Gastrointestinal Cancer News: ASCO GI Symposium 2012
The American Society of Clinical Oncology (ASCO) hosted a specialized meeting in San Francisco to assemble the world’s experts in gastrointestinal oncology. A summary of significant findings from the ASCO 2012 Gastrointestinal Cancers Symposium is provided by a member of N-of-One’s Oncology Council, who attended the meeting. A variety of interesting studies describing targeted therapies were presented. These new approaches may lead to incremental improvements in patient care, either directly or through further research, as described below.
Dr. Axel Grothey’s presentation of the CORRECT trial generated the most buzz. CORRECT was a Phase 3, randomized, double-blind, placebo-controlled trial of the multi-targeted tyrosine kinase inhibitor regorafenib given to patients with metastatic colorectal cancer that had progressed on all standard therapies. The drug inhibits multiple kinases implicated in angiogenic (VEGFR1-3, TIE2), oncogenic (KIT, PDGFR, RET) and stromal (PDGFRβ, FGFR) signaling. The trial randomized 760 patients to regorafenib given once daily for 3 weeks on and 1 week off or to placebo using a 2:1 design. Median overall survival was 6.4 months in the experimental group and 5.0 months in the placebo-treated group (hazard ratio 0.77). Although the response rate with regorafenib was only 1.6% (0.4% in the control group), the disease control rate was 44% (15% in the control group). Moreover, although the median progression free survival was only 1.9 months (1.7 months in the control group), the Kaplan-Meier analysis revealed a separation of the PFS curves after the first 2 months. Grade 3/4 toxicities in the experimental group included hand-foot syndrome (17%), fatigue (9%), and diarrhea (8%). Treatment was discontinued due to toxicity in 8.2% of the experimental group compared to 1.2% of the control group. Taken together, these data suggest that a subset of patients benefit from clinically significant disease control with an acceptable toxicity profile. The challenge, of course, will be to identify these patients prospectively. Although broad target coverage may underlie regorafenib’s efficacy, it also may complicate efforts to identify predictive biomarkers.
A second interesting presentation was given by Dr. Manish Shah, in which he discussed the results from an unplanned subset analysis of the AVAGAST study. AVAGAST was an international randomized trial of cisplatin and capecitabine +/- bevacizumab in patients with previously untreated metastatic gastric cancer. The study did not meet its primary endpoint of increased overall survival, but there was an intriguing suggestion of benefit in the subset of patients from non-Asian sites of enrollment (i.e. European and pan-American). In fact, Dr. Shah discussed work from his group and others suggesting that there are at least three subtypes of gastric cancer with distinct pathology and geographic distribution. Type I tumors are found within the proximal stomach and are associated with gastroesophageal reflux disease and obesity. Type II tumors are diffuse cancers with a submucosal pattern of spread. Type III tumors are found within the distal stomach and antrum, and are associated with H. pylori infection. The presented subset analysis examined the effect of adding bevacizumab to chemotherapy within each gastric cancer subtype, revealing improved survival in non-Asian patients with type II and type III tumors (HR of 0.68 and 0.72, respectively). Patients with these tumors had higher levels of plasma VEGF-A and lower levels of tumor NRP-1 expression, suggesting potential biomarkers that may help further define subsets of gastric cancer patients likely to benefit from anti-angiogenic strategies.
Additional presentations revealed disappointing results from studies examining the addition of brivanib to cetuximab in patients with colorectal cancer and the role of the mTOR inhibitor everolimus in gastric cancer. Finally, despite previously published data suggesting that patients with colorectal cancer and codon 13 KRAS mutations may benefit from anti-EGFR therapy with cetuximab, a combined analysis of three panitumumab studies revealed no benefit in this population.
In summary, the meeting witnessed the introduction of a new therapy likely to gain approval for patients with colorectal cancer, as well as some disappointments and a number of intriguing findings suggesting avenues of future research. Clearly, we need to keep striving for truly individualized therapy for patients with gastrointestinal cancers.
