Anti-EGFR Therapies: How to Select Patients



Anti-EGFR Therapies: How to Select Patients


Fred R. Hirsch

Tetsuya Mitsudomi

Pasi A. Jänne



Epidermal growth factor receptor (EGFR) inhibitors have proven effective in some patients with advanced non-small cell lung cancer (NSCLC) previously untreated and/or treated with chemotherapy.1 Most data are published on the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Objective response rates in phase II studies with gefitinib and erlotinib are 10% to 18% in western populations and up to 27% in Asian populations.2,3,4,5,6,7,8 In addition, a substantial fraction of NSCLC patients, who failed previous chemotherapy, achieve long-term stable disease (SD), leading to disease control rate (DCR) exceeding 50% of patients and often associated with symptomatic improvement and prolonged survival. Thus, developing a biomarker capable of predicting DCR is equally if not more important than one predicting only those who have objective response.

Two large placebo controlled randomized studies were performed with EGFR TKIs as second-or third-line therapy.6,7 The BR.21 study with erlotinib showed for the first time a survival benefit for a targeted therapy in NSCLC, whereas the Iressa Survival Evaluation in Lung Cancer (ISEL) study with gefitinib did not demonstrate a significant survival advantage, although subset analysis in the latter study did show survival benefit in certain clinical subgroups (i.e., never-smokers and Asians).7 In both studies, clinical effect of EGFR TKIs on survival was seen also in patients with “unfavorable” clinical characteristics (e.g., men, smokers, and patients with tumors of squamous histology).7,8 Thus, clinical features appear insufficient for identifying those patients who would and would not have survival benefit from these new agents.

After encouraging results of EGFR TKIs in relapsed patient categories, it was natural to test these drugs in combination with standard first-line chemotherapy of advanced NSCLC. In large prospective randomized studies, standard chemotherapy doublets were given in combination with EGFR TKIs or placebo, followed by maintenance with active drugs or placebo.9,10,11,12 No benefit from adding EGFR TKIs to standard chemotherapy was observed in any of the four studies, and again clinical characteristics (except for never-smoking status in the TRIBUTE study) could not identify subsets of patients who benefited from combination therapy.

Thus, the search for other measures (i.e., biomarkers) for selection of patients for the EGFR TKIs was mandatory.

The use of monoclonal antibodies, mainly cetuximab has been studied in NSCLC, and most recently the results from the FLEX (First Line in Lung Cancer with ErbituX) study, which is a comparison of cisplatin/vinorelbine with or without cetuximab in EGFR immunohistochemistry (IHC) positive was presented (see later).13 The latter study showed a survival benefit for patients having cetuximab added to the chemotherapy in first-line therapy for advanced NSCLC patients with EGFR protein-expressing tumors. Although the survival benefit (median survival, 11.3 vs. 10.1 months; hazard ratio [HR] = 0.87) was statistically significant, the efficacy seems not to be dramatically improved, and the study calls for a better biomarker selection of patients to this type of therapy. Another study (BMS 099), which compared chemotherapy with or without cetuximab as first-line therapy in advanced unselected NSCLC did not meet the primary end point of prolonged progression-free survival (PFS).14 Thus, selection of NSCLC patients to EGFR inhibitors based on EGFR markers might be crucial for outcome both with EGFR TKIs as well as with monoclonal antibodies. Potential clinical and molecular biomarkers for selection of patients to EGFR inhibitors for NSCLC is discussed later.


CLINICAL FACTORS

Early Clinical Trials In the phase I trials of gefitinib, tumor response was exclusively seen in NSCLC (4/16 in NSCLC and 0/48 in other types of cancer in United States/European study, 5/23 in NSCLC and 0/8 in other types of cancer in Japanese study).2,3 Especially in Japanese study, all four responders were with adenocarcinoma and three fourths were female patients.2


