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Journal of Clinical Oncology, Vol 26, No 22 (August 1), 2008: pp. 3665-3667 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.2676
Challenges and Pitfalls of Combining Targeted Agents in Phase I StudiesHarvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA For many years, oncologists have adhered to the principle that more is better, based on the observation that the dose-response curve of various cytotoxic agents shows a steep increase over a clinically achievable range of drug concentrations. Although this concept is largely derived from in vitro data using cell lines, and even though it has been challenged by well-conducted randomized trials,1,2 we still use the maximum-tolerated dose (MTD) as the preferred metric for dose finding in phase I clinical trials of classical cytotoxic agents. Such an approach is not unreasonable, because it recognizes the possibility that lower doses might not be as effective, and even if they were, we generally have not had the courage to find out. However, targeted therapies have forced us to rethink this paradigm. For agents such as bevacizumab, it is difficult to rigorously define a dose-limiting toxicity, because the relationship between toxicity and drug dose is generally quite flat. Other agents, such as the signal transduction inhibitors, generally do have an MTD, as defined by dose-related toxicities such as diarrhea, skin changes, constitutional symptoms, and—in some cases—bone marrow suppression or hypertension, depending on the agent. However, for either monoclonal antibodies like bevacizumab, or oral tyrosine kinase inhibitors such as sorafenib, the need to push the dose to the MTD to obtain an optimal clinical effect is an assumption that is generally unproven. For most targeted agents, we simply do not have a good understanding of the relationship between the MTD and the dose required to achieve the desired therapeutic effect. The difficulty in determining the optimal clinical doses of targeted agents is further compounded when these agents are used in combination. In this issue of Journal of Clinical Oncology, Azad et al3 report the results of a phase I trial of a combination of bevacizumab and sorafenib in 39 patients with a variety of tumor types. Bevacizumab is a humanized monoclonal antibody that neutralizes vascular endothelial growth factor (VEGF), and sorafenib is an oral tyrosine kinase inhibitor with multiple targets that include VEGF receptor, platelet-derived growth factor receptor, and Raf kinase.4,5 Because both agents share the VEGF pathway as targets, and because each agent has single-agent activity in a variety of clinical settings, it was thought that additive or synergistic effects might be observed when they were used in combination. The authors found that a regimen of daily oral sorafenib and every 2 weeks intravenous bevacizumab was difficult to tolerate, even at the lowest dose level of sorafenib 200 mg twice daily and bevacizumab 5 mg/kg every 2 weeks. A significant number of patients experienced fatigue, hand-foot syndrome, hypertension, proteinuria, and thrombocytopenia, with 24 of 39 patients experiencing either grade 3 or 4 toxicity at this dose level (Table 3 in Azad et al3). These problems required further dose reduction of sorafenib to 200 mg daily, as opposed to twice daily, in 74% of patients. One patient died of hemoptysis in association with a cavitating pulmonary hilar mass. Two patients with ovarian cancer developed an enterocutaneous fistula at the site of disease regression, and one patient with melanoma experienced an appendiceal perforation. Although none of these side effects represents a new toxicity signal for these agents, it seems that the incidence of adverse events was greater than what would be expected through the use of each agent alone at standard doses. For reference, a standard dose of bevacizumab in combination with paclitaxel and carboplatin for non–small-cell lung cancer is 15 mg/kg every 3 weeks, and a standard dose of single-agent sorafenib in the treatment of renal cell cancer is 400 mg twice daily.5,6 The authors show compelling evidence for at least additive toxicity of this combination, and they conclude that a further refinement in the sorafenib dose or schedule will be needed in future studies. The enhanced toxicity of this combination did not seem to be related to a pharmacologic interaction between these two drugs, on the basis of pharmacokinetic analysis comparing single-agent with dual-drug therapy. One may ask why future studies should even be performed, given these results. Here we have a rational combination of two agents that target the VEGF pathway, but the toxicity is significant for unexplained reasons, and the final