By: Raymond C Wadlow, MD, Virginia Cancer Specialists
References:
Grothey 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.
Shah et al, J Clin Oncol 30, 2012 (suppl 4; abstr 5) Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin plus bevacizumab (bev) or placebo in patients (pts) with advanced gastric cancer.
Dr. Axel Grothey’s presentation of the CORRECT trial generated the most buzz. CORRECT was a Phase 3, randomized, double-blind, placebo-controlled trial of the multi-targeted tyrosine kinase inhibitor regorafenib given to patients with metastatic colorectal cancer that had progressed on all standard therapies. The drug inhibits multiple kinases implicated in angiogenic (VEGFR1-3, TIE2), oncogenic (KIT, PDGFR, RET) and stromal (PDGFRβ, FGFR) signaling. The trial randomized 760 patients to regorafenib given once daily for 3 weeks on and 1 week off or to placebo using a 2:1 design. Median overall survival was 6.4 months in the experimental group and 5.0 months in the placebo-treated group (hazard ratio 0.77). Although the response rate with regorafenib was only 1.6% (0.4% in the control group), the disease control rate was 44% (15% in the control group). Moreover, although the median progression free survival was only 1.9 months (1.7 months in the control group), the Kaplan-Meier analysis revealed a separation of the PFS curves after the first 2 months. Grade 3/4 toxicities in the experimental group included hand-foot syndrome (17%), fatigue (9%), and diarrhea (8%). Treatment was discontinued due to toxicity in 8.2% of the experimental group compared to 1.2% of the control group. Taken together, these data suggest that a subset of patients benefit from clinically significant disease control with an acceptable toxicity profile. The challenge, of course, will be to identify these patients prospectively. Although broad target coverage may underlie regorafenib’s efficacy, it also may complicate efforts to identify predictive biomarkers.
A second interesting presentation was given by Dr. Manish Shah, in which he discussed the results from an unplanned subset analysis of the AVAGAST study. AVAGAST was an international randomized trial of cisplatin and capecitabine +/- bevacizumab in patients with previously untreated metastatic gastric cancer. The study did not meet its primary endpoint of increased overall survival, but there was an intriguing suggestion of benefit in the subset of patients from non-Asian sites of enrollment (i.e. European and pan-American). In fact, Dr. Shah discussed work from his group and others suggesting that there are at least three subtypes of gastric cancer with distinct pathology and geographic distribution. Type I tumors are found within the proximal stomach and are associated with gastroesophageal reflux disease and obesity. Type II tumors are diffuse cancers with a submucosal pattern of spread. Type III tumors are found within the distal stomach and antrum, and are associated with H. pylori infection. The presented subset analysis examined the effect of adding bevacizumab to chemotherapy within each gastric cancer subtype, revealing improved survival in non-Asian patients with type II and type III tumors (HR of 0.68 and 0.72, respectively). Patients with these tumors had higher levels of plasma VEGF-A and lower levels of tumor NRP-1 expression, suggesting potential biomarkers that may help further define subsets of gastric cancer patients likely to benefit from anti-angiogenic strategies.
Additional presentations revealed disappointing results from studies examining the addition of brivanib to cetuximab in patients with colorectal cancer and the role of the mTOR inhibitor everolimus in gastric cancer. Finally, despite previously published data suggesting that patients with colorectal cancer and codon 13 KRAS mutations may benefit from anti-EGFR therapy with cetuximab, a combined analysis of three panitumumab studies revealed no benefit in this population.
In summary, the meeting witnessed the introduction of a new therapy likely to gain approval for patients with colorectal cancer, as well as some disappointments and a number of intriguing findings suggesting avenues of future research. Clearly, we need to keep striving for truly individualized therapy for patients with gastrointestinal cancers.
By: Raymond C Wadlow, MD, Virginia Cancer Specialists
References:
Grothey 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.
Shah et al, J Clin Oncol 30, 2012 (suppl 4; abstr 5) Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin plus bevacizumab (bev) or placebo in patients (pts) with advanced gastric cancer.
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