EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer

Lung Cancer 73 (2011) 249–255

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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Review

EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer Yaping Xu a , Yiping Zhang b , Shenglin Ma a,c,∗ a b c

Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, China

a r t i c l e

i n f o

Article history: Received 12 December 2010 Received in revised form 5 April 2011 Accepted 29 April 2011 Keywords: Non-small cell lung cancer Targeted therapy Epidermal growth factor receptor Tyrosine kinase inhibitor Monoclonal antibody Radiotherapy

a b s t r a c t Currently, a combination of chemotherapy and radiotherapy is the standard treatment approach for locally advanced non-small cell lung cancer (NSCLC). However, the clinical outcomes are still disappointing, with the 5-year survival rate being only approximately 20%. Further improvement in treatment outcome for patients with locally advanced NSCLC will require the development of more effective combined-modality therapies. Increasing attention has focused on the integration of targeted agents into current therapies. Many preclinical studies in this area have targeted the epidermal growth factor receptor (EGFR) signaling pathway to increase radiosensitivity. The in vitro rationale for targeting EGFR and concurrent ionizing radiation is well established, but to date, rare clinical data could provide proofof-principle. In this review article, we briefly discuss pre-clinical data and the rationale and report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to summarize the present state-of-the-art of this particular combination in NSCLC. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is the leading cause of cancer-related death in the world. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers. About one-third of patients present with locally advanced stage III NSCLC, the majority of whom have unresectable bulky disease or extensive mediastinal lymphadenopathy, making curative treatment a challenge. The current standard of care for patients with unresectable locally advanced NSCLC is concurrent chemotherapy and definitive thoracic radiation therapy (TRT); however, most treated individuals experience disease recurrence, with the 5-year survival rate being only ∼20% [1–3]. Further improvement in treatment outcome for patients with locally advanced NSCLC will require the development of more effective combined-modality therapies. Over the past 15 years, many advances have been made in understanding the cellular and molecular basis of carcinogenesis [4]. This work has allowed the identification of genetic and molecular alterations that are necessary for tumor growth and specific to only tumor cells. The progressive availability of new anticancer agents, including specific inhibitors of proteins generated from

∗ Corresponding author at: Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310006, China. Tel.: +86 571 87065701; fax: +86 571 87914773. E-mail address: [email protected] (S. Ma). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.04.017

these genomic alterations, has made a profound paradigm shift for the medical oncologist. Whereas conventional chemotherapy can effectively destroy tumor cells by interfering with metabolic pathways, the newer targeted therapies specifically inhibit the expression or activity of the proteins underlying cellular transformation and tumor proliferation [5]. Given its high incidence and mortality rate, NSCLC has been the subject of many studies to characterize the mechanisms leading to tumor initiation and progression. One of the main molecular alterations identified was the overexpression of the receptor to the epidermal growth factor (EGFR). EGFR plays a crucial role in cellular proliferation, inhibition of apoptosis, angiogenesis, metastasis, and chemoradioresistance [6]. Targeting the EGFR pathway is a well-established strategy and can be achieved either by monoclonal antibodies directed against the extracellular domain of the receptor or by small molecules that act by inhibiting EGFRspecific tyrosine kinases [7]. Stressors including irradiation can lead to autocrine secretion of the EGFR-ligand TGF-␣ and thereby to an activation of the receptor [8,9]. Although EGFR inhibitors in themselves are not curative in solid tumors, their combination with radiotherapy might improve local tumor control due to interactions between both treatments [10]. Currently, the in vitro rationale for targeting EGFR and concurrent ionizing radiation is well established, but to date, rare clinical data could provide proofof-principle. In this review article, we briefly discuss pre-clinical data and the rationale and report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to

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summarize the present state-of-the-art of this particular combination in NSCLC.

effect on the sensitivity to inhibitors of the EGFR [28,29]. Finally, there has also been some data to suggest that amplification of the EGFR may be associated with a better response to cetuximab [30].

