Some molecularly targeted agents are proving to be less effective, not more so, when administered earlier in the disease course. Researchers say this is counterintuitive, because advanced disease is associated with treatment refractoriness, and cancer agents will typically perform better in the adjuvant treatment setting than in the metastatic treatment setting.
One such “failure” made headline news last summer, when results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial were announced at the American Society of Clinical Oncology (ASCO) annual meeting. Unexpectedly, bevacizumab did not improve outcomes in early-stage colon cancer, although it had become a standard treatment in advanced colon cancer.
“We failed, and nobody likes to fail,” Norman Wolmark, MD, principal investigator, commented at a press conference. “Actually, it wasn’t bevacizumab that failed. If anything,we failed to provide our patients with a novel intervention that would increase cures.”
The NSABP randomized 2710 patients with stage II and III colorectal cancer to a standard chemotherapy regimen or the same plus bevacizumab for 6 additional months. At a median follow-up of 36 months, disease-free survival (DFS) was 75.5% in the control armand 77.4%in the bevacizumab arm (hazard ratio, 0.89; P = .05). A significant benefitwas, however, observed for the 1 year that patients were actually taking bevacizumab: a 3.6% absolute improvement inDFS and a 40%relative risk reduction (P = .004). “So bevacizumab was effective, but this efficacy disappeared after bevacizumab was stopped,” Dr Wolmark said. “The challenge is to learn howto use bevacizumab to its maximum potential in the adjuvant setting.”
Equally surprising was the recent announcement that cetuximab (Erbitux) confers no benefit for stage III resected colon cancer. In a randomized phase 3 trial of 1847 patients with colon cancer selected for the presence of nonmutated (wild-type) KRAS tumors (which are associated with cetuximab’s benefit in advanced disease), the addition of cetuximab provided no value over standard chemotherapy alone. Three-year DFS was approximately 74% in each arm, and 3-year overall survival (OS) was 87% with chemotherapy and 82% with chemotherapy plus cetuximab (P = .06), reported investigator Steven R. Alberts, MD, at the ASCO 2010 annual meeting.
These findings, while disappointing, have important implications, according to Dr Alberts. “For one thing, what we learn in metastatic disease does not always apply to the adjuvant setting,” he said. “The findings also indicate that disease in earlier stages may be different from disease in later stages.”
Jennifer Obel, MD, of NorthShore University HealthSystem in Evanston, IL, commented that this study, combined with others, “casts doubt on whether biologics will play a role in early-stage colon cancer.”And in earlystage non–small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) failed to provide benefit over resection alone in a Canadian study of 503 patients with resected stage IB-IIIA NSCLC. In an exploratory analysis, the presence of EGFR-sensitizing mutations (which are associated with response to EGFR inhibitors in advanced disease) were not predictive of a survival benefit, reported Glenwood D. Goss, MD, and colleagues from the Ottawa Hospital Research Institute in Canada. OS was 5.1 years in the placebo arm and 3.7 years in the gefitinib arm in patients with EGFR mutations.
“It is yet to be demonstrated that a targeted agent improves overall survival in NSCLC in the adjuvant setting, and, for the present, chemotherapy in good performance patients remains the treatment of choice,” Dr Goss concluded.
