Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
* Correspondence to: Dr G. Giaccone, Department of Medical Oncology, Vrije Universiteit Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel: +31-20-4444321; Fax: +31-20-444079; Email: g.giaccone{at}vumc.nl
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Abstract |
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Key words: HER1/EGFR, Iressa, predictive marker, surrogate market, Tarceva, tyrosine kinase inhibitor
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Introduction |
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Preclinical and early clinical studies with HER1/EGFR-targeted agents were very encouraging. Various studies showed that these agents are selective for their target, active across many types of solid tumours and better tolerated than chemotherapy [1217
]. In addition, phase II trials showed they had clinical activity against a range of solid tumours. In particular, phase II trials of single-agent erlotinib or gefitinib in patients with advanced, refractory NSCLC and cetuximab in combination with irinotecan in advanced, refractory colorectal cancer were particularly encouraging [18
21
]. These findings showed that a proportion of patients (1030%) have major responses to these agents. These encouraging results prompted the initiation of large-scale phase III trials. At the forefront were trials examining gefitinib (INTACT 1 and 2) or erlotinib (TALENT and TRIBUTE), in combination with one of two standard chemotherapy regimens (gemcitabine and cisplatin or carboplatin and paclitaxel) for the first-line treatment of advanced NSCLC. Disappointingly, these studies failed to meet their primary endpoint of improvement in overall survival [22
25
]. Several hypotheses have been put forward to explain the outcome: (i) HER1/EGFR responsive patients were not pre-selected for therapy; (ii) an antagonistic effect resulting from concomitant use of chemotherapy with TK inhibitors; (iii) the chemotherapy and TK inhibitor may be targeting the same cell population and therefore this regimen has no added benefit; and (iv) no added benefit of a three-drug versus a two-drug regimen (as previously observed in patients with advanced NSCLC treated with chemotherapy) [26
28
].
Other phase III trials are examining HER1/EGFR-targeted agents in various indications and settings (Table 3). Importantly, based on evidence of activity in NSCLC, a randomised, double-blind, placebo-controlled phase III trial, conducted in collaboration with the NCIC, examined second/third-line erlotinib monotherapy 150 mg/day in patients with advanced, refractory NSCLC (BR.21). Preliminary analysis shows a clear survival benefit with erlotinib over placebo, as well as improved time to symptomatic deterioration, progression-free survival and response rate [29]. A similar trial of gefitinib in patients with advanced, refractory NSCLC is also in progress.
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Selecting the optimal dose for TK inhibitors |
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For orally administered agents, many factors influence the amount of active drug that eventually reaches the receptor. In particular, inter-patient differences can have a marked effect on the drug's absorption and metabolism and therefore can explain differences in toxicity as well as activity. Data from preclinical studies appear to confirm that higher plasma exposure produces greater inhibition of HER1/EGFR autophosphorylation [12, 13
, 32
]. Phase I studies have shown that administering TK inhibitors at the MTD results in higher plasma exposure, which may result in greater inhibition of HER1/EGFR activity. The plasma exposure (AUC024) with erlotinib given at 150 mg/day is 38.42 µg·h/ml [13
]. Similar exposure (36.08 µg·h/ml) is achieved with gefitinib at 700 mg/day, the approximate MTD [32
]. However, presently, gefitinib is administered at lower doses of 250 mg/day (registered dose) or 500 mg/day (used in some trials). So, TK inhibitors can be dosed at MTD, for the reasons outlined previously, or at a lower dose which, theoretically, is sufficient to inhibit the receptor, but avoids excess drug exposure so minimising toxicity [33
]. Current clinical data do not allow us to conclude which approach is optimal in terms of efficacy and toxicity. Further preclinical studies will help us understand receptor binding and downstream signalling, allowing clear definition of the dose level required to achieve complete binding and total inhibition.
Preclinical studies show both agents reach the cellular receptor; erlotinib effectively enters the tumour from the plasma (tumour:plasma ratio, 0.4), indicating high plasma exposure that results in high tumour exposure [12]. A study with gefitinib suggests that it is extensively distributed into tissue because of its high volume of distribution [34
]. At the maximal time point, the tumour to plasma ratio for gefitinib is high (tumor:plasma ratio = 4:14). Therefore, there may be differences between these two agents, although subtle, which could lead to different clinical outcomes. However, ongoing preclinical studies with both agents will clarify the relationship between plasma and tumour-drug concentration and clinical outcome.