doses of each agent are subtherapeutic as compared with the doses used in single-agent trials of these same agents. Nonetheless, there is good reason to pursue this regimen, a reason that is fortuitous and not the usual purview of a phase I trial. The authors are pursuing this regimen primarily because of an unexpectedly high response rate in patients with relapsed ovarian cancer. Specifically, partial responses were observed in six (46%) of 13 patients as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), compared with the approximately 16% to 21% response rate expected with bevacizumab alone.4,7 It is impossible to know whether this high response rate is related to the combination of bevacizumab and sorafenib or whether it might have been seen with bevacizumab alone in this small patient cohort. Information regarding the number of prior regimens and whether the patients were platinum resistant was not provided for the ovarian cancer cohort. Although no evidence of bowel perforation was observed in these patients with ovarian cancer, this serious complication will require close monitoring in future studies.4 As with all promising phase I or II data, this response rate will need to be confirmed in a larger trial, and this combination should not be used outside of an investigational setting. Furthermore, with 74% of patients requiring a dose reduction of sorafenib to 200 mg daily, it is difficult to conclude that dose level 1 of this regimen is the MTD (Table 1 in Azad et al3). If the authors choose to modify this regimen by changing the dose or schedule of sorafenib, it will be important to consider how this might affect the activity of the combination as presently reported. This is especially the case for sorafenib, which seems to have more favorable pharmacokinetics when administered on a twice daily schedule.8 If we blind ourselves to the response data, which are typically not a primary end point of phase I trials, we would have probably concluded that this toxic regimen is unworthy of further consideration based on the use of subtherapeutic dosing. This calls into question our concept of how targeted therapy should be dosed, especially in combination, and also causes us to examine our prejudices regarding the need to combine drugs with nonoverlapping toxicities to preserve the dose-intensities of each agent. What, exactly, is the optimal dose-intensity of bevacizumab or sorafenib? I do not know, and neither does anyone else (it is easy to proclaim one's ignorance when you are in good company). It is interesting to note that in the early development of bevacizumab, a randomized phase II study was performed in metastatic colon cancer, demonstrating that 5 mg/kg of bevacizumab every 2 weeks was at least as good and perhaps even better than 10 mg/kg.9 Accordingly, the 5 mg/kg dose of bevacizumab was used in the randomized phase III trial comparing bevacizumab plus irinotecan, fluorouracil, and leucovorin with irinotecan, fluorouracil, and leucovorin alone in the first-line, metastatic setting.10 Nonetheless, for the subsequent randomized phase III trial that compared bevacizumab plus folinic acid, fluorouracil, and oxaliplatin with folinic acid, fluorouracil, and oxaliplatin alone in the second-line setting, a bevacizumab dose of 10 mg/kg was chosen.11 To my knowledge, there are no compelling data to strongly support a dose response of bevacizumab over the dose range of 5 to 10 mg/kg for metastatic colorectal cancer. Indeed, a subsequent retrospective analysis of the second-line study showed no difference in outcome for patients requiring a bevacizumab dose reduction from 10 mg/kg to 5 mg/kg.12 In non–small-cell lung cancer, a randomized phase II study with small numbers of patients suggested, but did not prove, that 15 mg/kg of bevacizumab every 3 weeks in combination with paclitaxel and carboplatin was superior to the 7.5 mg/kg dose.13 Predictably, the randomized phase III study used the 15 mg/kg dose but left open the question of whether the 7.5 mg/kg dose might have been just as good, with perhaps less toxicity and less cost.6 Likewise, the relationship between sorafenib dose and either area under the curve or maximum concentration is not straightforward within the dose range of 200 to 400 mg twice daily. Thus although the area under the curve and maximum concentration values are generally higher with 400 mg compared with 200 mg of sorafenib, there is a great deal of overlap and interpatient variability.8,14 These pharmacokinetic observations have a pharmacodynamic corollary, provided by monitoring the extracellular signal-regulated kinase (ERK) phosphorylation status of peripheral-blood leukocytes. Inhibition of phorbol myristate acetate–induced ERK phosphorylation can be observed in