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Originally published as JCO Early Release 10.1200/JCO.2007.12.8900 on September 17 2007 © 2007 American Society of Clinical Oncology.
Combined Antiangiogenesis and Antiepidermal Growth Factor Receptor Targeting in the Treatment of Cancer: Hold Back, We Are Not There Yet
Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain This issue of the Journal of Clinical Oncology (JCO) contains the results of two randomized phase II studies evaluating the activity of combined targeted therapy directed at the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In the first study, Bowel Oncology and Cetuximab Antibody (BOND)-2, 83 patients with metastatic colorectal carcinoma (CRC) refractory to irinotecan-based chemotherapy were randomly assigned to receive the combination of the anti-EGFR monoclonal antibody cetuximab, the anti-VEGF monoclonal antibody bevacizumab, and irinotecan (CBI) or cetuximab plus bevacizumab (CB).1 Both arms demonstrated promising activity compared with historical controls, and there was a suggestion that the addition of bevacizumab improved the antitumor activity of cetuximab either alone or in combination with irinotecan. In the second study, 104 patients with previously untreated renal cell carcinoma (RCC) received bevacizumab in combination with the EGFR tyrosine kinase inhibitor erlotinib or with placebo.2 In this study, the addition of erlotinib to bevacizumab was well tolerated, but did not provide additional clinical benefit compared with bevacizumab alone. In summary, the combination of the anti-VEGF antibody bevacizumab with an anti-EGFR agent was positive in patients with CRC, whereas it did not provide any additional benefit to bevacizumab alone in patients with RCC. In this editorial, we review the potential reason(s) for these discordant results and explore the implications of these studies for future research and daily clinical practice. First, both studies were designed based on a strong rationale exploring combined antiangiogenesis and anti-EGFR approaches. Solid tumors are genetically complex, and with rare exceptions, it is unlikely that a given tumor will be entirely dependent on one abnormally activated kinase or signaling pathway for its malignant behavior. There is also a considerable level of compensatory cross talk among receptors within one signaling pathway, as well as cross talk among distinct signaling pathways regulating cell proliferation, trafficking, and survival. As with conventional chemotherapeutic agents, which are often most effective when administered as combination therapies, rationally developed combinations of molecularly targeted agents are likely to be more potent than single-agent therapies. In the case of the potential interactions between EGFR signaling and angiogenesis, several studies have shown that both EGFR monoclonal antibodies and tyrosine kinase inhibitors reduce VEGF levels and microvessel density in tumors that regress on EGFR blockade.3,4 Interestingly, tumor cells with acquired resistance to cetuximab exhibit increased expression and secretion of VEGF, and forced expression of VEGF in sensitive cancer cells renders them resistant to cetuximab in vivo.5 These data suggest that inhibition of EGFR-dependent tumor neoangiogenesis is central for the antitumor effect of EGFR inhibitors; in turn, enhanced angiogenesis may endow tumors with resistance to EGFR blockade. Therefore, it is not surprising that the combination of antiangiogenic and anti-EGFR agents has showed greater antitumor activity than when these agents are administered alone.6-8 However, even carefully characterized preclinical models have limitations. For example, renal carcinoma cell lines are sensitive to cetuximab in vitro,9 whereas a series of clinical trials in RCC with anti-EGFR agents uniformly have shown lack of activity in patients. In this regard, the findings from the study by Bukowski et al2 in this issue of JCO provide one more piece of evidence for the lack of activity of anti-EGFR agents in RCC, and also raises the question as to whether single-agent activity may be required for any anti-EGFR agent to be incorporated into a combined-therapy approach. Conversely, the interpretation of the BOND-2 study in patients with refractory CRC seems to be more complex. This study follows the same approach as the initial BOND study, in which a total of 329 patients with EGFR-expressing colorectal cancer refractory to irinotecan-based chemotherapy were randomly assigned to receive cetuximab or irinotecan plus cetuximab.10 The combination treatment was superior to cetuximab as a single agent, both in terms of response rate (23% v 11%; P = .007) and median progression-free survival (PFS; 4.1 v 1.5 months; P < .001). The trial was not powered to demonstrate any advantage in overall (OS) survival, and half of the patients receiving cetuximab as a single agent