Finally, phase II studies have shown that rash, the most commonly reported adverse event for HER1/EGFR targeted agents, may predict response/survival to both erlotinib and cetuximab [18, 35
]. However, the value of rash as an efficacy marker for gefitinib remains to be established. While some phase II trials show a correlation between rash and response [36
, 37
], others do not [38
]. This relationship is discussed in more detail later. As rash is dose related [13
, 32
], we can hypothesise that dosing to MTD may improve outcome. However, this hypothesis needs further study, as the concept of increasing toxicity to increase activity has been used in chemotherapy for decades and it may not be accurate. Clearly, dosing to MTD may increase the toxicity of these agents to a level similar to chemotherapy, although the side effects are clearly of a different nature.
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Identifying appropriate dosing schedules and combination regimens |
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Many preclinical studies have examined the effectiveness of combining HER1/EGFR TK inhibitors with chemotherapy, and several of these studies reported additive or synergistic activities [39, 40
]. However, the negative results of the gefitinib and erlotinib phase III combination trials as first-line therapy for NSCLC indicate that HER1/EGFR-targeted agents given concomitantly with chemotherapy are not effective. Sequencing drug delivery may be preferable, given the demonstrated efficacy of HER1/EGFR TK inhibitors as monotherapy.
As it is known that docetaxel causes M-phase cell-cycle arrest, it has been hypothesised that the specific cell-cycle effects of erlotinib and docetaxel may influence the cytotoxic response to different sequences of combined drug administrations [41]. In a preclinical study, human NSCLC cells were treated with erlotinib alone (1 µM, 24 h), docetaxel alone (50 nM, 18 h), both drugs simultaneously (24 h), or erlotinibdocetaxel and docetaxelerlotinib sequences. All combinations significantly induced cell-cycle arrest. However, the greatest degree of cell death or apoptosis was observed when erlotinib was delivered after docetaxel, supporting sequential use.
Recent preclinical studies with gefitinib have assessed the effectiveness of sequential delivery in combination with chemotherapy. In a human head and neck cancer cell line, sequential administration of gefitinib and cisplatin5-fluorouracil (5-FU) inhibited cell proliferation more effectively than either treatment alone [42]. In addition, sequential administration of gefitinib and paclitaxel was significantly more effective than continuous dosing at sensitising tumours to paclitaxel [43
]. Against this background, several clinical studies are ongoing/planned to examine sequential dosing regimens of erlotinib or gefitinib with chemotherapy in patients with various solid tumour types. Ongoing studies include a phase II study of chemoradiation followed by gefitinib in unresectable stage IIIA/B NSCLC and a phase II study with induction gefitinib and paclitaxel plus carboplatin followed either by radiotherapy or concomitant radiotherapy with once weekly paclitaxel plus carboplatin in stage II NSCLC. A phase II trial of gemcitabine plus cisplatin in sequence with gefitinib in patients with stage IIIA N2 NSCLC is ongoing in the European Organisation for Research and Treatment of Cancer (EORTC). Several studies are also ongoing, assessing the activity of single-agent erlotinib and gefitinib in first-line treatment of advanced NSCLC. Patients who do not benefit from this therapy will switch to combination chemotherapy. Eventually randomised studies will need to be performed to assess accurately the role of these agents in first-line therapy versus standard chemotherapy.
Obviously, the combination of several targeted therapies offers the advantage of targeting multiple pathways, as well as a better toxicity profile compared with conventional chemotherapy. HER1/EGFR TK inhibitors are at the forefront of the clinical development of targeted therapy and are therefore attractive partners for investigation with other agents. The combination of HER1/EGFR TK inhibitors with angiogenesis inhibitors is particularly interesting. Bevacizumab (AvastinTM), a humanised, recombinant anti-vascular endothelial growth factor (VEGF) MAb, has been recently approved by the Federal Drug Administration (FDA) in the USA in combination with 5-FU-based chemotherapy as a first-line therapy for patients with colorectal cancer [44]. Preclinical studies show that HER1/EGFR inhibitors prevent expression of VEGF, bFGF, TGF-
and IL-8 by tumour cells. Therefore, we can hypothesise that targeting both VEGF and HER1/EGFR should result in dual inhibition of the angiogenic system, which might maximise tumour-growth inhibition. Indeed, data show that combining bevacizumab with erlotinib has an additive inhibitory effect on the growth of human colon tumour xenografts [45
]. Gefitinib has also been shown to enhance the activity of another vascular targeting agent ZD6126 in colorectal cancer and NSCLC xenograft models [46
]. Against this background, a phase II trial of bevacizumab in combination with erlotinib was initiated in patients with advanced, recurrent NSCLC [47
]. Encouraging activity was observed and the most common adverse events (rash, diarrhoea and proteinuria) were never more than mild to moderate. In addition, preliminary data suggest that there is no pharmacokinetic interaction between these agents [47
]. Therefore, these data suggest that combining erlotinib with bevacizumab is feasible and warrants further investigation.
