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Originally published as JCO Early Release 10.1200/JCO.2008.21.2522 on December 29 2008 © 2009 American Society of Clinical Oncology.
Dual-Antibody Therapy in Advanced Colorectal Cancer: Gather Ye Rosebuds While Ye MayDivision of Medical Oncology, University of British Columbia and British Columbia Cancer Agency, Vancouver, British Columbia, Canada 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 irinotecan- and oxaliplatin-based chemotherapy when added during first- or second-line therapy, particularly in regard to prolonging progression-free survival (PFS).1–3 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.4–7 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.8 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.9,10 Bokemeyer et al9 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 al10 present a randomized phase III trial utilizing oxaliplatin- or 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 first-line 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 oxaliplatin- or 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 irinotecan-based 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 capecitabine and oxaliplatin versus FOLFOX with or without bevacizumab, showed a median PFS of 9.4 months for chemotherapy plus bevacizumab3. In common with OPUS, the 30% desired improvement for PFS with the addition of the experimental agent panitumumab was optimistic. In addition, allowing many different schedules and performing tumor assessment infrequently (every 12 weeks) may have affected results. However, PACCE did not fail to meet its primary objective simply because of statistical assumptions, the manner in which chemotherapy was administered, or when computed tomography scans were done. Despite its progression-related end point, approximately two thirds of patients in PACCE discontinued treatment for reasons unrelated to worsening of their cancer. There were more grade 3 or greater events on the panitumumab arms of both cohorts, and dose-intensity for the chemotherapy agents was lower on the arms with panitumumab, possibly because of delays or reductions related to adverse effects. PFS was statistically significantly worse in the panitumumab arm of the oxaliplatin cohort and descriptively inferior in the irinotecan cohort. Median OS was markedly shorter for patients given panitumumab in the oxaliplatin cohort but was essentially identical in patients on the irinotecan arm, whether or not they received panitumumab. Additional analysis demonstrated that PFS favored the control group (in both chemotherapy cohorts) regardless of KRAS status. The authors concluded that the PACCE results do not support the use of panitumumab in combination with bevacizumab and oxaliplatin–based or irinotecan-based chemotherapy, and this conclusion is correct as stated. What have we learned from these two studies, and what remains to be determined? Let us start with the easy lessons. Numerous trials, including OPUS, now demonstrate that adding an antibody directed against the EGFR to standard chemotherapy improves PFS in selected patients with advanced mCRC.6,9 Specifically, we have solid evidence for a benefit from the combination of cetuximab with either oxaliplatin- or irinotecan-based regimens. Consistent with the OPUS results are the preliminary data from the CRYSTAL trial (fluorouracil, leucovorin, and irinotecan [FOLFIRI], with or without cetuximab, in untreated mCRC), as well as other studies, showing that benefit from cetuximab is restricted to patients whose tumors contained wild-type KRAS. 7,9 We can now definitively say that cetuximab and panitumumab should be used only in patients with wild-type KRAS. Whether the anti-EGFR antibodies are merely ineffective in patients with mutated KRAS (as suggested by CRYSTAL) or whether they are actually deleterious (as seen in OPUS) does not matter: they should not be used. Of course, this means unequivocally that oncologists must test patients for tumor KRAS status before using this class of drugs in any line of therapy. Luckily, such testing is now widely commercially available, and capable of being performed in a timely fashion. Where do we go from here? It is likely that additional markers besides KRAS will come into play, allowing us to further refine this auspicious beginning to the era of individualizing therapy for patients with mCRC. These might include the novel candidate tumor suppressor gene phosphatase and tensin homolog (PTEN), and BRAF.11,12 Of course, OPUS does not tell us which agent, cetuximab or bevacizumab, is the superior biologic in patients with untreated advanced CRC. A few years ago, there was great debate about whether FOLFOX or FOLFIRI chemotherapy was more effective for first-line therapy in mCRC patients. We now know that both chemotherapeutic regimens offer equivalent efficacy, which leads treating physicians to choose the appropriate regimen on the basis of the toxicities most or least desired.13,14 We are approaching a similar situation in determining the best first-line biologic, recognizing that the available agents comprise two different classes of drugs that may have variable effects on ORR, PFS, and OS. Bevacizumab is clearly the most commonly used agent in this setting in North America, but