Dual-Antibody Therapy in Advanced Colorectal Cancer: Gather Ye Rosebuds While Ye May

Abstract

Antibodies directed at either vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) are certainly successful in treating metastatic colon cancer (mCRC). Bevacizumab, a VEGFA antagonist, enhances the efficacy of irinotecanand oxaliplatin-based chemotherapy when added during firstor second-line therapy, particularly in regard to prolonging progressionfree survival (PFS). Cetuximab and panitumumab, antibodies to the EGFR, have single-agent activity against mCRC; cetuximab also augments the effects of irinotecan-based chemotherapy across at least three lines of treatment. Of course, in oncology we are all taught that “more is always better.” With cross-talk between the VEGF and EGF pathways, dual inhibition through simultaneous use of both classes of antibodies is attractive. Indeed, BOND-2 (Bevacizumab and Irinotecan Compared With Cetuximab and Bevacizumab Alone in Irinotecan-Refractory Colorectal Cancer), a randomized phase II feasibility study, showed that the triple combination of irinotecan, cetuximab, and bevacizumab achieved surprisingly strong results in irinotecan-refractory mCRC, with an objective response rate of 37%, time to progression of 7.3 months, and median overall survival of 14.5 months. Two articles published in this issue of Journal of Clinical Oncology address different methods of using antibody therapy in mCRC; both answer some important questions but also potentially raise even more. Bokemeyer et al report a randomized phase II study of oxaliplatin-based chemotherapy, with or without cetuximab, concluding that a subset of patients receiving first-line therapy dramatically benefits from the addition of that antibody. Hecht et al present a randomized phase III trial utilizing oxaliplatinor irinotecan-based chemotherapy plus bevacizumab, with or without the anti-EGFR antibody panitumumab, which resulted in a worse outcome for previously untreated patients who received both antibodies when given with cytotoxic drugs. The OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of mCRC) study compared the use of fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) plus cetuximab versus FOLFOX-4 alone in patients with previously untreated incurable mCRC. The primary objective was to see whether the addition of the antibody improved the overall response rate (ORR) compared with chemotherapy alone. Important secondary objectives included the determination of rates of potentially curative metastasectomy, duration of response, PFS, overall survival (OS), and safety. A retrospective subgroup analysis done “on regulatory request” investigated the potential relationship between PFS/ORR and tumor KRAS mutational status. Minor study quirks included analyzing efficacy only in patients who received at least one dose of study treatment (not the more common standard of assessing all randomly assigned patients by intent to treat) and selecting an extraordinarily high bar—an odds ratio of 2.33—for benefit with the addition of cetuximab. In the original patient population, adding cetuximab improved the ORR by an absolute increase of 10% (36% to 46%), which did not reach the original goal (the achieved odds ratio was 1.52). Median PFS was identical on both arms at 7.2 months. However, cetuximab was effective in the population with tumors that demonstrated wild-type KRAS. The ORR increased from 37% to 61% (odds ratio, 2.544; P .011), and PFS improved as well. There was no major change in median PFS at 7.2 v 7.7 months. However, simple visual inspection of the PFS curves shows an early, potentially clinically significant, and maintained separation between those receiving chemotherapy alone and those receiving FOLFOX-4 plus cetuximab, with a hazard ratio of 0.570. Remarkably, in the KRAS mutant population, the ORR, median PFS, and overall PFS were markedly worse for patients who received cetuximab. Although this might be explained by an imbalance in performance status on the mutant tumor arm that favored those treated with chemotherapy alone, the possibility of a negative interaction between chemotherapy and cetuximab in this population cannot be ruled out. The authors correctly conclude that the addition of cetuximab to chemotherapy meaningfully improved the ORR in firstline treatment of mCRC patients with wild-type KRAS tumors. In the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study, healthy advanced mCRC patients without previous treatment for metastatic disease were randomly assigned between bevacizumab and chemotherapy or bevacizumab, chemotherapy, and panitumumab. At the investigators’ choice, patients could be given oxaliplatinor irinotecan-based cytotoxic treatment, with the doses and schedules of the selected regimens also unspecified. The primary objective of the trial was to see whether the addition of the anti-EGFR antibody improved PFS in the oxaliplatin-based cohort. Because of anticipated (and realized) small numbers enrolled onto irinotecanbased treatment, this cohort had a primary safety objective, while all efficacy end points were descriptive. After one of many planned safety and response analyses, panitumumab was discontinued in both cohorts because of decreased PFS and increased toxicity associated with that agent. Again, statistical assumptions on PACCE were a bit uncharacteristic; the 12-month PFS assumed for the control arm was quite long (in comparison, results from NO16966, which compared JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 5 FEBRUARY 1