Further combinations of HER1/EGFR TK inhibitors and other targeted agents are being investigated. We hope these combinations will provide benefit for patients with hard-to-treat cancers. Key ongoing studies are examining HER1/EGFR TK inhibitors in combination with: bortezomib, a proteasome inhibitor; celecoxib and rofecoxib, cyclooxygenase-2 inhibitors; pemetrexed, an antifolate; bexarotene, a retinoid receptor (RXR) ligand; and pertuzumab and trastuzumzab, anti-HER2 MAbs.
Finally, recent preclinical data showing synergistic activity when a HER1/EGFR TK inhibitor and an anti-HER1/EGFR MAb are combined are particularly interesting. Gefitinib plus cetuximab had a greater than additive effect on cell proliferation, apoptosis and HER1/EGFR-dependent signalling, compared with either agent alone [48]. Examining this combination in a clinical trial is warranted.
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Predictive markers of response |
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Pérez-Soler and colleagues [56] examined molecular changes in response with erlotinib in six parental and chemoresistant cell lines, and molecular changes associated with acquired resistance to erlotinib. There was increased sensitivity to erlotinib in three chemoresistant cell lines and the IC50 for erlotinib was 420 times lower than in the corresponding parental cell lines. Expression of HER1/EGFR and pHER1/EGFR was higher in the chemoresistant than parental cell lines. All chemoresistant clones overexpressed fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) genes by 2.334.2- and 2.614.6-fold, respectively, compared with the parental cells. In vivo, tumour formation and growth were faster with the resistant than parental cells and associated with E- and C-cadherin downregulation. In general, it was found that increased sensitivity to erlotinib is associated with increases in HER1/EGFR expression and activated HER1/EGFR expression, and the expression of genes involved in other signalling pathways. These data also suggest that acquired resistance to chemotherapy may increase sensitivity to HER1/EGFR. Against this background, HER1/EGFR-targeted agents should be examined, particularly for patients with advanced disease that is refractory to chemotherapy. The findings also show that cross-resistance with chemotherapy is rare. In another study, tumour specimens from 31 patients collected prior to treatment with gefitinib were analysed using gene-expression profiling. Seven patients had a partial response and six patients had prolonged disease stabilisation. Expression of signal transducers and activators of transcription (STAT5A, STAT5B) and
-catenin correlated with clinical response.
One potential resistance gene [gefitinib-resistant gene 1 (GRG-1)] was expressed at higher levels in samples from patients with disease progression [57]. However, larger studies are required to confirm these preliminary data. We hope that further understanding of resistance mechanisms through state-of-the-art techniques, such as gene-expression profiling, will help us to identify critical marker(s) and allow us to select patients most likely to benefit from therapy with TK inhibitors.
Interestingly, individual patient characteristics may also predict outcome for HER1/EGFR-targeted agents. In IDEAL 1, a performance status (PS) of 01, prior immunotherapy/hormonal therapy, female gender and adenocarcinoma histology were all identified as prognosticators of objective response [19, 38
]. Of note, PS is a well-known predictor of response/survival following first-line chemotherapy in patients with NSCLC. Miller and colleagues [58
] analysed data from 140 patients with NSCLC treated with gefitinib monotherapy on a clinical trial (n=13) or compassionate use programme (n=127). Multivariate analysis found that BAC features (P=0.005) and being a never-smoker (P=0.007) were the only predictors of response to therapy [58
]. These data are supported by recent findings with erlotinib, which show that non-smoking patients with adenocarcinoma (with BAC features) are more likely to respond to therapy than individuals with adenocarcinoma (with BAC features) who have smoked (46% non-smokers versus 21% smokers; (P=0.09) [59
].