Two phase II trials of gefitinib, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2, showed that certain patient subgroups appeared to have a higher response rate, namely women, adenocarcinoma, and Japanese.4,5 In IDEAL 1 conducted in Japan and European countries, 210 patients with one or two prior chemotherapy regimens were randomly assigned either to have 250 or 500 mg of gefitinib. Objective tumor response rate was similar between the two groups (18.4% and 19.0% for 250- and 500-mg group, respectively). In contrast, adverse events were more common in the 500-mg group. In the 250-mg group, 15.5% of the patients had AEs requiring a short-treatment interruption, and none required a dose reduction, 28.3% and 10.4% of the patients in the 500-mg group required a treatment interruption and a dose reduction, respectively. Response rate was higher for Japanese patients than non-Japanese patients (27.5% vs. 10.4%; p = 0.0023). Multivariate analysis revealed that performance status (PS), sex, histology, and prior immuno/hormonal therapy were significant predictive factors at the 10% significance level. A similarly designed randomized phase II trial conducted in the United States (IDEAL 2) revealed that overall response rate was 10% (12% in 250-mg group and 9% in 500- mg group). In this trial, patients with stage IIIB/IV diseases, for which they had received at least two chemotherapy regimens, were eligible. Response rate was again higher in women (19%) than in men (3%), in adenocarcinomas (13%) than other histologic types (4%).

Miller et al.15 were the first to report that smoking history as well as bronchioloalveolar pathologic subtypes predict sensitivity to gefitinib. Overall, a partial radiographic response was observed in 21 (15%) of 139 patients with advanced NSCLC. Never-smokers have a significantly higher response rate than former/current smokers (36% vs. 8%; p <0.001).15 In addition, adenocarcinoma with bronchioloalveolar features had higher response rate (38%) than other adenocarcinomas (14%, p <0.001).5 Multivariate analysis confirmed that these two factors were independent predictors of response (p = 0.006 and 0.004, respectively). However, gender was not identified as a significant predictor in both univariate and multivariate analyses. The authors speculated that this was because of comigration of smoking and gender.15

Subsequent Studies Following this observation, various groups confirmed that response to gefitinib or erlotinib very much affected patients’ clinical backgrounds. In observation of over 4000 patients taken from previously published literature (Table 49.1), TKI response was dependent on smoking history (never-smokers 38% vs. former/current smokers 10%), gender (men 13% vs. women 36%), histologic type (adenocarcinoma 27% vs. nonadenocarcinoma 7%), and ethnicity (East Asians 29% vs. others 8%).

Several authors further showed that higher response rate was linked to longer survival in each patient subset. For example, Ando et al.16 showed that median survival time (MST) after gefitinib treatment was 16.6 and 7.7 months in female and male patients, 15.6 and 7.6 months in never-smokers and former/current smokers, and 12.1 and 6.3 months in patients with adenocarcinoma and with other histologic types, respectively. In addition, multivariate analysis by the Cox regression model revealed that women, no smoking history, adenocarcinoma as well as absence of metastatic disease, good PS, previous chest surgery are independent prognostic factors.16

Clinical Predictors in Randomized Phase III Trials Aforementioned trends were also seen in randomized controlled clinical trials. In four randomized trials comparing TKI plus platinum doublet chemotherapy versus platinum doublet chemotherapy, namely Iressa NSCLC Trial Assessing Combination Treatment (INTACT) 1 and 2 using gefitinib, TALENT and TRIBUTE using erlotinib, addition of TKI did not yield survival advantage over platinum doublet.9,10,11,12 However, subgroup analysis of TRIBUTE showed that addition of erlotinib to carboplatin plus paclitaxel confer an advantage in overall survival in patients who reported never smoking (MST, 23 vs. 10 months; HR, 0.49; 95% confidence interval [CI], 0.28 to 0.85).12 None of other factors including gender, race, PS, or histology were predictive for overall survival.12 The favorable predictive role of never smoking was also demonstrated for patients with bronchioloalveolar carcinomas (BAC).17

In a randomized, placebo-controlled trial to determine whether erlotinib prolongs survival in NSCLC patients after the failure of first-or second-line chemotherapy (BR.21), erlotinib significantly prolongs survival with MST of 6.7 versus 4.7 months (HR, 0.70; p <0.001).6In this trial, tumor response was significantly better in never-smokers than former/current smokers (25% vs. 4%; p <0.001).12 Furthermore, smoking history was an independent prognostic factor (p = 0.048), as well as erlotinib treatment (p = 0.002), Asian ethnicity (p = 0.01), and adenocarcinoma histology (p = 0.004). In their exploratory subgroup analyses, a benefit from erlotinib was dependent on smoking history, with HR of 0.9 (p = 0.14) in former/current smokers and 0.4 (p <0.001) in never-smokers.6

