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Originally published as JCO Early Release 10.1200/JCO.2005.11.890 on March 7 2005 © 2005 American Society of Clinical Oncology.
Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer
From the Medical Oncology Service, Vall d'Hebron Research Institute and Vall d'Hebron University Hospital, Barcelona, Spain; and Departments of Medicine and Cancer Biology and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, TN Address reprint requests to José Baselga, MD, Medical Oncology Service, Vall d'Hebron Research Institute and Vall d'Hebron University Hospital, Paseo Vall d'Hebron 119-129, Barcelona 08035, Spain; e-mail: jbaselga{at}vhebron.net. ABSTRACT The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis. INTRODUCTION In recent years, the field of cancer therapy has witnessed the emergence of novel targeted strategies that inhibit specific cancer pathways and key molecules in tumor growth and progression. Among them, one class of compounds that has shown great progress are those targeting tyrosine kinases (TKs), their ligands, and signal transducers. Protein kinases regulate most of the signal transduction in eukaryotic cells, and by modification of substrate activity, they also control many cellular processes important in cancer cells, including metabolism, transcription, cell-cycle progression, cytoskeletal rearrangement and cell movement, apoptosis, and differentiation.1 There are more than 90 known protein kinase genes in the human genome; 58 encode transmembrane receptor TKs distributed into 20 subfamilies, and 32 encode cytoplasmic, nonreceptor TKs in 10 subfamilies.2 In normal cells, the activity of protein TKs is tightly regulated. However, perturbation of protein kinase signaling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation. Receptor TKs are a subclass of transmembrane-spanning receptors endowed with intrinsic, ligand-stimulatable, catalytic activity. These receptors, when mutated or altered structurally, can become potent oncogenes that lead to cellular transformation. The epidermal growth factor receptor (EGFR) is a transmembrane receptor TK of the ErbB (also known as HER) family that is abnormally activated in many epithelial tumors. Several mechanisms lead to aberrant receptor activation, including receptor overexpression, gene amplification, activating mutations, overexpression of receptor ligands, and/or loss of their negative regulatory mechanisms. Receptor activation leads to recruitment and phosphorylation of several intracellular substrates, which, in turn, engage mitogenic signaling and other tumor-promoting activities. Over 20 years ago, Mendelsohn et al proposed that the EGFR was a target for cancer therapy.3,4 With two classes of anti-EGFR agents with established clinical activity in cancer, this hypothesis has now been confirmed. These are monoclonal antibodies directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate (ATP) -competitive inhibitors of the receptor's TK.5 Since the last review of this subject in the Journal of Clinical Oncology (JCO),5 major advances have been made in our knowledge of both the basic science of the EGFR network and the clinical activity of these agents. It is therefore most fitting in this Special Series issue to critically review the clinical data as well as trying to identify some future directions in this research field. MONOCLONAL ANTIBODIES DIRECTED AT THE ERBB (HER) FAMILY Monoclonal antibodies (MAbs) against the HER-receptor family include antibodies that prevent ligand binding and ligand-dependent receptor activation (such as anti-EGFR antibodies), antibodies that interfere with ligand-independent receptor activation (such as the anti-HER-2 antibody trastuzumab), and a new class of antireceptor antibodies that prevent receptor heterodimerization (Table 1).
Anti-EGFR antibodies that interfere with ligand-dependent receptor activation have shown clinical activity in a variety of solid tumors including colon, head and neck, non–small-cell lung cancer (NSCLC), and renal cell carcinomas. Single-agent clinical trials have been conducted in these tumor types and a substantial proportion of studies have also incorporated anti-EGFR MAbs to commonly used combination chemotherapy regimens. As expected, the clinical development of anti-EGFR antibodies is highly dependent on the tumor type being studied, requiring for each tumor different study end points, tumor-based chemotherapy regimens, and potential for integration with radiation therapy (RT). Therefore, the clinical data with anti-EGFR antibodies will be reviewed separately for each tumor type.
