Advanced Colorectal Cancer

LOS ANGELES—Two Phase III international trials have shown that treatment with cetuximab benefits patients as second- and third-line treatment for advanced colorectal cancer. But overall survival did not increase in the second-line treatment trial, and partial and complete response rates were low in both. This led some to again question whether either are realistic goals in the setting of advanced disease.Figure: Derek Jonker, MD: “The results are clear and unambiguous—the addition of cetuximab delayed tumor growth, which resulted in patients living longer.”Reports from both trials were featured in a late-breaker session here at the American Association for Cancer Research Annual Meeting. The CO.17 trial, led by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) in cooperation with the Australasian Gastro-Intestinal Trials Group (AGITG), tested cetuximab monotherapy with best supportive care against best supportive care alone in patients with pretreated metastatic epidermal growth factor receptor [EGFR]-positive colorectal carcinoma. Those researchers, led by Derek Jonker, MD, Assistant Professor at the University of Ottawa, reported a 23% improvement in survival (from a mean of 4.6 o 6.1 months), but only a 6.6% response rate. And the Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) trial, comparing cetuximab plus irinotecan with irinotecan alone, found that the combination was superior in increasing progression-free survival, at 4.0 versus 2.6 months. But there was no statistically significant difference between the study arms in overall survival. Dr. Jonker noted that no patient on best supportive care showed a response, but that patients who did respond had prolonged responses. “The results are clear and unambiguous—the addition of cetuximab delayed tumor growth, which resulted in patients living longer,” he said. He said this is the first time a biologically targeted therapy given on its own has improved survival in colorectal cancer. It is also the first time an EGFR-targeting drug has achieved this same goal. Treatment with cetuximab also resulted in a significant improvement in the risk of disease progression. Between November 2003 and August 2005, a total of 572 patients were enrolled, all having received an anti-thymidylate synthase inhibitor (for example, fluorouracil or capecitabine) and having failed to respond to both irinotecan and oxaliplatin unless those drugs were contraindicated.Figure: Richard M. Goldberg, MD: “These [two studies] give us the preponderance of evidence we need to conclude that cetuximab is a real drug of use in patients with colorectal cancer—that alone it is superior to best supportive care, and that it is superior when combined with irinotecan compared with irinotecan alone.”Patients were randomly assigned to receive a loading dose of cetuximab at 400 mg/m2 followed by a weekly infusion of 250 mg/m2 plus best supportive care (287 patients); or to receive best supportive care alone (285 patients). The patients' median age was 63, and 35% had received prior radiotherapy—13% adjuvant, 19% palliative, and 3% both. Grade 3 toxicities were more frequent in the cetuximab arm, including rash/desquamation, at 12% vs 0%, infection without neutropenia at 13% vs 5%, confusion at 6% vs 2%, and hypomagnesemia at 6% vs 0%. Only Grade 3 anemia was more common in the best supportive care arm—11% vs 4% for cetuximab. Suggests that Giving Earlier Is Better The EPIC data suggest that if cetuximab is used earlier during the course of colorectal cancer, as second-line therapy, progression-free survival is longer and there is a higher chance of a tumor response, said the study's principal investigator, Alberto F. Sobrero, MD, Head of the Department of Medical Oncology at Hospital San Martino in Genoa, Italy. Dr. Sobrero reported that treatment with the combination regimen resulted in significantly longer progression-free survival than treatment with irinotecan alone—4.0 vs 2.6 months, a 55% increase. The relative response was 16% for the combination vs 4% for the single-drug arm. But the primary endpoint of improvement in overall survival was not met: about 11 months for the combination vs about 10 months for irinotecan alone. Dr. Sobrero said this was likely due to the fact that approximately half of the patients in the irinotecan-alone received the cetuximab-irinotecan combination post-trial, while only 7.5% of those in the combination therapy arm continued to receive the same combination after progression or discontinuation from study therapy. “In retrospect, overall survival was not the best choice for a primary endpoint,” he said. EPIC included 1,298 patients who failed to respond to prior treatment with an oxaliplatin-based regimen including a fluoropyrimidine. Patients (median age of 62) received either standard therapy with irinotecan at 350 mg/m2 every three weeks (650 patients); or the combination of cetuximab at 400 mg/m2 followed by 250 mg/m2 weekly and irinotecan at 350 mg/m2 every three weeks (648 patients). Patients received treatment for much longer with the combination—five cycles vs three—but the combination was also slightly more toxic, mainly incrementing diarrhea and skin rash. Commentary In a commentary after the two presentations, Richard M. Goldberg, MD, Professor and Chief of the Division of Hematology/Oncology at the University of North Carolina at Chapel Hill, said after the two presentations that cetuximab was licensed in the United States and elsewhere based on Phase II data but that it was not fully approved, which led to these two trials. “These give us the preponderance of evidence we need to conclude that cetuximab is a real drug of use in patients with colorectal cancer—that alone it is superior to best supportive care, and that it is superior when combined with irinotecan compared with irinotecan alone,” he said. He noted that the studies corroborated what he and others have seen in the clinic—that while few advanced colorectal cancer patients respond to the drug, those who do respond have a very meaningful response. Regarding the issue of overall survival, Dr. Goldberg said negotiations between the FDA and drug companies are “an arcane dance.” “In the EPIC trial, the survival endpoint was mandated, but there is a good suggestion that the crossover allowed in the protocol obscured the outcomes. Many of us who are clinical trialists have argued for a progression-free survival endpoint, which isolates the effect of the treatment given. “I think one illustration of these studies is that that's an appropriate thing for the FDA to reconsider in evaluating these trials,” Dr. Goldberg said. He noted that both studies reported a modest amount of toxicity, particularly an acneiform rash that he said can become quite troubling in some patients. As in earlier studies of the drug, the rash appears to correlate with time to survival—i.e., those who had no acne in these trials lived for approximately six months, while those who had Grade 3 acne or greater lived for approximately 15 months. “What we sorely need is a marker that tells, ‘I don't need to treat somebody with a drug they're not going to respond to,’ rather than give them the drug and wait for them to break out” with acne, Dr. Goldberg said, adding that the ongoing CRYSTAL trial is testing cetuximab as first-line therapy, and the PETACC 8 and NCCTG NO147 trials are using it in the adjuvant setting.

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