In contrast, similar placebo-controlled randomized trial using gefitinib in place of erlotinib, ISEL trial, failed to show overall survival advantage in gefitinib treatment group (median survival, 5.6 vs. 5.1 months; p = 0.087).7 However, gefitinib prolongs survival in never-smokers (MST, 8.9 vs. 6.1 months; p = 0.012) as well as in Asian patients (MST, 9.5 vs. 5.5 months; p = 0.010) in preplanned subset analyses.7

The results of two randomized phase II trials comparing gefitinib with docetaxel were recently reported. V15-32 conducted in Japan failed,18 but similarly designed Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST)19 was able to show noninferiority of gefitinib to docetaxel in patients with NSCLC having been treated with one or two chemotherapy regimens. None of clinical parameters such as sex, PS, smoking status, age, ethnicity (INTEREST only) significantly affected overall survival in the both trials.18,19 These somewhat unexpected observations are at least partly attributed to high crossover rate especially in V15-32, that is, 53% of patients with docetaxel arm received gefitinib upon progression and 36% of patients with gefitinib arm received docetaxel,18 whereas the rates were 31% and 37% in INTEREST,19 respectively. Other concern was that rates of nonsmokers were not equal in V15-32 (i.e., 29% of gefitinib arm were nonsmokers, whereas 36% of docetaxel arm were nonsmokers).18










TABLE 49.1 Relationship between Tumor Response and Clinical Parameters in Patients with Lung Cancer Treated with EGFR TKI






























