cetuximab also has proven efficacy with FOLFIRI (CRYSTAL) and now FOLFOX (OPUS).7,9 We do not have phase III trial results that compare bevacizumab to cetuximab. However, this remains one of the objectives of C80405, the ongoing North American Intergroup phase III trial for first-line therapy in mCRC patients.15 Of course, this argument applies only to patients with wild-type KRAS because benefits obtained with bevacizumab seem to be independent of KRAS status. Patients with mutated KRAS who receive first-line therapy are clearly better served by chemotherapy plus bevacizumab (it is, of course, also reasonable to test new agents in this patient population).16 It does appear that cetuximab, but not bevacizumab, significantly improves response rates when added to modern chemotherapy.3,7 Thus, patients whose disease might be rendered surgically curable if their tumors were significantly downsized might be better off receiving an anti-EGFR antibody. Indeed, both OPUS and CRYSTAL reported higher rates of potentially curative metastasectomy in patients treated with cetuximab plus chemotherapy compared with those who received chemotherapy alone.7,9 In the absence of these considerations, however, toxicity and perhaps financial issues might currently drive the decision of which biologic to combine with chemotherapy. The more difficult question to answer is whether combining anti-VEGF and anti-EGFR antibodies, at least in the setting of cytotoxic chemotherapy, has definitively proven to be detrimental, or at least not helpful. PACCE reported excess toxicity and higher death rates from the combination of panitumumab, bevacizumab, and chemotherapy, with a worsening of PFS in the KRAS wild-type patients. Another recently reported trial, CAIRO-2, tested the combination of capecitabine plus oxaliplatin chemotherapy with bevacizumab, with or without cetuximab, in patients with untreated mCRC; the primary end point was an improvement in PFS with the use of two antibodies.17 In CAIRO-2, adding cetuximab worsened PFS for the whole population. Subset analysis demonstrated there was no effect seen in patients with wild-type KRAS, but a marked detrimental effect was observed in those with mutated KRAS. Panitumumab supporters would suggest that PACCE results were negative because of its absence of strict dose-modification guidelines. On PACCE, a large percentage of patients went off study as a result of toxicity and therefore likely received less than ideal amounts of chemotherapy. It is possible that they could have been maintained for some longer period without disease progression, had more stringent dose-modification guidelines been in place. However, unlike PACCE, CAIRO-2 reported inferior results for the triple combination with no significant change in the percentage of patients who discontinued therapy because of toxicity, and study discontinuation without progression cannot really be blamed for the failure of the double-antibody therapy. The possibility of a negative interaction between bevacizumab and anti-EGFR antibodies, or one involving two antibodies and chemotherapy, cannot be ruled out, although we do not really have any known mechanisms behind such potential interactions. Thus, we now have an appealing result from a randomized phase II study (BOND-2) and at least two negative results from randomized phase III trials (PACCE and CAIRO-2).8,10,17 Again, one recommendation is easy. Adding an anti-EGFR antibody to bevacizumab plus chemotherapy (whether chemotherapy is based on oxaliplatin or irinotecan) is currently contraindicated off study. KRAS status has no impact on this decision, though only patients with wild-type KRAS are candidates for any therapy with anti-EGFR antibodies. What should be done, however, with ongoing trials that include an arm with both antibody classes? Are we so sure that combining antibodies might be hurtful (or that it is to be avoided) that it is unethical to put patients on such a study? C80405 is the North American Intergroup trial that is comparing FOLFOX- or FOLFIRI-based chemotherapy (investigator choice) with either bevacizumab, cetuximab, or both antibodies, in untreated advanced mCRC.15 The decision was made after the 44th Annual Meeting of the American Society of Clinical Oncology (2008) to continue the study with its existing arms, modifying it to include only patients with wild-type KRAS. This indicated that at least some experts feel the jury is still out on the double-antibody question in that population. As coprincipal investigator on this study, I am well aware of the amount of discussion that went into this decision. Should patient advocates and physician investigators still support this trial? The answer is yes. Although meeting an end point of improved OS now seems like an exceedingly high bar, the dual-biologic arm might still offer select benefits such as higher response rates (and thus potentially more curative metastasectomies in patients with significant tumor downsizing). Also, the embedded correlative studies will perhaps identify a unique population that does markedly benefit from an anti-VEGF and anti-EGFR antibody given in combination. PACCE has demonstrated less ideal outcomes in patients with wild-type KRAS given double-antibody therapy, whereas other trials have not, so aggressive monitoring