2. Methods An English-language literature search was conducted. Data for this review were identified by searches of Medline and Cancerlit. The search terms ‘EGFR’, ‘tyrosine kinase inhibitor’, ‘monoclonal antibody’, ‘clinical trial’, ‘phase I’, ‘phase II’, ‘phase III’, ‘radiotherapy’ and ‘non-small cell lung cancer’ were used. References identified from within retrieved articles were also used. There was no limitation on the year of publication. 3. Role of EGFR inhibitors in NSCLC Expression of EGFR is found in 40–80% of NSCLC. In the clinic, the expression of the EGFR has been identified as an unfavorable prognostic factor in a meta-analysis including 14 studies primarily based on immunohistochemical data [11]. The frequent expression of the EGFR in NSCLC led to the development of selective pharmacological inhibitors of the tyrosine kinase of EGFR, including two the most studied agents that have obtained a permit for marketing gefitinib and erlotinib: gefitinib (Iressa® , ZD1839, AstraZeneca, United Kingdom) and erlotinib (Tarceva® , OSI774, Roche, Switzerland). EGFR inhibitor was shown to increase overall survival of NSCLC patients in a phase III trial [12]. However, unlike the use of HER2 expression as a prognostic marker for trastuzumab response in breast cancer patients, the expression of EGFR or its phosphorylated form (P-EGFR) by the tumor are not consistent predictors of the response to the EGFR inhibitors [13]. In 2004, several investigations showed that clinical findings corresponded to the existence of activating mutations of the tyrosine kinase domain of EGFR [14–16]. The presence of these mutations of EGFR has also recently been identified as an independent favorable prognostic factor in cases of advanced NSCLC [17–21]. All these mutations lead to constitutive activation of the EGFR kinase by altering the conformation of the binding domain of adenosine triphosphate, the substrate of tyrosine phosphorylation. Inhibitors of tyrosine kinase, originally synthesized to inhibit wild-type EGFR, occupy the same site as adenosine triphosphate. These activating mutations stabilize this region of the tyrosine kinase and make them more active, thereby making them better targets for the inhibitors. At the cellular level, these mutations cause an “oncogenic addiction” to the EGFR signaling pathway, whose activation is necessary and sufficient to sustain the proliferation of tumor cells. EGFR is therefore the true transformational agent for these cells, since its inhibition by targeted inhibitors leads to apoptosis [22]. This concept of “oncogenic addiction” has also been confirmed in the clinic in cases of NSCLC with activating mutations of EGFR, where patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKI) showed a rapid and complete response [23]. More recently, cetuximab (Erbitux® , IMC225, Bristol-MyersSquibb, USA), an anti-EGFR monoclonal antibody, originally developed for refractory colorectal cancer in combination with irinotecan, was evaluated in advanced NSCLC, either alone [24] or in combination with carboplatin and paclitaxel or carboplatin and gemcitabine [25,26]. Following the results of a randomized trial which showed 1 year survival benefit of 5% when the agent was used in combination with cisplatin and vinorelbine in advanced NSCLC [27]. These studies highlighted the lack of correlation between the response to cetuximab and the expression of EGFR mutations, contrary to what is observed for gefitinib or erlotinib. The factors that determine the efficacy of cetuximab in NSCLC are currently unknown, although a few studies have suggested that KRAS may be associated with resistance to cetuximab, similar to their