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Overall


Smoking


Gender


Histology


Ethnicity


Author Year


TKI


Design


N


CR+PR


RR




N


CR+PR


RR




N


CR+PR


RR




N


CR+PR


RR




N


CR+PR


RR


Fukuoka et al. 20034


G


Rand P-II


208


38


18


%



N/A







N/A






N/A




Asian


102


29


28


%























Other


108


11


10


%


Kris et al. 20035


G


Rand P-II


216


22


10


%



N/A





Male


123


4


3


%


Adeno


146


19


13


%













Female


93


18


19


%


Other


70


3


4


%


Perez-Soler 20048


E


P-II


57


7


12


%












Adeno


35


4


11


%


















Other


22


3


14


%


Takano et al. 2004158


G


Retro


98


32


33


%


NS


32


20


63


%


Male


66


15


23


%


Adeno


81


31


38


%


Asian


98


32


33


%








S


66


12


18


%


Female


32


17


53


%


Other


17


1


6


%


Kaneda et al. 200430


G


Retro


101


20


20


%


NS


55


15


33


%


Male


64


6


9


%


Adeno


81


20


25


%


Asian


101


20


20


%








S


46


5


9


%


Female


37


14


38


%


Other


20


0


0


%


Huang et al. 200468


G


Retro


16


9


56


%


NS


12


7


58


%


Male


4


2


50


%


Adeno


15


9


60


%


Asian


16


9


56


%








S


4


2


50


%


Female


12


5


42


%


Other


1


0


0


%


Miller et al. 200415


G


Retro


139


21


15


%


NS


36


13


36


%


Male


48


4


8


%


Adeno


108


21


19


%








S


103


8


8


%


Female


91


17


19


%


Other


31


0


0


%


Other


139


21


15


%


Kris et al. 200417


E


Retro


59


15


25


%


NS


19


7


37


%








S


21


4


19


%


Lim 2005154


G


Retro


110


35


32


%


NS


66


31


47


%


Male


52


10


19


%


Asian


110


35


47


%








S


44


4



%


Female


58


25


43


%


Shepherd et al. 20056


E


P-III


427


38


9


%


NS


93


23


25


%


Male


281


17


6


%


Adeno


209


29


14


%


Asian


53


10


19


%








S


311


12


4


%


Female


146


21


14


%


Other


218


9


4


%


Other


374


28


8


%


Kim et al. 200531


G


Retro


80


20


25


%


NS


17


10


59


%


Male


61


12


20


%


Adeno


39


16


41


%


Asian


80


20


25


%








S


63


10


16


%


Female


19


8


42


%


Other


41


4


10


%


Lee et al. 200520


G


P-II


36


25


69


%


NS


36


25


69


%


Male


3


1


33


%


Adeno


36


25


69


%


Asian


36


25


69


%








S


0


0


0


%


Female


33


24


73


%


Other





%


Mitsudomi et al. 200567


G


Retro


50


26


52


%


NS


25


17


68


%


Male


27


11


41


%


Adeno


43


25


58


%


Asian


50


26


52


%








S


25


9


36


%


Female


23


15


65


%


Other


7


1


14


%


Takano et al. 200561


G


Retro


66


35


53


%


NS


43


28


65


%


Male


40


17


43


%


Adeno


62


34


55


%


Asian


66


35


53


%








S


23


7


30


%


Female


26


18


69


%


Other


4


1


25


%


Cappuzzo et al. 200540


G


Prospective plus EAP


102


14


14


%


NS


15


6


40


%


Male


67


4


6


%


Adeno


63


11


17


%








S


87


8


9


%


Female


35


10


29


%


Other


39


3


8


%


Other


102


14


14


%


Han et al. 200570


G


Retro


90


22


24


%


NS


43


15


35


%


Male


54


8


15


%


Adeno


58


20


34


%


Asian


90


22


24


%








S


47


7


15


%


Female


36


14


39


%


Other


32


2


6


%


Zhang et al. 2005159


G


Retro


98


31


32


%


NS


58


25


43


%


Male


56


11


20


%


Adeno


75


31


41


%


Asian


98


31


32


%








S


37


6


16


%


Female


39


20


51


%


Other


20


0


0


%


Tokumo et al. 200569


G


Retro


21


10


48


%


NS


8


6


75


%


Male


13


6


46


%


Adeno


15


9


60


%


Asian


21


10


48


%








S


13


4


31


%


Female


8


4


50


%


Other


6


1


17


%


Thatcher et al. 20057


G


P-III


959


77


8


%


NS


204


37


18


%


Male




5


%


Adeno




11.9


%


Asian


209


26


12


%








S


755


40


5.3


%


Female




15


%


Other




4.8


%


Other


750


51


7


%


Tomizawa et al. 2005155


G


Retro


20


14


70


%


NS


11


10


91


%


Male


9


5


56


%


Adeno


18


13


72


%


Asian


20


14


70


%








S


9


4


44


%


Female


11


9


82


%


Other


2


1


50


%


Other


0


0


0


%


Ando et al. 200616


G


Retro


1713


348


20


%


NS


653


225


35


%


Male


1086


126


12


%


Adeno


1288


311


24


%


Asian


20


14


70


%








S


1012


116


12


%


Female


627


222


35


%


Other


414


34


8


%


Other


0


0


0


%


Niho et al. 2006160


G


P-II first line


40


12


30


%


NS


8


6


75


%


Male


24


3


13


%


Adeno


30


11


37


%


Asian


40


12


30


%








S


32


6


19


%


Female


16


9


56


%


Other


10


1


10


%


Suzuki et al. 2006156


G


P-II first line


34


9


27


%


NS


11


5


46


%


Male


21


2


10


%


Adeno


25


7


28


%


Asian


34


9


27


%








S


23


4


17


%


Female


13


7


54


%


Other


9


2


22


%


Satouchi et al. 2007157


G


Retro


221


54


24


%


NS


89


37


42


%


Male


142


20


14


%


Adeno


196


52


27


%


Asian


221


54


24


%








S


131


17


13


%


Female


79


34


43


%


Other


25


2


8


%


Other


0


0


0


%


Tamura et al. 200734


E


P-II


106


30


28


%


NS




51


%


Male




17


%


Adeno






Asian


106


30


28


%








S




14


%


Female




50


%


Other






Other


0


0


0


%


Total




4232


964


23


%


NS


1515


561


37


%


Male


2241


284


13


%


Adeno


2623


698


26.6


%


Asian


1571


463


29


%









S


2852


285


10


%


Female


1434


511


36


%


Other


988


68


7


%


Other


1473


125


8


%


CR, complete response; E, erlotinib; EAP, expanded access program; G, gefitinib; N/A, not applicable; NS, non-smoker; P-II, phase II study; P-III, phase III study; PR, partial response; Rand P-II, randomized phase II study; RR, response rate; S, smokers; TKI, tyrosine kinase inhibitor.