In colon cancer, antitumor activity was first observed with cetuximab, a chimeric immunoglobulin G2 MAb derived from the mouse MAb 225.6 An initial observation that cetuximab could reverse resistance to chemotherapy in patients with advanced, chemotherapy-refractory colon cancer7 led to a series of confirmatory studies in the laboratory and in the clinic. In a colorectal cancer model, cetuximab was found to reverse resistance to irinotecan.8 This finding was followed by a study by Saltz et al9 that showed activity of the combination of irinotecan and cetuximab in patients that had previously experienced treatment failure with irinotecan. Subsequently, a larger and well-controlled randomized study10 confirmed these findings in a similar patient population. In this last study, patients with advanced colon cancer that had received at least two cycles of irinotecan-containing chemotherapy, and that had documented progression on irinotecan, were randomly assigned to receive cetuximab alone or cetuximab in combination with the same dose and schedule of irinotecan on which they had progressed. The study included a total of 329 patients and demonstrated a significantly higher response rate in the arm containing irinotecan and cetuximab than in the cetuximab monotherapy arm (22.9% [95% CI, 17.5% to 29.1%] v 10.8% [95% CI, 5.7% to 18.1%]; P = .007). The modest single-agent activity of cetuximab in irinotecan-refractory disease ( Other anti-EGFR MAbs have been studied in colon cancer including ABX-EGF and EMD 72000. The fully human MAb ABX-EGF (panitumumab)13 was shown to be active in a phase II study in advanced disease. In this study, 15 (10%) of 148 patients that had experienced failure with first-line chemotherapy achieved a clinical response to ABX-EGF. Likewise, antitumor activity against colon cancer has been observed with the humanized MAb EMD 72000.14,15 Squamous cell carcinoma of the head and neck (SCCHN) is also a highly EGFR-dependent tumor5 and, similar to colon cancer, clinical activity with MAbs was observed early on in their clinical development.16 In SCCHN, anti-EGFR antibodies have been studied as a single agent and in combination with chemotherapy or radiation therapy. Initial studies in SCCHN were aimed at whether the addition of cetuximab could reverse chemotherapy resistance. In patients with advanced disease refractory to platinum salts, the addition of cetuximab to the same dose and schedule of platinum that the patients had progressed on resulted in a response rate of 10% and a median survival of approximately 6 months.17,18 More recently, in a similar patient population, the administration of cetuximab alone upon progression from chemotherapy has shown a response rate of 12%.19 This response rate is similar to the one with combined platinum and cetuximab, which raises the question of whether cetuximab as a single agent may be equally active and less toxic than the addition of cetuximab to platinum. The results from these studies strongly suggest that cetuximab compares favorably with the expected response rate and survival in a similar refractory patient population treated with second-line chemotherapeutic agents. In support of this, a recently conducted, large, retrospective study in patients with SCCHN that had progressed to first-line platinum-based therapy, and that had similar features compared with the patients participating in the cetuximab studies, observed that in this setting the response rate to a variety of conventional chemotherapy agents was only 3.4% and the median survival was of approximately 3 months, about half of the observed in the cetuximab trials.20 In the first-line setting, a recently reported phase III trial examined the impact of combining cetuximab with high-dose radiation on locoregional control and survival in 424 patients with locally advanced SCCHN.21 Patients were randomly assigned to receive radiation alone for 6 to 7 weeks, or radiation plus weekly cetuximab. The addition of cetuximab demonstrated a statistically significant prolongation in overall survival (54 v 28 months; P = .02) and improved locoregional control at 2 years (56% v 48%; P = .02). This clinical benefit was achieved with minimal enhancement in overall toxicity from curative-intent RT. The feasibility of combining RT and anti-EGFR antibodies has also been shown with the humanized MAb h-R3.22 Taken together, these results validate the approach of combined RT plus anti-EGFR therapies. Areas of ongoing research, in addition to patient selection strategies that are being discussed elsewhere in this article, include how to integrate anti-EGFR MAbs with combined radiation and chemotherapy approaches. The favorable outcome with the combination of anti-EGFR antibodies and RT in SCCHN suggests that a similar approach, with or without chemotherapy, may be warranted in other epithelial EGFR-dependent and RT-sensitive tumors such as esophageal and rectal cancer. In NSCLC, a randomized phase II study has compared the use of a conventional chemotherapy regimen (cisplatin and vinorelbine) given alone or in combination with cetuximab.23 Patients treated with cetuximab had a higher response rate (31.7% v 20.0%) and a more prolonged time to disease progression (4.7 v 4.2 months) than patients treated with chemotherapy alone. This activity is currently being confirmed in a large phase III study. As mentioned, there is a new class of MAbs that prevents receptor heterodimerization. An example of this class of HER-dimerization inhibitors is the MAb pertuzumab (or 2C4).24 This antibody binds to HER-2 and sterically hinders ligand-associated heterodimerization of HER-2 with other HER kinase family members, thereby inhibiting intracellular signaling. Preclinical activity of pertuzumab in breast and prostate cancer cell lines has been shown to be independent of a high level of HER-2. In this issue of the JCO is the report of the initial phase I study in patients showing the safety and feasibility of this approach, in addition to some evidence of clinical activity.25 Single-agent phase II studies of pertuzumab are underway in patients with ovarian carcinoma, NSCLC, prostate and breast cancer. SMALL MOLECULE HER TK INHIBITORS This class of agents competes with ATP binding to the TK domain of the receptor, which inhibits TK activation and subsequently leads to blockade of EGFR signaling pathways. There is a significant number of this class of agents that are currently under clinical development (Table 2). They differ among themselves mainly on their potency against the different members of the HER-receptor family and their capacity to preferentially inhibit a single receptor type or, on the contrary, to inhibit other HER receptors or other TK-receptor families.