4. Rationale and preclinical studies of combination treatment with radiotherapy and EGFR inhibitors From the observation that irradiation can activate the EGFR, and from the correlation of EGFR expression with local tumor control in preclinical and clinical studies, the combination of radiotherapy or radiochemotherapy with inhibitors of the EGFR appears to be a rational and highly promising avenue for cancer research. In fact radiotherapy might be an optimal modality for integration with such targeted approaches. First, overexpression of EGFR in xenograft models of some carcinoma is associated with resistance to the cytotoxic effects of irradiation [31]. Second, in vitro, irradiation leads to autophosphorylation of the EGFR in various cell lines [32], resulting in an increase in cell proliferation [33], suggesting that the EGFR may have a role in radiation-induced tumor repopulation. Third, specific targeting of tumor cells by EGFR inhibitors could allow for an increase in the effects of radiation on the tumor, while preserving healthy cells from the radiation-induced side effects [34]. EGFR tyrosine kinase inhibitors have been extensively evaluated in combination with standard chemotherapy regimens in chemotherapy-naive patients with advanced NSCLC with no benefit in the response rate, Progression-free survival (PFS) or overall survival (OS) [35–38]. One possible explanation is that EGFR tyrosine kinase inhibitors induce cell cycle arrest in the G1 phase, which makes the cells less sensitive to cytotoxic agents. In vitro, the radiosensitization induced by gefitinib, regardless of whether they overexpress the EGFR, is between 1.2 and 1.6 [34,39]. The mechanism of this radiosensitization occurs as a result of several effects: first, the stimulation of the intrinsic apoptotic pathway; second, induction of cell cycle arrest in G0/G1, thereby reducing the number of cells in the S phase, which are more resistant to the effects of ionizing radiation. Gefitinib activity causes an increase of p27(Kip1) stability that correlates with Jab1 down-regulation leading to the gefitinib-triggered G1 cell cycle block and apoptosis [39–41]; third, by inhibiting the repair of double-strand DNA breaks induced by irradiation [32]. However, the cell lines with activating mutations of EGFR are more sensitive to the pro-apoptotic effects of radiation, even in the absence of exposure to these inhibitors [42]. These data are not contradictory if one considers the “oncogenic shock” model, in which cells carrying mutations of EGFR have a balanced activation of pro-and anti-apoptotic signals that can be quickly be tipped in favor of apoptosis following exposure to inhibitors of the EGFR, or also to ionizing radiation [43]. 5. Clinical studies of combination treatment with radiotherapy and EGFR inhibitors 5.1. Tyrosine kinase inhibitors (TKI): gefitinib and erlotinib All the data concerning combining TKI with TRT in clinical trials are summarized in Table 1. Seven studies have evaluated the feasibility of their combination with radiotherapy. Okamoto’s feasibility study assessed the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive TRT in patients with unresectable NSCLC of stage III [44]. Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were

Table 1 Tyrosine kinase inhibitors against EGFR and TRT in clinical trials. Trial

Phase

Okamoto et al. [44]

A feasibility study

Center et al. [45]

I

Rothschild et al. [46]

I

A tolerability study

Ready et al. [48]

II

Choong et al. [50]

Martinez et al. [51]

I

II

Patients

TKI

Chemotherapy

RT

DLT

7

Gefitinib

None

60 Gy

NR

16

Gefitinib

Docetaxel at escalating doses from 15 to 30 mg/m2

70 Gy

A

5

Gefitinib

None

63 Gy

Docetaxel dose of 25 mg/m2 None

B

9

Concurrent chemotherapy: cisplatin

23

Gefitinib

A

21

Gefitinib

B

39

A

17

B

17

A B

10 13

Erlotinib at escalating dose from 50 to 150 mg/day

None Erlotinib

Induction chemotherapy: carboplatin/irinotecan/paclitaxel; concurrent chemotherapy: carboplatin/paclitaxel Induction chemotherapy: carboplatin/paclitaxel

Induction and concurrent chemotherapy: carboplatin/paclitaxel Concurrent chemotherapy: cisplatin/etoposide; consolidate chemotherapy: docetaxel Induction and concurrent chemotherapy: carboplatin/paclitaxel None

22.2%

74 Gy

NR

66 Gy

NR

66 Gy

66 Gy

Grades 3–4–5 primary toxicities

Elevated ALT 33%; elevated AST 33%; pneumonitis 11% Hematologic toxicity 27%; esophageal toxicity 27%; pulmonary toxicities 20% Vomiting 20% Vomiting 22%, diarrhea 11%; asthenia 22%; epilepsy 11%; cataract 11%; elevated liver enzymes 11%; hematologic toxicity 11%; infection 22%; esophagitis 22%; pulmonary toxicities 11% Hematologic toxicity 19%; esophagitis 19.5%; cardiac arrhythmia 9.5% Acute high-grade infield toxicities were not clearly increased compared with historical CRT data.