were switched to the combination treatment when progression of the disease was documented. Nevertheless, a better median OS was observed in those patients receiving the combination as first-line treatment (8.6 v 6.9 months). In the BOND-2 study, patients refractory to irinotecan-based chemotherapy were randomly assigned to receive CBI or CB.1 Although the study was closed to accrual before the completion of target size (150 patients) due to poor accrual after the commercialization of bevacizumab, the results of the study showed promising activity: the CBI arm had a 37% response rate, time to progression of 7.9 months, and OS of 14.5 months; the biologic-alone arm of CB was also active, with a 20% response rate, time to progression of 5.6 months, and an OS of 11.4 months. These results compare favorably to those of the BOND study. It is important to note that more patients (88%) in the BOND-2 study had received prior treatment with oxaliplatin-based chemotherapy than did those in the BOND study (63%), indicating that the BOND-2 study population was even more refractory. Toxicities in the BOND-2 study were as predicted, with no clear indication of synergistic toxicity. Cetuximab-related grade 3 toxicities were headache related to the first infusion, skin rash, and paronychial cracking. Bevacizumab-related serious adverse events included GI and arterial thrombotic events. The incidence of these events was not higher than expected, although no clear assumptions can be drawn from this limited-size study. The promising results from the study by Saltz et al1 are being challenged by the recently completed Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study. This is a large (more than 1,000 patients), phase IIIB, randomized, open-label clinical trial evaluating oxaliplatin- and irinotecan-based chemotherapy plus bevacizumab, with and without the anti-EGFR antibody panitumumab, in the first-line treatment of patients with metastatic CRC. Most of the patients received oxaliplatin-based chemotherapy (mainly infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX]), and this population was the basis for the primary end point, PFS, and calculation of the sample size. The Data Monitoring Committee (DMC) recommended discontinuation of panitumumab as a consequence of a preplanned interim analysis of safety and PFS after the first 231 events, which showed a statistically significant difference in PFS in favor of the control arm. The interim analysis of OS also demonstrated a statistically significant difference favoring the control arm.11 Hecht et al12 recently presented the first data on this study, which showed an increased incidence of serious adverse events in the panitumumab-containing arm (56% v 37%), with a similar centrally reviewed response rate (39% v 41%), but a reduced median PFS (9.0 v 10.5 months; hazard ratio = 1.29; 95% CI, 1.05 to 1.58) and OS (18.6 v not reached; hazard ratio = 1.44; 95% CI, 1.10 to 1.88). The finding that panitumumab administration does not add clinical benefit to conventional oxaliplatin-based chemotherapy plus bevacizumab in the first-line setting of metastatic CRC is disparate from the findings in the BOND-2 study. Furthermore, these results were not anticipated, given that panitumumab has well-documented single-agent activity in patients with refractory metastatic CRC.13 In addition, available safety data of panitumumab do not suggest a different toxicity profile for panitumumab and cetuximab. There are, however, potential explanations for the discordant results between the PACCE and the BOND-2 studies. The first consideration is that panitumumab and cetuximab, although both targeting the EGFR ectodomain, are not identical. Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody with the potential to induce antibody-dependent cellular cytotoxicity, whereas panitumumab is a fully human immunoglobulin G2 monoclonal antibody without any predictable antibody-dependent cellular cytotoxicity activity. In addition, a specific interaction between panitumumab and bevacizumab, resulting in more adverse effects compared with the combination of cetuximab and bevacizumab, cannot be ruled out at this point. The second consideration is related to the type and doses of the chemotherapy regimens used in combination with the monoclonal antibodies in the two studies. In the BOND-2 study, single-agent irinotecan was administered at the dose and schedule shown to be safe in each patient with the previous treatments, whereas in the PACCE study, full doses of oxaliplatin-based chemotherapy (mainly FOLFOX) were administered. It could well be that the increased toxicity of the combination resulted in dose reductions that resulted in lower and less efficacious doses of chemotherapy and bevacizumab. This is supported by the lower dose-intensity for both observed in the panitumumab-containing arm.12 It is also possible that the increased toxicity