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Identifying surrogate markers of activity |
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Likewise, median survival of head and neck cancer patients with no grade 1 and grade 24 skin rash was 4.0, 5.0 and 7.4 months, respectively [61]. Overall, survival for patients with grades 24 skin rash was significantly longer compared with those with no rash (P=0.045). However, the difference was not statistically significant between patients with no rash and those with grade 1 rash (P=0.14) (Figure 2). Also, no relationship was found between the development and severity of rash and pharmacokinetic activity (median plasma concentration of erlotinib and its major metabolite OSI-420). Interestingly, however, a relationship was found between the median plasma concentration of both erlotinib and OSI-420 at 510-h post-dosing and survival [61
]. HER1/EGFR polymorphisms could be responsible for the differences in skin toxicity and tumour response among patients. Indeed, previous studies have shown a dinucleotide (CA) repeat polymorphism in intron 1 of HER1/EGFR, ranging from 14 to 21 repeats. It has been suggested that this polymorphism regulates HER1/EGFR expression and may play a crucial role in individual variability [62
, 63
]. Ongoing preclinical studies will give us a better understanding of the genetic polymorphisms of HER1/EGFR that may influence the efficacy and toxicity profile of HER1/EGFR TK inhibitors.
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A phase II trial of gefitinib at the higher recommended dose of 500 mg/day in patients with head and neck squamous cell cancer (HNSCC) found a strong correlation between skin toxicity and response (P=0.004), progression-free survival (P=0.0002) and overall survival (P=0.001) [36]. A recent study of patients treated with gefitinib on the compassionate use programme also found a strong correlation between skin rash and response/survival. Two hundred patients with stage III/IV, refractory disease were enrolled at the Dana Farber Partners Cancer Care Affiliated Institute, and had a median of two prior chemotherapy regimens (range 06). Only 156 patients were evaluable for response. Five of seven patients (71.4%) with a partial response and 35 of 60 patients (58.3%) with stable disease developed skin rash. Importantly, patients who developed any grade of skin rash survived significantly longer than those without rash (10 months versus 4.5 months, respectively; P <0.0001) [37
]. Another study analysed early-onset skin rash in patients enrolled in IDEAL 1 and 2 and found no significant difference in response rate between those with early-onset skin rash and those without [38
].
Results of a randomised study comparing cetuximab monotherapy with cetuximab plus irinotecan for patients with irinotecan-refractory metastatic colorectal cancer, show a correlation between skin rash and response rate/survival. Response rate and median survival were significantly greater in patients with rash than those without (25.8% versus 6.3% and 9.1 months versus 3 months for the combination therapy; 13% versus 0% and 8.1 months versus 2.5 months, for the monotherapy) [65]. Findings from four further trials of cetuximab alone or with chemotherapy in patients with colorectal, head and neck and pancreatic cancer also show a significant correlation between rash and survival (cetuximab and irinotecan in colorectal cancer, P=0.0001; cetuximab, P=0.06; cetuximab and cisplatin, P=0.004; cetuximab and gemcitabine, P=0.004) [35
].
In summary, the data reported so far for erlotinib and cetuximab in various indications and different clinical settings support a correlation between rash and survival. For gefitinib, some studies, but not all, support a correlation between rash and response/survival. The reasons for these differences are not clear, but they could be a result of different dosing strategies, pharmacokinetic or pharmacogenetic heterogeneity among patients, or different reporting methodologies [skin rash is not clearly defined in the Common Toxicity Criteria (CTC)]. It is also possible that there are distinct pharmacological differences across the class of TK inhibitors, which suggests that markers of response for these agents may be different amongst the various agents.
Overall, these findings imply that some individuals with less severe or no rash would benefit from dose escalation to increase rash severity, highlighting a potential for improving clinical outcome. Because of the possible impact of dosing to increase rash on future trials, a phase II multicentre trial of erlotinib in advanced, refractory NSCLC patients has been initiated to investigate whether dose escalation to induce tolerable rash in the absence of other severe toxicities is feasible. More studies are required to understand whether rash predicts for outcome with HER1/EGFR-targeted agents and whether this is a result of the mechanism of action of these agents or because it predicts for a more responsive tumour in general. It is likely that, as with chemotherapy, toxicity may predict sufficient body exposure, however, it will not reflect tumour sensitivity to the drug.
Many studies with HER1/EGFR-targeted agents show that skin could be a useful surrogate tissue for evaluating the pharmacodynamic effects of therapy and identifying easily quantifiable surrogate markers of activity. Various pharmacodynamic studies have assessed the effects of HER1/EGFR-targeted agents in skin samples [66, 67
]. However, it is probable that the extent of inhibition in the skin and target tumour is different, but this has so far been difficult to assess [68
]. To date, no reliable marker has been clearly identified, although studies support the use of p27 as a surrogate marker of response [33
, 67
]. Further studies are examining these markers in greater detail, and staining and quantification procedures need careful validation.