Efficacy

RR

Survival

57%

MOS 11.5 months MOS 21 months

46%

21.4%

MOS 382 days

NR

MOS 16 months

53%

MOS 19 months

81%

MOS 13 months

65%

MOS 10.2 months

5.9%

Esophagitis 17.6%; vomiting 5.9%; ototoxicity 5.9%; diarrhea 11.8%; dehydration 17.6%; pneumonitis 5.9% Esophagitis 35.3%

59%

MOS 13.7 months

NR NR

Pneumonitis 10%; radiodermitis 8%;

55.5% 83.3%

NR NR

5.9%

Y. Xu et al. / Lung Cancer 73 (2011) 249–255

Stinchcombe et al. [47]

Group

Abbreviations: TKI = tyrosine kinase inhibitor; DLT = dose-limiting toxicity; RT = radiation therapy; RR = response rate; MOS = median overall survival; NR = not report.

251

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unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of >5 years. A phase I study assessed the effect of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional TRT followed by consolidative docetaxel and maintenance gefitinib for patients with stage III NSCLC [45]. Sixteen patients received three-dimensional conformal TRT to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. The overall response rate was 46%, and the median survival for all patients was 21 months. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2 , resulting in a maximum tolerated dose of 20 mg/(m2 week). Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The author concluded that concurrent TRT with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2 . More recently, another phase I study assessed the feasibility and tolerability of gefitinib with radiation or concurrent chemoradiation with cisplatin in patients with advanced NSCLC [46]. In this multicenter Phase I study, 5 patients with unresectable NSCLC received 250 mg gefitinib daily starting 1 week before radiation at a dose of 63 Gy (Step 1). After a first safety analysis, 9 patients were treated daily with 250 mg gefitinib plus chemoradiation in the form of radiation and weekly cisplatin 35 mg/m2 (Step 2). Fourteen patients were assessed in the two steps. In Step 1 (five patients were administered only gefitinib and radiation), no lung toxicities were seen, and there was no dose-limiting toxicity. Adverse events were skin and subcutaneous tissue reactions, limited to Grade 1–2. In Step 2, two of nine patients (22.2%) had dose-limiting toxicity. One patient suffered from dyspnea and dehydration associated with neutropenic pneumonia, and another showed elevated liver enzymes. In both steps combined, 5 of 14 patients (35.7%) experienced one or more treatment interruptions. In another tolerability study [47], Stage III NSCLC with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] of 5, irinotecan 100 mg/m2 , and paclitaxel 175 mg/m2 days 1 and 22) with pegfilgrastim support followed by concurrent chemotherapy (carboplatin AUC 2, and paclitaxel 45 mg/m2 weekly) and gefitinib 250 mg daily beginning on day 43 with three-dimensional conformal TRT to 74 Gy. 23 patients received treatment on the trial. Induction chemotherapy with pegfilgrastim support was well tolerated and active (partial response rate, 24%; stable disease, 76%; early progression, 0%). Twenty-one patients initiated the concurrent chemoradiation, and 20 patients completed therapy to 74 Gy. The primary toxicities of concurrent chemoradiation were grade 3 esophagitis (19.5%) and cardiac arrhythmia (atrial fibrillation) (9.5%). The median PFS and OS were 9 months (95% confidence intervals [CI]: 7–13 months) and 16 months (95% CI: 10–20 months), respectively. The author concluded that treatment with induction chemotherapy and gefitinib concurrent with 3-dimensional conformal TRT has an acceptable toxicity and tolerability, but the survival results were disappointing. The CALGB 30106 trial is a Phase II trial evaluating