Based on the early clinical activity observed in the phase I studies, anti-EGFR TK inhibitors (TKIs) were preferentially studied in patients with advanced NSCLC. The documentation of clinical responses observed in the large monotherapy trials with the EGFR TKIs gefitinib and erlotinib generated a high degree of enthusiasm.26-28 This enthusiasm, however, was followed by a dose of realism when a series of large phase III studies in unselected patients failed to show additional benefit when erlotinib or gefitinib were given in combination with conventional chemotherapy.29-32 The field has now undergone renewed interest by a series of new findings that will have a profound impact on the potential role of these agents in the treatment of patients with NSCLC: first, the results of two well-powered, placebo-controlled, randomized studies with single-agent erlotinib (BR.21) or gefitinib (Iressa Survival Evaluation in Lung cancer [ISEL]) have become available; and second, the discovery of EGFR gene mutations in the receptor TK domain and their association with a high response rate to these small molecule inhibitors. The first reported randomized single-agent versus placebo trial was the BR. 21 study. Patients with NSCLC after first- or second-line chemotherapy were randomly assigned to receive erlotinib 150 mg/d or placebo (2:1 randomization). The primary end point was survival, with secondary end points of progression free survival (PFS), response, toxicity, and quality of life. A total of 731 patients entered the study and, as per inclusion criteria, were heavily pretreated: 50% had received two prior chemotherapy regimens, 93% had received platinum, and 37% prior taxanes. Patient characteristics were well balanced. Overall response to erlotinib was 8.9% (95% CI, 6.6% to 12.0%; P < .001), with a median treatment duration of 34.2 weeks. Statistically significant and clinically relevant differences were observed for overall survival (6.7 v 4.7 months; P = .001) and PFS (2.2 v 1.8 months; P < .001). The results of a similar study with gefitinib (ISEL) have just been released (www.astrazeneca.com/pressrelease/4245.aspx). In this large study, 1,692 patients were randomly assigned to receive gefitinib 250 mg/d versus placebo. Although there was a similar response rate as that observed with erlotinib in BR.21, in the ISEL study, gefitinib failed to statistically prolong survival in comparison to placebo in the overall population (hazard ratio [HR] = 0.89; P = .11; median, 5.6 v 5.1 months) or in patients with adenocarcinoma (HR = 0.83; P = .07; median, 6.3 v 5.4 months). The reason for the discordance between these two studies is unknown at this time. One potential explanation is that these two agents, by promiscuously cross-reacting with other kinases or by different binding to the EGFR kinase domain, may have a different activity profile. A second, not mutually exclusive, possibility is that they were used at doses with different biochemical potency against the EGFR. In transient transfection studies, phosphorylation of the wild-type EGFR is inhibited 50% by 0.1 µM gefitinib and 100% by 2.0 µM, whereas the respective values for mutant EGFR (L858R and del747-752) were approximately 0.015 and 0.2 µM.33 Of note, the steady-state plasma levels of gefitinib (250 mg/d) and erlotinib (150 mg/d) are approximately < 1 µmol/L and 3 µM, respectively.34,35 Therefore, although at these doses both small molecules would have attained adequate plasma concentrations to block mutant EGFR signaling, a 250-mg dose of gefitinib might have been insufficient to completely inhibit the activated wild-type EGFR. However, this speculation is countered by the fact that in monotherapy trials with 250 or 500 mg/d gefitinib, the response rate in patients with chemotherapy-refractory NSCLC was identical regardless of the dose.26,27 Whether the difference in the outcome of these two trials can be explained by the fact that erlotinib was used at a higher equivalent dose than gefitinib requires further investigation. In all the studies, there was a strong indication that a subset of patients with NSCLC seemed to benefit more substantially from therapy with gefitinib and erlotinib. Patients with bronchioalveolar carcinoma, never-smokers, females, and Japanese patients had a higher response rate and greater clinical benefit. Although this could suggest the existence of a subpopulation of patients with EGFR-dependent tumors, it can not be ruled out that pharmacogenomic differences among this group of patients could result in more drug exposure in the tumor. As the review in this issue by Pao and Miller36 describes in detail, these clinical findings have now been followed by the recent discovery of somatic mutations in exons 18 through 21 encoding the TK domain of the EGFR, and the close association between these mutations and clinical responses to these agents.33,37,38 In this issue of the JCO, an additional report provides evidence of the relationship between the presence of mutations and response to anti-EGFR TKI.39 There is a suggestion, however, that the clinical benefit observed with anti-EGFR TKIs is not restricted to those patients harboring EGFR gene mutations. Although patients with receptor mutations may have an increased response rate to an EGFR TKI and have a longer survival, the relatively small fraction of patients who had tumor responses in BR.21 is unlikely to explain the observed survival benefit. The implication