Clinical Trials for Patients Selected by Clinical Factors Prompted by these observations, Lee et al.20 conducted phase II trial to evaluate the efficacy of gefitinib as a first-line therapy in never-smokers with advanced or metastatic adenocarcinoma in Korea. Out of 36 patients who were assessable for response, 25 patients (69%) had partial response and 4 (19%) had stable disease, yielding 88% of disease control rate.16 This amazingly high rate could be achieved possibly because patients had a combination of three predictors of good response. Interestingly, they did not see difference in response between adenocarcinoma with bronchioloalveolar features (3/7, 43%) and that without bronchioloalveolar features (22/29, 76%) (p = 0.16).20

Although the contribution of each factor to the positive results is unknown, this study clearly supports the further study of EGFR TKI as a first-line therapy in certain subsets of NSCLC patients. This was prospectively investigated in Iressa Pan-Asia Study (IPASS), a phase III trial investigating gefitinib versus carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected subjects with stage IIIB/IV adenocarcinoma having no or light smoking history in East and South East Asia.21 The result was recently reported to be positive and details were discussed later in this chapter.

Histology As shown in Tables 49.1, response rate for patients with adenocarcinoma was 27% compared with 7% in patients with other histologic types. As discussed earlier, Miller et al.15 reported that patients with bronchioloalveolar histologic type predict sensitivity to gefitinib. Out of 139 NSCLC patients they reviewed, 21 (15%; 95% CI, 9% to 21%) experienced a partial radiographic response. In this study, the authors defined NSCLC of bronchioloalveolar subtype as adenocarcinoma with bronchioloalveolar features, bronchioloalveolar carcinoma with focal invasion, or pure bronchioloalveolar cancer. However, this definition of bronchioloalveolar features are not strictly followed to World Health Organization (WHO) criteria in which bronchioloalveolar cell carcinoma is defined as noninvasive, in situ carcinoma.15 However, these observations do not preclude patients with nonadenocarcinoma histology from candidates of EGFR-TKI therapy. In aforementioned BR.21 trial comparing erlotinib with best supportive care, patients with nonadenocarcinoma histology also had a survival benefit with an HR of 0.8 (p = 0.07).6

Adenosquamous carcinoma is defined as having components of both squamous cell carcinoma and adenocarcinoma with each comprising at least 10% of the tumor. Although the majority of patients with this histologic type are smokers, several investigators reported similar incidence of EGFR mutation in adenosquamous cell carcinoma, one of putative predictive markers as discussed later. For example, Kang et al.,22 Toyooka et al.,23 and Sasaki et al.24 reported that EGFR mutation was present in 11/25, 3/11, and 4/26 adenosquamous carcinomas, respectively. Although most patients were not treated with EGFR TKI, patients with adenosquamous histology harboring EGFR mutation can be candidates for EGFR-TKI therapy. Interestingly, these authors agree in that identical EGFR mutation is present in both squamous and adenocarcinoma components in the same adenosquamous tumor.22,23,24 In addition, at least a part of patients with squamous cell carcinoma who responded to EGFR TKI in the literature may, in fact, be those with squamous cell carcinoma with adenocarcinoma component with EGFR mutation.

Similarly, Fukui et al.25 reported that one of six patients with combined small cell carcinoma and adenocarcinoma of the lung had EGFR L858R mutation. This mutation was again present in both small cell and adenocarcinoma components.

Skin Toxicity Skin toxicity is most common adverse event relating to EGFR-TKI therapy. For example, during treatment with gefitinib 250 mg/day or erlotinib 150 mg/day, skin toxicity occurred in 62%4 and 75% of the patients.26 In a phase II trial of erlotinib, skin rash correlated with tumor response and overall survival. MSTs for patients without rash, those with grade 1, and those with grade 2 or 3 were 1.5, 8.5, and 19.6 months, respectively.8 Similarly, Jänne et al.27 reported a correlation between skin rash and survival in patients on an expanded access study. MST for patients with skin toxicity of any grade was 10 months that was significantly longer than 4.5 months for patients without skin toxicity (p = 0.0001).27