the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III NSCLC [48]. In this trail, all patients received two cycles of paclitaxel (200 mg/m2 ) and carboplatin (AUC 6) plus gefitinib (250 mg daily). Poor-risk stratum 1 (≥5% weight loss and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily. Good-risk stratum 2 (<5% weight loss and performance status 0–1) received the same radiotherapy with gefitinib 250 mg daily and paclitaxel 50 mg/m2 weekly plus carboplatin AUC 2. Consolidation gefitinib until progression was started after all toxicities were grade ≤2. It was observed that acute high-grade infield toxicities were not significantly increased compared with historical CRT data. Poor-risk (N = 21) median PFS was 13.4 months (95% CI: 6.4–25.2) and median OS 19.0 months (95% CI: 9.9–28.4). Goodrisk (N = 39) median PFS was 9.2 months (95% CI: 6.7–12.2), and median OS was 13 months (95% CI: 8.5–17.2). Thirteen of 45 tumors analyzed had activating EGFR mutations and two of the 13 tumors also had T790 M mutations. There was no apparent survival difference with EGFR-activating mutations versus wild type. These findings indicate that the survival of poor-risk patients with wildtype or mutated EGFR receiving sequential CRT with gefitinib was promising, but the survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations. Currently, a follow-up phase II trial in poor-risk patients has been conducted to test the hypothesis that small molecule inhibition of EGFR with radiation alone is beneficial in stage III NSCLC (CALGB 30605). The results for good-risk patients in this trial receiving gefitinib as part of a concurrent CRT regimen are consistent with the inferior survival seen when gefitinib is given as maintenance therapy after concurrent CRT for stage III NSCLC in SWOG S0023 [49]. The mechanism for inferior survival when gefitinib is given after or during CRT in stage III NSCLC is unknown. One could hypothesize that the inhibition of multiple molecular pathways by the multitargeted small molecule gefitinib may be antagonistic with CRT although this hypothesis needs to be tested [48,49]. Choong’s study is a phase I trial of erlotinib-based multimodality therapy for inoperable stage III NSCLC [50]. Patients with unresectable stage III NSCLC were enrolled in this 2-arm doseescalation study. Erlotinib, given only during CRT, was escalated from 50 to 150 mg/day in 3–6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m2 IV days 1, 8, 29, 36), etoposide (50 mg/m2 IV days 1–5, 29–33) and chest radiotherapy (66 Gy, 2 Gy/day) followed by docetaxel (75 mg/m2 IV Q 21 days) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m2 ) for two 21-day cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/week) and paclitaxel (50 mg/(m2 week)). Seventeen patients were treated in each arm. Dose-escalation of erlotinib to 150 mg/day was possible on both CRT regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 CRT toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash was 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference. Addition of standard-dose erlotinib to CRT is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach. Recently, a phase II randomized trial assessed the possibility of using concomitant erlotinib and standard radiation (to a total dose of 66 Gy) in 30 patients with unresectable NSCLC who had one contraindication to chemotherapy [51]. Erlotinib was continued during maintenance treatment for 6 months for patients who had received concomitant

radiotherapy. The rates of esophageal, skin and lung toxicity were lower in the combination arm than in the patients treated with radiation alone (23% vs. 40%, 50% vs. 8%, and 8% vs. 20%, respectively). However, the response rate was significantly higher in patients treated with erlotinib (83% vs. 56%).

MOS 22 months

MOS 22 months

MOS 22.7 months

MOS >12 months

NR Cetuximab 51 B

NR 70 Gy None 48 A II

Abbreviations: TKI = tyrosine kinase inhibitor; DLT = dose-limiting toxicity; RT = radiation therapy; RR = response rate; MOS = median overall survival; NR = not report.