is that factors other than EGFR mutations may play a role in the observed clinical benefit in BR.21. This is not surprising, as other molecular mechanisms such as EGFR gene amplification and receptor ligand overexpression can also endow the receptor with a "gain of function" potentially leading to EGFR dependence and, in turn, sensitivity to single-agent EGFR inhibitors. Along those lines, in a subset analysis of BR.21 with a limited number of tumor samples, the benefit in survival was greater in those patients that had higher levels of EGFR expression. Furthermore, EGFR gene amplification has also been recently reported in NSCLC and it has been shown to correlate with high levels of receptor expression.40 Preliminary data have now suggested a strong correlation between EGFR gene amplification and response to gefitinib in NSCLC (Fred Hirsch, personal communication, May 2004).41 Whether amplification of the EGFR locus correlates with the mutations reported in NSCLC is unknown. Studies are currently underway to correlate EGFR gene amplification and clinical benefit from anti-EGFR therapies in a similar fashion as it occurs in the case of ErbB2-amplified tumors and reponse to the anti-HER2 MAb trastuzumab in patients with breast cancer. Whether clinical activity with anti-EGFR TKIs will be observed against other tumor types is being investigated. In pancreatic carcinoma, the addition of erlotinib to conventional chemotherapy has been shown in a phase III study to improve survival (www.gene.com/gene/news/press-releases). In addition to advances in anti-EGFR therapies, there is emerging clinical data with small molecule TKIs that target other members of the ErbB (HER) -receptor family. A phase I study of lapatinib (GW572016), a dual inhibitor of the EGFR and HER-2,42,43 is reported in this issue of the JCO. In this study, lapatinib showed clinical activity in patients with trastuzumab-refractory breast cancer.44 Patients were randomly assigned to receive doses of lapatinib from 500 to 1,600 mg/d. Four clinical responses were observed, all of them in patients with HER-2-overexpressing tumors. The activity of lapatinib has been further documented in two ongoing phase II studies with single-agent lapatinib in patients with advanced, HER-2-overexpressing breast cancer that had been previously treated with trastuzumab.45,46 In these studies, lapatinib was given at a dose of 1,500 mg/d in a heavily pretreated population. In a planned interim analysis after enrollment of 40 patients in each study, the activity of lapatinib has been confirmed with an objective response rate of 9.8%45 and 7.5%,46 respectively. Currently, there are ongoing studies with lapatinib and trastuzumab as well as phase III studies of lapatinib and chemotherapy. In addition, clinical development is ongoing with other dual EGFR HER-2 TKIs such as BMS-599626 and AEE788 (Table 2).47 IMPLICATIONS FOR THE DEVELOPMENT OF ANTIRECEPTOR AGENTS The clinical studies with anti-EGFR and anti-HER-2 agents have shown us some important points that should aid in the successful development of these and other molecule-targeted agents. The first point is the usefulness of having available tumor tissue from patients participating in these trials in order to study the features that may be correlated with increased sensitivity and/or resistance to these agents. The second is that the concept of oncogene dependence48 also applies to the EGFR family of receptors: There is clearly a subset of patients that harbor EGFR mutations that, even at an advanced tumor stage, are exquisitely sensitive to these agents. While there is strong evidence that not only will patients with mutant EGFR benefit from these therapies (see above), it is likely that this subgroup of patients will enjoy long-lasting objective responses. These data imply the need for a new classification of tumors based on their mutational status. It is also possible that other mutations may play a role in sensitivity or resistance to these and other signal transduction inhibitors. Parenthetically, a recent study reported that EGFR mutations were highly associated with a nonsmoking history, but never occurred in tumors with K-ras mutations.49 The lower response rate to EGFR TKIs in smokers with NSCLC,50,51 and the ability of K-ras to signal in the absence of input from the EGFR, would imply the possiblity that K-ras mutations are a marker of resistance to EGFR inhibitors52 and that such patients should be considered for alternative therapies (Fig 1).53,54 More recently, mutations in the phosphatidyilinositol-3 kinase (PI3K) gene in glioblastoma, colorectal, ovarian, and breast cancer55-57 have been identified. These data suggest that these tumors are indeed PI3K-signaling dependent and, as such, are highly sensitive to inhibitors of the PI3K-Akt-mTOR pathway. Intragenic somatic mutations of HER-2 (ErbB2) in a small cohort (< 10%) of NSCLC have also been discovered recently.58 They involve in-frame insertions and a missense substitution that overlap with the analogous structural domain of the in-frame EGFR deletions associated with NSCLC. Interestingly, they were not detected in lung cancers with EGFR mutations and appeared to be limited to patients with lung adenocarcinoma. Unlike with EGFR mutations, ErbB2 mutations occurred in smokers and ex-smokers. The functional effects of this mutation and the sensitivity of tumors bearing this mutant receptor to anti-HER-2 agents are unknown.
