Biologic agents in the treatment of colorectal cancer: the last decade; the lost decade?

T start of the new millennium brought with it the promise of solving the human genome and the capacity to design new drugs and antibodies. As a result, it also brought with it the expectations that the progress in treating disease, cancer included, would be rapid and substantial. Indeed, by the year 2000 several new “biologic” or “targeted” agents promised to be effective in cancer treatment. Imatinib turned an untreatable sarcoma, gastrointestinal stromal tumor (GIST), into one that could be managed in many patients with twice daily oral medication. And, although not as dramatic in their effect, antibodies against the EGFR and VEGF pathways had cleared the regulatory hurdles and were becoming available by early 2004 for the routine treatment of metastatic colorectal cancer. The U.S. cooperative groups were poised to take advantage of the wealth of new biologic agents and less novel but different chemotherapeutics; the challenge was how bold to be and what magnitude of improvement to expect. As two of the cooperative groups worked on proposals with different combinations and designs, the hope for effıciency ultimately led to the single joint effort that became the Intergroup advanced colorectal cancer study: CALGB/SWOG #80405. As designed, this three-armed study built fırst on a chemotherapy backbone of the treating physician’s choice: FOLFOX or FOLFIRI since data then, as now, suggested that these two regimens represented the best of our combinations of the cytotoxic agents developed in the previous decades, that they were of similar effıcacy, and had toxicity profıles which were of similar intensity but different character. The study then tested the value of adding bevacizumab alone, cetuximab alone, or both antibodies to the chemotherapy. A paraffın bloc was required for EGFR staining, although patients would be enrolled without the knowledge of the result. A total of 2,289 patients would be accrued to power the study to demonstrate a Hazard Ratio of 1.25 in favor of the dual biologics (27.5 vs. 22 months) with expected accrual taking 30 months. The study closed to accrual in March 2012, 96 months after it had opened. The fınal accrual was as about as planned, although just 1,177 patients with KRAS wild type tumors would be analyzed in the two-arm study comparing chemotherapy with either bevacizumab or cetuximab. The hazard ratio remained the same for a 2-sided test. Now, nearly 10 years, seven “Dear Doctor” letters, and numerous amendments later, we await the results of that study. But rather than having expectations for major clinical advances, we have turned our hopes to the correlative science component, enabled by the mandated collection of biospecimens. It is this aspect of the trial that now holds out the most hope for a paradigm change. The primary hypothesis of the study, that dual antibody therapy would represent a safe and more effıcacious therapy for patientswithmetastatic colorectal cancer, has already all but been refuted. Couldwe have known that the questionswould change, the assumptions would be wrong, and that it would take us ten years to fınd out? Looking back, what mistakes can we now identify that we, as a cancer community, made?More importantly, what canwe learn froma critical and constructive look at our mistakes, our thought processes, our efforts, and our results thatmight inform our current and future projects and accelerate progress in the fıght to develop better treatments for patients with colorectal cancer?