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Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp. 1639-1641 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.8384
Targeted Therapy Trials: Approval Strategies, Target Validation, or Helping Patients?Centro de Oncologia, Hospital Sirio-Libanes, Sao Paulo, Brazil
Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX We are witnessing the coming of age for molecular-targeted agents as a treatment strategy for malignancies in general and metastatic colorectal cancer (MCRC) in particular. We can now select from three different monoclonal antibodies (MoABs), targeting either the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) for MCRC. However, the excitement associated with the availability of these new drugs has to be tempered by the fact that the longest median survival reported in any large randomized trial in MCRC remains less than 24 months, regardless of treatment regimen, and suggests that we may be hitting a ceiling.1 Furthermore, to our knowledge, there are no completed trials that have actually demonstrated the addition of the EGFR-targeted MoABs results in a significant increase in median overall survival (OS) compared with chemotherapy alone in any line of therapy, in part due to cross-over study design and the use of new agents outside of clinical trials. In the past, the US Food and Drug Administration (FDA) approved most new agents based on improvements in OS. However, the availability of multiple lines of effective therapy results in a confounding effect on any single regimen's real impact on OS. In addition, better regimens meant that the duration of trials would have to increase to reach a primary end point of OS, a significant problem in a rapidly evolving field. Slowly, a consensus has been achieved, whereby a significant improvement in progression-free survival (PFS) is an acceptable surrogate end point for an improvement in OS, and the FDA has accepted it as the primary end point in registration trials. Both EGFR-targeted MoABs currently available (cetuximab and panitumumab) were approved by the FDA based on improvements in PFS, without having demonstrated a statistically significant benefit in OS. In this issue of the Journal of Clinical Oncology, Van Cutsem et al2 present the results of the pivotal trial with panitumumab that led to its FDA approval. It is a carefully designed and well-powered randomized phase III clinical trial comparing best supportive care (BSC) against BSC plus panitumumab. It was an open-label trial, but significant steps were taken to avoid any potential bias. Panitumumab is the first FDA-approved fully human MoAB targeting the EGFR. The complete human nature of the MoAB leads to a lower risk of anaphylaxis, a concern when chimeric MoABs are used, and its relatively long half-life allows for dosing every 2 weeks. The MoAB's target is the EGFR, a cell surface receptor with tyrosine kinase activity that mediates proliferation signals and a number of processes related to cell survival, including the activation of the mitogen-activated protein kinases and phosphatidylinositol-3 phosphate kinase/AKT pathways.3 The EGFR has already been validated as a target for the treatment of MCRC in studies using cetuximab,4 a chimeric MoAB also directed against this receptor. The trial reported by Van Cutsem et al was powered to demonstrate at least a 33% decrease in the relative progression rate for patients receiving BSC plus single-agent panitumumab compared with BSC alone. The results confirm the validity of EGFR as a target, the activity of panitumumab as a single agent, and the concept that anti-EGFR therapy can still benefit patients who have progressed on multiple lines of therapy. The trial was positive for its end points, with a single-agent response rate of 8%, and a 46% decrease in the relative progression rate for the patients treated with the antibody (P < .0001). However, the absolute improvement for the entire population treated is not nearly as impressive as the relative benefit might indicate. The median PFS was improved by only 0.7 weeks (7.3 to 8.0). The authors point out that the expected time to progression is very short for patients with refractory disease, and that the mean PFS improved from 8.5 to 13.8 weeks. Although logical, there are problems with this thought process. Not long ago, one could have used the same argument when evaluating second-line regimens for patients with MCRC who had progressed after single-agent fluorouracil in the first line. However, both irinotecan and oxaliplatin regimens, when used as second-line therapies, not only demonstrated activity in the form of response rates, but also were able to significantly improve median PFS and OS. The use of the mean instead of the median may better capture the effect of therapy by giving greater weight to the few patients who derive substantial benefit from the treatment. Yet this evaluation mechanism is not a commonly reported parameter, and a few outliers may unduly influence the results. The lack of an OS benefit is not surprising considering that the majority of patients in the BSC arm were allowed to cross over to treatment with panitumumab after progression, and that the relative benefit was similar for the patients who received panitumumab after progression. Although the cross-over may have influenced the OS, it was the correct, ethical way of conducting this trial. The authors did attempt to sort the effect of treatment on survival by censoring the BSC patients who responded after the cross-over to panitumumab, but this analysis is prone to selection bias. Those patients who were censored might have done better even without any further treatment, and the lack of a response may be a sign of worse prognosis independent of the treatment being offered. In addition to the above discussion, results from this trial also confirm the fact that immunohistochemical expression of EGFR is not a predictive factor for efficacy. In fact, the trial design was modified to allow accrual of patients with only 1% of tumor cells staining positive for EGFR, to be more inclusive rather than exclusive. This issue warrants discussion. If the investigators in this trial believed that anti-EGFR therapy would be effective in patients where only 1% of tumor cells stained positive for EGFR, they must have had relatively little confidence in the methods used to detect EGFR expression. EGFR is expressed almost universally on epithelial cells, including tumor cells of epithelial origin. Thus, EGFR tumor cell positivity should not be required for the use of an anti-EGFR agent, either in a clinical trial or in practice. This is supported by the fact that patients with EGFR-negative