Other potential surrogate markers of activity are also being investigated. One potential marker identified in the IDEAL 1 and 2 trials is rapid improvement of disease-related symptoms [38]. Data from IDEAL 1 and 2 showed that 69% and 100% of patients with an objective response had improved symptoms. Given that palliation is the major goal in this patient population, reducing symptoms with minimal toxicity is of great importance.
Positron emission tomography (PET) is being investigated as a diagnostic tool. PET scans are being incorporated into phase II/III trials with various HER1/EGFR-targeted agents and these findings should provide more information on imaging as a marker of therapeutic efficacy.
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Molecular profiling: a breakthrough technology for the future |
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The type and locus of these mutations were similar in all three studies, suggesting a link with tumour development per se and maybe a direct relationship with NSCLC. Interestingly, most of the responsive patients with HER1/EGFR mutations were women who had never smoked, nearly half of whom had BAC. Japanese patients also showed an increased incidence of mutations [68]. Interestingly, these mutations were clustered around the active adenosine triphosphate (ATP) binding site and some of these mutations were also common in independent tumour samples.
Taken together, these studies show that 25 of 31 (81%) tumours from individuals who responded to gefitinib or erlotinib had mutations in the HER1/EGFR-TK domain (Table 4). Although this is a breakthrough, these results should be confirmed in larger investigations. It is possible that the samples are not representative of mutations in the EGFR gene at the time of treatment. Pre-exposure tissue samples were not available from all patients who responded to gefitinib, so mutations may have been induced by chemotherapy. However, samples were available from all patients who responded to erlotinib, making this scenario unlikely. In vitro induction of similar mutations in cell lines showed that they increased receptor activation compared with wild-type receptor [63] and in all three studies was associated with enhanced sensitivity to gefitinib and/or erlotinib. These studies suggest that the prevalence of such mutations in patients with NSCLC is around 813%, similar to the observed response rates with gefitinib [19
, 20
]. However, Paez et al. [68
] examined unselected NSCLC samples from patients not treated with gefitinib and found somatic TK mutations in 26% (15/58) of Japanese samples and only 2% (1/61) of US samples; this frequency of mutation is different from the response rate to gefitinib reported in Japanese and non-Japanese patients in a large phase II trial (27.5% and 10.1%, respectively) [19
]. A number of patients did not achieve the standard definition of a major response in either study, but nevertheless benefited substantially from treatment (improvement of symptoms and reduction in tumour measurements). Clinical experience with gefitinib, and other HER1/EGFR-targeted agents, indicates that patients with minor responses and stable disease also benefit, particularly in terms of improved quality of life. Given these data, it appears that TK mutations may not predict benefit in all patients. Furthermore, response does not always correlate well with survival, and factors that predict response to an agent may not necessarily predict survival accurately. Notwithstanding these limitations, it is a major discovery that mutations in the ATP-binding pocket of the TK domain of the EGFR gene predict major responses to gefitinib and erlotinib.
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Clearly more studies are warranted to confirm these results with other EGFR inhibitors and other tumour types.
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Summary |
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The influence of pharmacokinetics on treatment outcome remains to be established. In particular, further research is required before the optimal dosing strategy for HER1/EGFR-TK inhibitors is defined. Dosing at MTD ensures that a high plasma concentration is attained, but it is unclear at what concentration complete receptor and downstream signalling is achieved.
Phase III trials of erlotinib and gefitinib in NSCLC indicate that their concomitant use with chemotherapy does not provide additional benefit and ongoing studies are focusing on sequential administration. Preclinical sequencing data are encouraging and will hopefully translate to the clinical setting. Trials are also combining HER1/EGFR-targeted agents with other targeted therapies. Hopefully, clinical benefit will be derived through the targeting of multiple pathways and these regimens will be less toxic than conventional chemotherapy combinations.
The greatest challenge in optimising the use of TK inhibitors is posed by patient heterogeneity. Mounting evidence indicates that factors such as gender, tumour histology, smoking status and ethnicity predict for response, as do the activation of downstream signalling pathways such as MAPK, AKT and STAT. Of particular interest is the observation that, while current data cannot support the use of HER1/EGFR expression levels as a predictor of response, mutations in the receptor might be powerful predictors of clinical outcome.
It is hoped that well-conducted randomised controlled trials will continue to confirm the role of HER1/EGFR-targeted agents in the treatment of early and late-stage cancers and that gene-chip and array technologies will allow us to fully investigate predictors of response, allowing treatment to be tailored for individual patients based on genotype, tumour phenotype or other factors.
Received for publication July 19, 2004. Revision received October 26, 2004. Accepted for publication November 30, 2004.
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