with early efficacy and safety assessments will continue to be necessary on C80405. To date, with 1,474 patients entered, the Data Safety and Monitoring Board has not invoked early closure of any arm for toxicity concerns. Finally, it is possible that some interaction between the two antibodies and cytotoxic chemotherapy led to undesirable outcomes in PACCE and CAIRO-2. Trials that utilize only the antibodies together, especially in the maintenance setting, are eminently reasonable as well. A different decision was made with S0600. This study was the second-line Intergroup trial testing irinotecan-based chemotherapy plus cetuximab, or with 5 or 10 mg of bevacizumab biweekly, in patients for whom oxaliplatin-based chemotherapy plus bevacizumab had already failed.18 In discussion with the National Cancer Institute, investigators decided to close arms containing both anti-VEGF and anti-EGFR antibodies. Was there evidence that second-line use of combined antibodies, compared with first-line, was more dangerous or less likely to be effective? No. Was there a hint that irinotecan-based chemotherapy, compared with oxaliplatin-based treatment, did especially poorly in conjunction with double antibodies, or that it was more toxic? The opposite is more likely the case. The decisions on C80405 and S0600 were made at different times and by (mostly) different investigators, which reflects some evolution in sentiment regarding double-antibody therapy and some differences in interpretation of how definitive recent studies really have been. I was involved in both decisions, and without stronger justification, I can only say that they both seemed acceptable at the time and the place they were made. Using biologic therapy in mCRC is a concept that is now firmly embedded in many treatment paradigms. Antibodies to either VEGF or the EGFR, utilized as the sole targeted agent, clearly have a place in the therapy of advanced mCRC. PACCE and OPUS have helped refine our knowledge and will clearly affect biologic use off study, including combining the two classes of antibodies. As with all malignancies, themes and fads developed in the evolution of mCRC therapy require rigorous testing, and investigators must be willing to rethink, retrench, and occasionally retreat, when faced with new evidence. Although not beyond hope of recovery, the concept of using double-antibody therapy in mCRC is falling out of favor. C80405 offers one last chance to combine anti-VEGF and anti-EGFR antibodies with chemotherapy for first-line mCRC, but this treatment paradigm may be gone tomorrow. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Charles D. Blanke, Oncothyreon (C), Novartis (C), Genentech (C), Sanofi-aventis (C) Stock Ownership: None Honoraria: None Research Funding: Charles D. Blanke, Novartis Expert Testimony: None Other Remuneration: None REFERENCES
1. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342, 2004. 2. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544, 2007. 3. Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 26:2013–2019, 2008. 4. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048, 2007. 5. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1639–1641, 2007. 6. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345, 2004. 7. Van Cutsem E, Nowacki M, Lang I, et al: Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer: The CRYSTAL trial. J Clin Oncol 25:164s; 2007 (suppl) abstr 4000. 8. Saltz LB, Lenz HJ, Kindler HL, et al: Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: The BOND-2 study. J Clin Oncol 25:4557–4561, 2007. 9. Bokemeyer C, Bondarenko I, Makhson A, et al: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671, 2009. 10. Hecht JR, Mitchell E, Chidiac T, et al: Randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680, 2009. 11. Frattini M, Saletti P, Romagnani E, et al: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145, 2007.[CrossRef][Medline] 12. Di Nicolantonio F, Martini M, Molinari F, et al: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol epub ahead of print on November 10, 2008. 13. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229–237, 2004. 14. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866–4875, 2005. 15. National Cancer Institute. Phase III randomized study of cetuximab and/or bevacizumab in combination with either oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX) or irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with previously untreated metastatic adenocarcinoma of the colon or rectum. http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=5463125. 16. Ince WL, Jubb AM, Holden SN, et al: Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97:981–989, 2005. 17. Punt CJ, Tol J, Rodenburg CJ, et al: Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer: The CAIRO2 study of the Dutch Colorectal Cancer Group. J Clin Oncol 26:180s; 2008 (suppl) abstr LBA 4011. 18. National Cancer Institute. Phase III randomized study of irinotecan hydrochloride-based chemotherapy and cetuximab with versus without bevacizumab in patients with metastatic colorectal cancer that progressed on first-line therapy. http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=5463203.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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