tumors appear to achieve similar benefit to those with EGFR-positive tumors. This fact can possibly be explained by the technical limitations of immunohistochemical staining. As with any important trial, there remain many unanswered questions. Although the trial confirmed the activity of single-agent panitumumab, from the perspective of the individual patient, the results are not very impressive. Considering the prior experience with the development of cetuximab in combination with chemotherapy,4 it is likely that the greater impact of the use of this MoAB will come from its use in combination with other active therapies. Such trials are under way, and the results should be available in the near future. This brings to light an important question: For whom are we doing these trials? We noted previously that the FDA now recognizes PFS as a reasonable end point for proof of efficacy and, thus, subsequent approval. There is a dialogue between investigators and the FDA that is critical in evaluating the efficacy of drugs under study and subsequent availability to patients. However, sometimes a trial achieves statistical significance, but it may be of minimal to modest benefit to patients (statistically significant, but of questionable clinical relevance). An example of this includes the addition of erlotinib to gemicitabine in a phase III clinical trial in pancreatic cancer, with a less-than-2-week improvement in median survival. Statistical significance was obtained, but the relative benefit to patients was modest, at best. It is important that investigators report data in a uniform manner across clinical trials, as emphasis on the most positive parameter may not allow for a level playing field. In addition to modest improvements in patient outcome, one must ask how relevant are the regimens studied in the current trial. Few oncologists use single-agent anti-EGFR therapy, as studies with cetuximab have shown superiority of anti-EGFR therapy when combined with chemotherapy, even when patients progressed on that chemotherapy regimen.4 Clinical trials should be designed primarily for patient benefit rather than purely as a registration strategy. Other important questions arise: Why are EGFR expression levels not important in determining which patients with tumors will respond? Why have only a minority of all the EGFR-positive tumors responded to the therapy? One would expect that the higher the EGFR expression level, the better the response to an anti-EGFR therapy. However, this was not observed in any of the trials investigating anti-EGFR antibodies for MCRC.5 Interestingly, several studies have demonstrated that EGFR levels were actually lower in colorectal cancers compared with surrounding normal mucosa.6,7 However, EGFR-activation was significantly higher in the tumor, confirming that the presence of a receptor is not nearly as important as the activation status of that receptor.7 These studies again inform us that EGFR expression levels in the primary tumor are unlikely to be a predictive factor for therapy. The lack of an efficient predictive marker that would allow us to select the patients most likely to benefit from anti-EGFR therapy remains a considerable challenge, particularly when the treatment is expensive and benefits only a fraction of the target population. The use of skin rash as a poor man's test to optimize anti-EGFR therapy is being explored currently, but this is not a true predictive marker because it is only assessable after the therapy has been initiated (it would be more appropriately called a "surrogate marker"). With the commercial availability of two MoABs against EGFR, identifying better predictive markers of sensitivity and resistance should be a top priority. Interesting candidates for such predictive markers include EGFR-activation/phosphorylation, the presence or absence of alternative dominant growth/survival signals (bypass pathways),8 and activation downstream mediators of survival (apoptosis family members). Unfortunately, unlike non–small-cell lung cancer, in which mutations in EGFR or EGFR gene copy number predict for response to therapy, there is no evidence at this time that these factors are predictive of efficacy in anti-EGFR therapies in MCRC. Previous trials with anti-EGFR-targeted MoABs had either been phase II trials without a control arm or trials comparing the use of an anti-EGFR antibody with the same MoAB plus chemotherapy. To our knowledge, the report by Van Cutsem et al is the first published trial comparing an anti-EGFR MoAB with BSC. It was a confirmatory step missing in the development of this type of therapy, as this design, with a BSC arm, is usually not well received by either patients or oncologists. Hence, this trial adds significantly to the validation of anti-EGFR therapy. Despite this, the relatively modest results indicate it is unlikely that single-agent panitumumab will become very popular, and the use of panitumumab will probably be determined by ongoing trials investigating the MoAB in combination with other active drugs. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: N/A Leadership: N/A Consultant: Paulo M. Hoff, Merck KGaA, Amgen; Lee M. Ellis, Amgen, ImClone Systems Inc Stock: N/A Honoraria: N/A Research Funds: Lee M. Ellis, Amgen, ImClone Systems Inc Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Paulo M. Hoff, Lee M. Ellis Data analysis and interpretation: Paulo M. Hoff, Lee M. Ellis Manuscript writing: Paulo M. Hoff, Lee M. Ellis Final approval of manuscript: Paulo M. Hoff, Lee M. Ellis REFERENCES
1. 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 2. Van Cutsem E, Peeters M, Siena S, et al: Open-label, randomized, 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 3. Bancroft CC, Chen Z, Yeh J, et al: Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer 99:538-548, 2002[CrossRef][Medline] 4. 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 5. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 6. Messersmith W, Oppenheimer D, Peralba J, et al: Assessment of epidermal growth factor receptor (EGFR) signaling in paired colorectal cancer and normal colon tissue samples using computer-aided immunohistochemical analysis. Cancer Biol Ther 4:1381-1386, 2005[Medline] 7. Piazzi G, Paterini P, Ceccarelli C, et al: Molecular determination of epidermal growth factor receptor in normal and neoplastic colorectal mucosa. Br J Cancer 95:1525-1528, 2006[CrossRef][Medline] 8. Camp ER, Summy J, Bauer TW, et al: Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 11:397-405, 2005 Related Article
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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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