OPTIMAL BIOLOGICAL DOSE AND RATIONAL BIOMARKER DEVELOPMENT The reported results with gefitinib and erlotinib, reviewed above, will likely add fuel to the fire of the ongoing debate on how to choose the appropriate therapeutic dose level with these agents. Based on our lack of full understanding of the determinants of response, an important question is whether these agents should be developed at their maximum tolerated dose or if efforts should be made at identifying the optimal biologic dose (OBD). The definition of the OBD of a targeted therapy may be based on pharmacokinetic end points or by demonstrating the desired biochemical effect on the target molecule or its downstream processes. An example of a pharmacokinetic-based OBD was the process that led to the selection of the current dose and schedule of cetuximab.59 Recent studies also indicate that this pharmacokinetically optimal dose and schedule of cetuximab results in inhibition of the EGFR in patients' skin.60
Studies on pharmacodynamic end points were incorporated earlier in the clinical development of small molecule EGFR TKIs. In the initial phase I studies of gefitinib, sequential skin biopsies were performed before and after 4 weeks of therapy.61 The skin was selected as the target tissue due to its easy access and the established role of the EGFR in renewal of the dermis.62,63 Inhibition of EGFR phosphorylation and EGFR-dependent downstream processes was detected at doses In a phase I study of the EGFR MAb EMD72000in patients with advanced carcinomas, there was complete inhibition of tumor p-EGFR and p-MAPK in all subjects, whereas p-Akt and Ki67 were only inhibited in responding patients.31,37 This suggests that some, but not all, downstream markers correlate with clinical response. Second, these data also raise the point that the OBD may need to be redefined: Instead of being defined as the dose resulting in satisfactory target inhibition (in this case the EGFR), perhaps it should be considered to be the dose having a maximal inhibition and/or induction on those target-dependent downstream markers that correlate most accurately with clinical benefit. CLINICAL BIOMARKER-DRIVEN STUDIES WITH ANTIRECEPTOR THERAPIES
The study of biomarkers of drug exposure and sensitivity in tumors, although feasible,68 is not easy due to the inherent difficulty of obtaining sequential tumor samples only for research purposes. One approach to circumvent this difficulty consists in the administration of the antireceptor therapy for patients with untreated, operable cancer immediately before definitive surgery. This approach, which can be applied to solid tumor types with accessible tissues (ie, breast, SCCHN, colorectal cancers, esophageal cancer, NSCLC), has been abundantly explored in breast cancers treated with antiestrogens. These studies have shown that A considerable validation of a neoadjuvant approach has been provided by the recently completed Immediate Preoperative Arimidex (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen (IMPACT) trial, a double-blind, randomized, neoadjuvant comparison of anastrozole with tamoxifen alone or combined in postmemopausal patients with ER-positive breast cancer.70 In a core biopsy obtained after 2 weeks of therapy, a statistically superior inhibition in Ki67 IHC was observed in tumors treated with anastrozole compared with the other two arms. Further, the reduction in Ki67 levels in IMPACT was parallel to the disease-free survival outcome in the large Anastrozole and Tamoxifen, Alone or in Combination (ATAC) adjuvant trial.71 This last study randomly assigned > 9,000 breast cancer patients to the same three arms postsurgically, and required 33 months of follow-up to reveal that anastrozole was more effective in delaying cancer recurrences and prolonging disease-free survival. These data suggest that had the less expensive and shorter IMPACT trial been done first, the results of this study could have streamlined the ATAC trial by potentially eliminating the need of a combination arm, thus saving significant costs and patients' time. In this issue of the JCO, an important follow-up study to IMPACT by the same group72 addresses the influence of ER, progesterone receptor (PgR), and HER-2 on the antiproliferative effect of anastrozole and tamoxifen. As expected, there was a positive relationship between ER levels and drug-induced suppression of Ki67. Ki67 was also reduced to a greater extent in patients with PgR-positive compared to the PgR-negative tumors. As shown by Ellis et al,73 the degree of short-term reduction in Ki67 in patients with HER-2-positive tumors was lower in the subgroup of patients treated with tamoxifen when compared with the aromatase inhibitor arm. There was also a major effect on PgR in the anastrozole-treated patients, with incremental decreases at 2 and 12 weeks. Taken together, the results of this study suggest a role for inhibition of Ki67 as a pharmacodynamic biomarker of hormonal therapy. Further clinical validation of these data, as well as the potential use of Ki67 in the development of other molecular therapies, remains to be investigated. This neoadjuvant approach is now being incorporated in the study of antireceptor TK agents in breast cancer. In this issue of the JCO, biomarker end points were used in a clinical trial in patients with locally advanced HER-2-overexpressing breast cancer.74 Patients were treated with weekly trastuzumab as a single agent for the first 3 weeks, followed by a combination of weekly trastuzumab and every-3-week docetaxel for a total of 12 weeks before primary surgery. Sequential core biopsies of the primary breast tumors were taken at diagnosis and at weeks 1 and 3 after the first dose of trastuzumab. Clinical responses to trastuzumab alone were observed after only 3 weeks of therapy. These responses correlated with a statistically significant increase in apoptosis at week 1, as measured by the proportion of TUNEL-positive tumor cells in treated tumor sections. Interestingly, a high basal level of p-Akt negated the drug-induced increase in tumor cell apoptosis and correlated with lack of clinical response. Several ongoing trials are incorporating similar approaches. However, it is anticipated that additional steps will be required for an optimal implementation of these biomarker-based studies. First, there is a need to standardize and quantitate, whenever possible, the scoring systems for biomarker assessment. For IHC, for example, this may require the implementation of automated quantitative digital analysis