71%

73%

62%

Hematologic toxicity 20%; esophagitis 8%; pneumonitis 7% Neutropenia 40%; febrile neutropenia 8%; thrombocytopenia 36%; nausea/vomiting 8%; esophagitis 32%; skin rash 2%; fatigue 22% Neutropenia 47%; febrile neutropenia 36%; thrombocytopenia 34%; nausea/vomiting 10%; esophagitis 24%; skin rash 21%; fatigue 17% NR

Group

Cetuximab 87 II

Blumenschein et al. [54] Govindan et al. [56]

63 Gy

RR

70% Lethargy 8.3%; pneumonitis 8.3% NR 64 Gy

Induction chemotherapy: platinum-based Concurrent and consolidate chemotherapy: carboplatin/paclitaxel Concurrent and consolidate chemotherapy: carboplatin/pemetrexed Cetuximab 12 I Hughes et al. [53]

RT Chemotherapy Monoclonal antibodies Phase

Patients

253

5.2. Monoclonal antibodies (MoAbs): cetuximab

Trial

Table 2 Monoclonal antibodies against EGFR and TRT in clinical trials.

DLT

Grades 3–4–5 primary toxicities

Efficacy

Survival

Y. Xu et al. / Lung Cancer 73 (2011) 249–255

All the data concerning combining cetuximab with TRT in clinical trials are summarized in Table 2. However, three studies have shown the potential of combining cetuximab with radiotherapy for lung cancer. For example, the results obtained in patients with squamous cell carcinoma of the head and neck carcinomas showed improvement in local control and overall survival [52]. Cetuximab alone was first evaluated at the full dose (initial doses of 400 mg/m2 and 250 mg/m2 weekly), in combination with standard radiation to a total dose of 64 Gy in stage III NSCLC [53]. In this preliminary study including 12 patients, severe pulmonary toxicity was observed in only three patients. In response to these results, the RTOG 0324 trial evaluated the combination of cetuximab and chemotherapy with carboplatin and paclitaxel, with concurrent radiation to a total dose of 60 Gy in patients with unresectable stage III NSCLC [54]. Patients received an initial dose of cetuximab followed by a weekly dose of cetuximab given concurrently with weekly paclitaxel, carboplatin, and 7 weeks of daily radiotherapy. Patients then received cetuximab once a week for 3 weeks followed by consolidation therapy of 6 weeks of cetuximab, paclitaxel, and carboplatin administered once a week. The RTOG 0324 showed a median survival of 22.7 months and a 2-year overall survival rate of 49.3%, which were higher than those achieved in past RTOG studies and highlights the potential use of cetuximab with chemoradiation in patients with unresectable NSCLC. Of interest, the response rate was higher in patients whose tumors had amplification of the EGFR as measured by FISH [55]. CALGB 30407 is a randomized phase II trial studied carboplatin, pemetrexed and thoracic radiation (70 Gy) with or without cetuximab in 99 patients with unresectable stage III NSCLC [56]. Patients in both arms received four cycles of consolidation therapy with pemetrexed. Compared to historic controls, survival was improved in both arms but similar in both treatment arms. Median survival times were 19 and 22 months, respectively, and response rates were 71% and 73%, respectively. 6. Conclusion Given the strong preclinical rationale for combining EGFR inhibitors with radiation, additional studies are crucial. However, phase I/II data and lack of long-term experience suggest that physicians should consider combined modality approaches with caution, considering uncommon but potentially severe toxicity. A more thorough understanding of underlying mechanisms is required in order to optimize EGFR targeting in radiotherapy settings. EGFRTKI with radiation-based treatment is still not of proven benefit in NSCLC and thus should only be done in the context of an approved clinical trial. Routine use of EGFR-TKIs with radiation in stage III disease outside of a clinical trial should be avoided. Recent data have demonstrated that testing patients for EGFR mutation is critical for proper selection when choosing a firstline therapy. Four large phase III trials compared the EGFR-TKI gefitinib versus standard platinum-based chemotherapy in firstline metastatic NSCLC [18–21]. All trials demonstrated that in NSCLC patients with EGFR mutations gefitinib produced a higher response rates and longer PFS than standard chemotherapy, further supporting the use of an EGFR-TKI in the first-line setting in selected patients. Further development of EGFR-TKI treatment in

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