The Marriage of Growth Factor Inhibitors and Chemotherapy: Bliss or Bust?

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Many clinical trials have demonstrated a benefit associated with the combination of growth factor, growth factor receptor, or signaling pathway inhibitors with cytotoxic chemotherapy; however, there are instances where such combinations have proven futile or antagonistic. Among the most successful combinations have been those utilizing antibodies targeting the extracelluar domain of the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER-2) with cetuximab and trastuzumab, respectively. As our ability to screen individual tumors for specific receptor and signaling pathway alterations becomes more facile, patterns that can serve to effectively guide our therapy are emerging. Recent investigations in patients with advanced colorectal cancer have identified KRAS mutation as a critical predictor of lack of clinical benefit from the anti-EGFR antibodies panitumumab and cetuximab. On further analysis, these same studies suggest a possible negative interaction between these antibodies and the fluoropyrimidines fluorouracil (FU) or capecitabine (CAP), which is most apparent in KRASmutated patients. Activating mutations in KRAS, a key regulator of cellular growth and proliferation, have been identified in 30% to 50% of patients with advanced colorectal cancer. The benefit of antiEGFR antibodies is almost entirely associated with patients whose colon cancers develop in the absence of KRAS mutation. Amado et al enrolled 423 patients with advanced and refractory colorectal cancer treated with either single-agent panitumumab or best supportive care with the option to cross over to panitumumab at the time of disease progression. Patients with wild-type KRAS enjoyed a median progression-free survival (PFS) of 12.3 months and an overall response rate of 17% in those treated with panitumumab versus a PFS of 7.3 months for the best supportive care group (HR, 0.45). Those with mutant KRAS enjoyed no benefit in PFS from the use of panitumumab (HR, 0.99) and had an overall response rate of 0%. Additional phase II investigations using cetuximab alone or with various chemotherapeutic agents in patients with advanced colorectal cancer also reported a negligible response rate in patients whose cancers contained mutant KRAS. Clinical results have recently been reported from four large, mature, multi-institutional, randomized clinical trials in which anti-EGFR antibodies were added to chemotherapy in approximately 1,500 untreated patients with advanced colorectal cancer and with defined KRAS status. The relevant outcomes data from these trials are listed in Table 1. The Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) and Capecitabine, Irinotecan, Oxaliplatin (CAIRO II) studies used oxaliplatin combined with fluoropyrimidine-based chemotherapy with or without cetuximab. Both studies demonstrate a reduction in response rate and PFS, as well as survival for CAIRO II, with the addition of the anti-EGFR antibody in patients whose cancers possess mutant KRAS and little if any additional benefit in PFS for patients with wild-type KRAS. Both the Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) investigations, using irinotecan-based chemotherapy, similarly demonstrate a decrement in benefit with the addition of the anti-EGFR antibody in patients with mutant KRAS tumors, although the effect is more modest, particularly with regard to PFS. Why might there be a decrement in benefit with the addition of anti-EGFR antibodies to chemotherapy in patients with mutant KRAS–containing cancers, particularly with oxaliplatin-based chemotherapy? Given that the negative trends occur in four independent trials with only two invariable constituents, namely a fluoropyrimidine and the anti-EGFR antibody, one hypothesis that could explain the clinical observation is a negative interaction at the cellular level between EGFR inhibition and the fluoropyrimidine. The greater negative effect with oxaliplatin versus irinotecan may be the result of oxaliplatin’s greater dependence on FU for its clinical activity. Preclinical investigations, as well as the study in the second-line setting reported by Rothenberg et al, clearly support the concept that the addition of FU to oxaliplatin results in greater than an additive interaction, whereas the single-agent activity of oxaliplatin is modest, particularly in contrast to irinotecan, which has respectable single-agent activity in patients with advanced colorectal cancer. The additional benefit of adding cetuximab to single-agent irinotecan in the Bowel Oncology Cetuximab Antibody (BOND) trial also suggests that any negative interaction between the anti-EGFR antibody and chemotherapy is related to the presence of a fluoropyrimidine in the regimen. The proposed antagonistic interaction between fluoropyrimidines and anti-EGFR antibodies may be explained by the fact that FU requires metabolically active cells in which to undergo the requisite multistep anabolism to the active forms of the drug. In wild-type KRAS cells, the anti-EGFR antibody may effectively control malignant cell growth, overshadowing a possible negative interaction between the antibody and chemotherapy. In KRAS-mutated cells, with no JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 27 NUMBER 10 APRIL 1 2009