patients treated with as little as 200 mg sorafenib twice daily, as well as with the more standard dose of 400 mg twice daily of this drug.14 These considerations suggest that lower doses of these agents, especially when used in combination to target a common pathway, are not necessarily subtherapeutic. I am not suggesting that we deviate from the results of well-designed clinical trials in renal cell cancer that show efficacy for sorafenib at a dose of 400 mg twice daily.5 But I am challenging the bias that there is something superior about this dose as compared with lower doses. When viewed in this way, perhaps it is not surprising that the study of Azad et al3 showed activity at relatively low doses of bevacizumab and sorafenib. Still, we are left with the disturbing fact that were it not for the responses seen in a handful of patients with ovarian cancer, this regimen might have been considered too toxic, at subtherapeutic doses, to justify further study. In my view, this underscores the importance of performing companion pharmacodynamic and functional radiographic studies in phase I trials of targeted agents.15,16 To the authors’ credit, they are now performing dynamic contrast-enhanced magnetic resonance imaging, [18F]fluorodeoxyglucose positron emission tomography, and proteomic analysis of serial tissue biopsies in an expansion phase of this study,17 but it would have been ideal to have included this kind of information in the current report. Although the authors mention that serial VEGF serum levels seemed to increase during treatment, this information is of limited value in assessing whether an antiangiogenic combination such as this is biologically active. An increase in tumor-derived VEGF levels could indicate tumor progression, just as it might indicate a compensatory response to an effective antiangiogenic agent. Of greater interest for this combination might be an assessment of pERK or pVEGF receptor status in serial biopsies, and inhibition of phorbol myristate acetate–induced ERK phosphorylation in peripheral-blood leukocytes. It is true that we may not always know which markers will be most predictive (eg, pERK status may not always predict for sorafenib activity18), but we have to start somewhere. Encouraging signals derived from pharmacodynamic and functional radiographic studies would be grounds for proceeding with phase II testing of combinations of targeted agents, even in the absence of a RECIST-defined response, and even in the presence of subtherapeutic dosing. Nonetheless, assuming that the high response rate with this combination in relapsed ovarian cancer is confirmed, the study by Azad et al3 tells us that our preconceived notions about what constitutes a clinically active dose of targeted agents, especially when used in combination, might sometimes be wrong. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 2. Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15:1858-1869, 1997 3. Azad NS, Posadas EM, Kwitkowski VE, et al: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26:3709-3714, 2008 4. Cannistra SA, Matulonis UA, Penson RT, et al: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180-5186, 2007 5. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007 6. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 7. Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study. J Clin Oncol 25:5165-5171, 2007 8. Clark JW, Eder JP, Ryan D, et al: Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11:5472-5480, 2005 9. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003 10. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al: Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502-3508, 2005 11. 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 12. Giantonio BJ, Catalano PJ, O'Dwyer PJ, et al: Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group's Study E3200. J Clin Oncol 24:153s, 2006 (suppl; abstr 3538) 13. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004 14. Strumberg D, Richly H, Hilger RA, et al: Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23:965-972, 2005 15. Spector NL, Xia W, Burris H 3rd, et al: Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol 23:2502-2512, 2005 16. Sleijfer S, Wiemer E: Dose selection in phase I studies: Why we should always go for the top. J Clin Oncol 26:1576-1578, 2008 17. Azad NS, Annunziata C, Barrett T, et al: Dual targeting of vascular endothelial growth factor (VEGF) with sorafenib and bevacizumab: Clinical and translational results. J Clin Oncol 25:148s, 2007 (suppl; abstr 3542) 18. Chang YS, Adnane J, Trail PA, et al: Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561-574, 2007[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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