in the panitumumab arm resulted in a shorter duration of therapy because of early treatment discontinuation, which would have also interfered with PFS and OS. Where do the results of the BOND-2 study published in this issue of JCO and the recently presented results from the PACCE study leave us when it comes to combinations of anti-VEGF and anti-EGFR therapies in CRC? Given that both studies have conflicting results, the fate of a combined antiangiogenesis and anti-EGFR agents approach now rests heavily on the results of the ongoing Cancer and Leukemia Group B/Southwest Oncology Group 80405 National Cancer Institute Intergroup study. This is a large, randomized, phase III study of the first-line treatment of metastatic CRC, with the physician's choice of chemotherapy (FOLFOX or fluorouracil, leucovorin, and irinotecan), which randomly assigns patients to receive either bevacizumab alone, cetuximab alone, or the combination of both, with the primary objective of demonstrating an increase in OS in the double-antibody arm. Because of the PACCE DMC alert, the Cancer and Leukemia Group B DMC conducted a safety evaluation of the patients included in the 80405 study, which reached the conclusion that the study should continue recruiting patients because no potential safety imbalances among the three arms were observed. These studies of combined antiangiogenic and anti-EGFR agents, once more, provide a powerful message that whatever preclinical models show, there is no substitute for good clinical data, and caution is required before large phase III studies are conducted. These data also emphasize the need to continue to develop biomarkers of sensitivity to targeted agents. Advances are being made in the identification of tumor markers of sensitivity to anti-EGFR agents in colorectal cancer, including expression of certain ligands and KRAS mutation status.14 Therefore, it might be of interest to perform exploratory studies to correlate clinical benefit with the expression of these biomarkers of EGFR sensitivity, given that it is likely that only a subgroup of patients may benefit more from EGFR blockade. One last point should be made. What are the implications of these studies for our daily clinical practice? The results of these studies do not support the use of combined anti-EGFR and anti-VEGF agents outside of clinical trials. As mentioned in the title, hold your double-antibody therapy: we are not there yet. AUTHORS' 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: José Baselga, Exelixis (C); Josep Tabernero, Roche (C) Stock Ownership: None Honoraria: Josep Tabernero, Roche, MercK KGaA Research Funding: José Baselga, Glaxo Smith-Kline; Josep Tabernero, Merck KGaA, Roche Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: José Baselga, Josep Tabernero Collection and assembly of data: Josep Tabernero Data analysis and interpretation: José Baselga Manuscript writing: José Baselga, Josep Tabernero Final approval of manuscript: José Baselga, Josep Tabernero NOTES published online ahead of print at www.jco.org on September 17, 2007. REFERENCES 1. 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 2. Bukowski RM, Kabbinavar FF, Figlin RA, et al: Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cancer. J Clin Oncol 25:4536-4541, 2007 3. Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523-1530, 1997[Abstract] 4. Perrotte P, Matsumoto T, Inoue K, et al: Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5:257-265, 1999 5. Viloria-Petit A, Crombet T, Jothy S, et al: Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res 61:5090-5101, 2001 6. Ciardiello F, Bianco R, Damiano V, et al: Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6:3739-3747, 2000 7. Jung YD, Mansfield PF, Akagi M, et al: Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 38:1133-1140, 2002[CrossRef][Medline] 8. Shaheen RM, Ahmad SA, Liu W, et al: Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85:584-589, 2001[CrossRef][Medline] 9. Atlas I, Mendelsohn J, Baselga J, et al: Growth regulation of human renal carcinoma cells: Role of transforming growth factor alpha. Cancer Res 52:3335-3339, 1992 10. 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 11. Amgen: Amgen discontinues Vectibix treatment in PACCE trial evaluating Vectibix as part of triple combination regimen. http://www.amgen.com/media/media_pr_detail.jsp?releaseID=977186 12. Hecht JR, Chidiac T, Mitchell E, et al: An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (Bev) for metastatic colorectal cancer (mCRC): Proceedings of the 9th World Congress on Gastrointestinal Cancer. Ann Oncol 18:vii21, 2007 (abstr 0-0033) 13. 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 25:1658-1664, 2007 14. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-RAS mutation status are associated with disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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