harbors KRAS mutations in exon 2 (about 40% of the patients) do not benefit from anti-EGFR therapies. The PRIME study has given us aditional insight and it appears that other activating RAS mutations may also predict lack of response to anti-EGFR therapies. With regards to BRAF mutations, they portend a poor prognosis, regardless of treatment. Heinemann V, Weikersthal LF, Decker T, et al. J Clin Oncol 31, 2013 (suppl; abstr LBA3506)
Tag: Colon Cancer
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.
ERBITUX® (Cetuximab)
The FDA on July 9, 2012 granted approval to ERBITUX® for use in combination with FOLFIRI (CAMPTOSAR® [Irinotecan], 5-fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use. ERBITUX® is a product of Eli Lilly and Co.
STIVARGA® (Regorafenib)
The FDA on September 27, 2012 approved STIVARGA® (Regorafenib) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, ELOXATIN® (Oxaliplatin)-, and CAMPTOSAR® (Irinotecan)-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. STIVARGA® tablets are a product of Bayer HealthCare Pharmaceuticals, Inc.
ZALTRAP® (Ziv-aflibercept injection)
The FDA on August 3, 2012 approved ZALTRAP® (Ziv-aflibercept injection), for use in combination with 5-fluorouracil, leucovorin, CAMPTOSAR® (Irinotecan) (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen. ZALTRAP® is a product of Sanofi U.S., Inc.
FDA approves STIVARGA® (Regorafenib) for Advanced Colorectal Cancer
SUMMARY: The FDA approved STIVARGA® (Regorafenib), an oral multi-kinase inhibitor for the treatment of patients with metastatic colorectal cancer (CRC) who have progressed on 5FU, ELOXATIN® (Oxaliplatin), CAMPTOSAR® (Irinotecan), anti- VEGF and anti-EGFR therapies. The approval was based on a phase III trial in which 760 patients with metastatic CRC who had progressed after approved standard therapies, were randomly assigned in a 2:1 ratio to receive either STIVARGA® plus best supportive care (BSC) or placebo plus BSC. Patients receiving STIVARGA® had a statistically significant improvement in the overall survival and progression free survival compared to placebo, without any unexpected toxicities. The most common side effects of STIVARGA® were fatigue, loss of appetite, hand-foot syndrome, diarrhea, mucositis, elevated blood pressure, and dysphonia. This important study gives a new option for individuals with advanced colorectal cancer. Grothey A, F. Sobrero AF, Siena S, et al. J Clin Oncol 30, 2012 (suppl 4; abstr LBA385)
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)
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)
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.