In general, data from multiple studies with cetuximab and erlotinib show a consistent relationship between rash and response/survival in NSCLC as well as other tumor types.28 However, this relationship is less consistent for gefitinib, reason for this discrepancy is currently not known.28

Other Clinical Factors Related to Efficacy of EGFR TKIs Several other factors are reported to be associated with response/survival of patients treated with gefitinib or erlotinib. These included absence of metastatic disease,16 good performance status,4,16,26,27,29,30 previous chest surgery,16 younger age,7,13 presence of prior platinum chemotherapy.6

Interstitial Lung Disease In Japan, considerable fraction of patients with gefitinib treatment suffer from fatal interstitial lung disease (ILD).32 Large multi-institutional retrospective analysis conducted by West Japan Clinical Oncology Group (WJOG) revealed that 70 (3.5%) cases and 31 deaths (1.6%) from gefitinib induced ILD among 1976 patients.16 In a prospective study conducted by AstraZeneca Japan, incidence of ILD was 5.81% (193/3322) and 83 died of disease (2.5% mortality).33 In combined analysis of two phase II studies of erlotinib monotherapy in Japan, ILD was observed 5 of 108 (4.6%).34 In WJOG study, gefitinib-induced ILD was significantly associated with male sex, smoking history, and coincidence of interstitial pneumonia.16 In AstraZeneca study, poor PS, smoking history, preexisting ILD, and prior history of chemotherapy were independently associated with ILD.33


However, incidence of ILD appears to be lower in other Asian countries than Japan except Taiwan. Chiu et al.35 from Taiwan reported that four patients with NSCLC having brain metastases out of 76 patients (5.8%) developed ILD. In contrast, ILD was observed in 3/485 patients treated with erlotinib compared with 3/242 patients in the placebo group in BR.21 study in which about 13% of patients are of Asian ethnicity.6 Similarly, the number of patients experiencing ILD as higher in Asian population than in the overall population; however, no difference was observed between the gefitinib and placebo groups (3% vs. 4%) in ISEL study in which about 20% of patients are of Asian ethnicity. 7 From Korea, no cases of gefitinib-related ILD was observed in 111 patients with advanced NSCLC on expanded access program. 29 It is difficult to understand difference of incidence of ILD among countries especially among several East Asian countries. However, variability in the criteria for ILD should exist making it difficult to estimate true incidence of gefitinib or erlotinib induced ILD among different countries. Therefore, eliminating patients with multiple risk factors for ILD from candidates of EGFR-TKI therapy is important for patient selection at least in several East Asian countries including Japan.


EGFR GENE COPY NUMBER

In breast cancer patients, amplification of the HER-2 gene (HER-2 is a member of the EGFR family) detected by fluorescence in situ hybridization (FISH) is a strong predictive factor for treatment benefit from anti-HER-2 monoclonal antibody, trastuzumab, and recommended for use in clinical practice.36 EGFR is an important signaling pathway for lung carcinogenesis37 and was demonstrated to have a negative prognostic impact.38,39 Thus, it was hypothesized that genomic gain of EGFR is a factor contributing to growth advantage of NSCLC cells and may be an important biomarker of sensitivity to EGFR TKIs. Investigators from the University of Colorado Cancer Center developed an original scoring system for EGFR gene copy number assessed by FISH in which tumors were classified into six categories, based on ascending number of gene copies per cell.40 FISH-negative samples were classified as those with no or low genomic gain (≥ four copies of the gene per cell in <40% of cells), and FISH-positive samples were defined as tumors with high gene copy number (≥ four copies of the gene per cell in ≥40% of cells) or gene amplification (tight gene clusters and a ratio of gene/chromosome per cell ≥2, or ≥15 gene copies per cell in ≥10% of the cells). To date, several major studies have addressed the association between EGFR gene copy number by FISH and treatment outcome to EGFR TKIs. All the published studies demonstrated clinically important treatment benefit in patients with high EGFR gene copy number with EGFR TKIs versus placebo, and this test is now being validated in prospective clinical studies in enriched population of NSCLC patients.

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Aug 25, 2016 | Posted by in CARDIOLOGY | Comments Off on Anti-EGFR Therapies: How to Select Patients

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