systems that are devoid of interobserver variability.75 This technology, in conjunction with tissue microarrays, may provide a high-throughput method that could be used in a similar fashion as cDNA microarrays.76 Second, it would be useful to demonstrate for these agents correlations between biomarker changes and pharmacokinetic values as shown by Tabernero et al68 in this issue. The goal here would be to define, as accurately as possible, an effect-exposure relationship for the study agent. The therapeutic dose and schedule being brought on to further clinical development would then be based on the integration of a series of pharmacodynamic markers, including target inhibition (biochemical effect), inhibition of target-dependent processes (functional effect), clinical activity, and adverse events. Additional technologies are being incorporated in this biomarker identification process. For example, cDNA arrays have allowed the identification of a series of genes that are differentially regulated by anti-EGFR therapies in preclinical models,77 and clinical trials to validate these findings are currently in progress. Likewise, protein arrays could be used for quantitative analysis of signal pathways inhibition.78 Currently, this approach is being envisioned, as with the antiestrogens, as an overall profiling strategy that can be used later for schedule and patient selection as well as for prioritization of different agents or combinations for further clinical development. At this time, we do not envision this approach to predict clinical benefit for individual patients. INTEGRATION WITH CONVENTIONAL ANTICANCER THERAPIES One area of great interest is how to translate into human trials the synergy of these agents with chemotherapy or radiation observed in preclinical models. An early example of concordance between preclinical and clinical data was provided with the anti-HER-2 MAb trastuzumab: The preclinical results with the combined treatment with trastuzumab and doxorubicin or paclitaxel79 were predictive of the improved survival with similar combinations that was observed in a pivotal phase III study in patients with advanced HER-2-overexpressing breast cancer.80 Further, detailed preclinical studies that have shown synergy of trastuzumab with platinum salts and vinka alkaloids81 have been correlated with very promising clinical activity with these combinations.82,83 In patients with advanced colorectal cancer, the combination of the anti-vascular endothelial growth factor (VEGF) MAb bevacizumab added to chemotherapy also resulted in improved survival when compared with chemotherapy alone.84 However, the correlation between preclinical models and clinical outcome has been less predictable with anti-EGFR agents. Despite positive preclinical studies of anti-EGFR TKIs in combination with chemotherapy,85,86 we have already referred to four large phase III clinical trials in patients with either locally advanced stage III disease or stage IV NSCLC who failed to show any benefit with the combined treatment.29-32 These well-conducted studies included thousands of patients and studied two different compounds (gefitinib and erlotinib). The reasons for these disappointing results are unknown and an antagonistic effect of the combination cannot be excluded.87 Antagonism between cytostatic and cytotoxic agents has been demonstrated with tamoxifen and chemotherapy in the adjuvant treatment of breast cancer.88 Thus, a similar situation of schedule-dependent antagonism could have occurred with anti-EGFR agents and chemotherapy. Another possibility would be that a cohort of patients harbors additional mutations in key signaling molecules. These mutations—or deletions—could render these tumors insensitive to EGFR blockade or, alternatively, EGFR blockade could result in a compensatory activation of these signaling pathways. For example, Ras, a signaling molecule downstream of the EGFR, is frequently mutated in NSCLC in smokers89; and K-ras mutations have been shown to result in primary resistance to gefitinib and erlotinib.52 Further, the effects of chemotherapy in combination with anti-EGFR agents in the presence of K-ras or other coexisting mutations are unknown. On the other hand, there has been a high degree of correlation between the preclinical models of RT and anti-EGFR MAbs90,91 and the outcome of the phase III study in SCCHN. This trial showed that the addition of cetuximab to RT improves survival and enhances local control when compared with radiation alone.21 Another area of clinical significance is whether EGFR inhibitors have the capacity to reverse acquired and primary resistance to conventional chemotherapy. The initial observation that cetuximab reversed resistance to chemotherapy in patients with chemotherapy-refractory colon cancer7 led to a series of confirmatory studies in the laboratory and in the clinic. In a colorectal cancer model, cetuximab was found to reverse resistance to irinotecan.8 This finding was followed by the initial observation by Saltz et al9 showing activity of the combination of irinotecan and cetuximab in patients that had experienced treatment failure with irinotecan. These data were confirmed in the randomized study, which also included a cetuximab-only arm.10 This last study clearly demonstrated the superiority of continuation of irinotecan beyond progression, a strong suggestion that cetuximab reverses, at least in part, resistance to irinotecan.10 In SCCHN, there is strong evidence of preclinical synergy of the combination of cisplatin and cetuximab.92 An earlier study reported that cetuximab in combination with cisplatin had activity in patients with SCCHN that had progressed on cisplatin.16 In follow-up studies in patients with advanced disease refractory to platinum salts, the addition of cetuximab to the same dose and schedule of platinum that the patients had progressed on showed clinical activity.17,18 However, the same response rate had been observed with the administration of cetuximab alone in a similar patient population.19 Although a study specifically designed to address this question has not been conducted in SCCHN, the available data do not support the notion that cetuximab reverses platinum resistance in SCCHN. Taken together, the lack of a universal concordance in outcome between preclinical models and human trials will have implications in the way we conduct future studies combining anti-EGFR agents and conventional therapeutics. First, preclinical models may only reflect a molecular subtype of a cancer whose prevalence in the cancer type at large is unknown and/or unpredictable. Therefore, it would seem appropriate not to commit large number of patients to expensive phase III trials with anti-EGFR agents (and other targeted agents) until some indication of preliminary activity has been gathered in the clinic with the combination under study. This could be achieved by conducting randomized phase II trials or, in those situations when the development time is critical, by incorporating early stopping rules in phase III designs. Second, in an era where cDNA arrays and proteomic technology are becoming increasingly available and used to identify molecular signatures of prognosis93 and response to conventional chemotherapy,94 our efforts have to be redirected at identifying either sensitive or, on the contrary, nonresponding phenotypes. Encouraging results have been reported with some markers predictive of sensitivity to anti-EGFR agents,95,96 some of which are being analyzed in the clinic. Although the procurement of fresh tumor tissue would be ideal to identify EGFR-sensitive genomic signatures, emerging technologies such as quantitative analysis of gene expression in paraffin-embedded tissue may permit to identify correlates of response in archival tumor material.97 A complementary approach would be to identify those patients that will have primary resistance to these agents. For example, if K-ras mutations are demonstrated in the clinic to predict for primary resistance to anti-EGFR agents, it may be desirable to exclude these patients from trials with anti-EGFR therapies, or to incorporate a combined anti-EGFR and an anti-Ras approach. This would be similar to current standards of care in breast cancer where ER-negative or single-copy HER-2 tumors do not benefit from antiestrogens or trastuzumab, respectively, and thus are not offered such therapies. Third, it seems reasonable that a "no tissue—no trial" rule should be strongly considered in exploratory studies with molecule-targeted agents when the molecular signature predictive of response (or lack of response) is not recognizable. The availability of tissue in all patients should allow the retrospective identification of a molecular profile or surrogate marker characteristic of responding tumors even when the overall signal of activity was limited to a small group of patients. In turn, this profile or marker can be prospectively used for patient enrollment into subsequent registration studies in selected patients. There is also a growing impetus to combine anti-EGFR agents with antiestrogens in breast cancer, as well as in prostate cancer. Although, anti-EGFR TKIs given as monotherapy in patients with breast cancer have shown disappointing low activity,67,98-100 the rationale for the combined approach stems from the cross talk between the ErbB receptors and ER signaling.101 In vitro data show that antiestrogen-resistant cells are highly sensitive to gefitinib.102 Furthermore, when antihormone-responsive MCF-7 breast cancer cells were treated with gefitinib in combination with tamoxifen or fulvestrant, there was added growth-inhibitory activity and the development of antihormone resistance was blocked or delayed.102,103 The molecular basis underlying the cross talk between ErbB and ER is currently being established. For example, studies in tumors from breast cancer patients have shown a high coexpression of the ER coactivator amplified in breast cancer-1 (AIB1) and that ErbB2 is associated with tamoxifen resistance.104 EGFR and ErbB2 signaling phosphorylates and activates both ER and AIB1 and, in this setting, tamoxifen behaves as an ER agonist. In experimental model systems, gefitinib blocks receptor cross talk and fully reverses tamoxifen resistance.105 These results indicate that the combination of gefitinib with hormonal therapy should be tested in the clinical setting and phase II trials are ongoing, including evaluation of gefitinib in combination with tamoxifen and with anastrozole. INTEGRATION WITH OTHER MOLECULE-TARGETED THERAPIES An area of clinical research with increasing activity is the combination of either anti-EGFR or anti-HER-2 growth factor inhibitors with other molecule-targeted therapies. The principle behind this combinatorial approach is two-fold. First, it is unlikely that a given tumor will be dependent on just one receptor or signaling pathway for its growth and survival. Second, there is a significant level of compensatory cross talk among receptors within a signaling network as well as with heterologous receptor systems.106 As with conventional therapies, however, it is proving difficult to prioritize how to rationally develop molecule-targeted combinations, more so with the large number of this class of agents that are entering clinical development. In order to rationalize a list of potential combinations, we have divided them in the following subgroups.
Combination of Antireceptor Therapies Taken together, these results led to the hypothesis that combinations of EGFR and HER-2 inhibitors will be synergistic against EGFR-positive, HER-2-overexpressing tumors. This hypothesis led to phase II studies of trastuzumab in combination with either gefitinib or erlotinib in patients with breast cancer. The results of the first phase II study have been recently reported.119 This study was conducted in patients with advanced HER-2-overexpressing breast cancer. Patients were treated with trastuzumab 2 mg/kg/wk and gefitinib 250 mg/d until disease progression. Detectable EGFR by IHC were not required for study entry. This study was interrupted because of failure to meet its predetermined median time to progression end point: the median time to progression was a disappointingly low 2.9 months, shorter than that reported with trastuzumab alone.120,121 Although the results of the ongoing studies with erlotinib and trastuzumab are not yet available, the unexpected outcome of this study questions once more the validity of currently used preclinical models. These data also suggest the need for alternative approaches that can anticipate such negative results and spare the implementation of such trials. The neoadjuvant design described by Moshin et al74 in this issue comes to mind as one that may allow exploratory comparisons of trastuzumab versus trastuzumab plus a partner drug. If more effective than trastuzumab alone, the combination should provide a signal of enhanced apoptosis that can be used to proceed to a phase II study with clinical endpoints (Fig 2). This speculation requires further research.
Another example is the combination of anti–insulin-like growth factor-I (IGF-I) receptor and anti-EGFR or anti-HER-2 therapies. Overexpression of the IGF-I receptor has been recently reported to abrogate the antitumor effect of EGFR TKIs and trastuzumab against human cancer cells.122,123 In these studies, simultaneous blockade of IGF-I receptor signaling restored tumor cell sensitivity to the EGFR and HER-2 inhibitors, providing a rationale for combined antireceptor therapies. This approach can be studied now with the availability of IGF-I receptor inhibitors.124
Combination of Antireceptor Therapy and Receptor-Downstream Signaling Molecules
Combination of Antireceptor Therapy and Agents Interfering With Other Essential Components Responsible for the Malignant Phenotype In this Special Series issue, we have one such example: the combination of anti-EGFR therapies and antiangiogenesis agents. Several studies have shown that both EGFR antibodies and small molecule kinase inhibitors reduce VEGF and factor VIII levels (by IHC) and microvessel density in tumors that regress upon EGFR blockade.128,129 Interestingly, tumor cells with acquired resistance to cetuximab exhibit increased expression and secretion of VEGF. Forced expression of VEGF in sensitive A431 cells renders them resistant to EGFR antibodies in vivo.130 These data imply that (1) subversion of EGFR-dependent tumor neoangiogenesis is central for the antitumor effect of EGFR inhibitors, and (2) enhanced angiogenesis can endow tumors with resistance to EGFR blockade. These results provide a strong rationale for combinations of anti-EGFR agents with angiogenesis inhibitors such as the one reported in this issue by Herbst et al.131 This manuscript describes a phase I/II study of bevacizumab and erlotinib given in combination in patients with NSCLC. The phase I portion of the trial did not show dose-limiting toxicities and the recommended dose was erlotinib 150 mg/d orally and bevacizumab 15 mg/kg intravenously every 21 days. A total of 40 patients were enrolled with a response rate of 20%, a median overall survival in 34 patients treated at the recommended dose of 12.6 months, and a PFS of 6.2 months. The authors rightly conclude that these results support the further development of this combination. Similarly, an ongoing study of bevacizumab and trastuzumab in patients with breast cancer overexpressing the HER-2 receptor has been shown to be safe and to have an encouraging response rate.132 In addition to the option of using anti-EGFR (or anti-HER-2) therapies in combination with anti-VEGF antibodies, there are now available a series of TKIs that block both the EGFR and HER-2 TKs on one hand and the VEGF receptor TK on the other.47,133 Whether it will be better to target the EGFR and VEGF receptor with two compounds, each targeting one system, or to use these new class of oral duals inhibitors, is not known at this time. SUMMARY The field of receptor-targeted therapy is rapidly evolving as new insights in receptor biology, as well as the results from a large number of clinical trials, are becoming available. Currently, these agents have an established role in NSCLC, pancreatic and colorectal cancer, and SCCHN, and, in the case of anti-HER-2 agents, in breast cancer. Important work needs to be done in the areas of patient selection (complementing and going beyond receptor mutations), selection of appropriate dose and schedules with new agents entering the clinic, and implementation of strategies to study the appropriate combinations both with conventional therapies as well as with other antisignaling agents. It is anticipated that the lessons learned in this area, in addition to moving the field of anti-EGFR therapy forward, will also be of assistance towards a more efficient development of the whole field of targeted therapy in cancer. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have 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. Consultant/Advisory Role: Jose Baselga, Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Roche; Carlos Arteaga, ACLARA BioSciences, Amgen, AstraZeneca, Bristol-Myers Squibb/Imclone, Eli Lilly, Sunesis. Honoraria: Jose Baselga, Amgen, GlaxoSmithKline, Merck, Roche. Research Funding: Jose Baselga, Bristol-Myers Squibb; Carlos Arteaga, Aventis, Eli Lilly, Genentech, Novartis, Telik. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue. NOTES Supported by a Spanish Science and Technology Ministry Grant SAF2003-03818 (J.B.), a Breast Cancer Research Foundation Grant (J.B.), National Institutes of Health R01 grant CA80915 (C.L.A.), Breast Cancer Specialized Program of Research Excellence (SPORE) Grant P50 CA98131, and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article. REFERENCES
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10%) was subsequently confirmed in this setting by another study.
150 mg/d, well below the maximum tolerated dose of 700 mg/d. Similar data have been obtained in skin biopsies of patients participating in clinical trials with other ATP-competitive inhibitors of the EGFR kinase such as erlotinib,
14 days of therapy with tamoxifen results in marked reduction of breast cancer proliferation as measured by Ki67 immunohistochemistry (IHC) in post-therapy tumor sections. Antiestrogen-induced inhibition of proliferation is limited to 