Oncology Research, Vol. 21, pp. 181–191 Printed in the USA. All rights reserved. Copyright Ó 2014 Cognizant Comm. Corp.

0965-0407/14 $90.00 + .00 DOI: http://dx.doi.org/10.3727/096504014X13887748696743 E-ISSN 1555-3906 www.cognizantcommunication.com

Phase II Study of Bevacizumab, Capecitabine, and Oxaliplatin Followed by Bevacizumab Plus Erlotinib as First-Line Therapy in Metastatic Colorectal Cancer Alberto Muñoz,* Carles Pericay,† Carlos García-Girón,‡ Vicente Alonso,§ Rosario Dueñas,¶ Luis Cirera,# Fernando Rivera,** Esther Falcó,†† Iñaki Alvarez Bustos,‡‡ and Antonieta Salud§§ *Hospital de Cruces, Barakaldo, Spain †Hospital Parc Taulí, Sabadell, Spain ‡Hospital General Yagüe, Burgos, Spain §Hospital Miguel Servet, Zaragoza, Spain ¶Complejo Hospitalario de Jaén, Jaén, Spain #Hospital Mutua de Terrasa, Terrassa, Spain **Hospital Marqués de Valdecilla, Santander, Spain ††Hospital Son Llatzer, Carretera Manacor, Palma, Mallorca, Spain ‡‡Hospital San Jorge, Huesca, Spain §§Hospital Arnau de Vilanova, Lérida, Lleida, Spain

This phase II trial investigated the efficacy of an induction regimen of bevacizumab, capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib as first-line therapy in patients with metastatic colorectal cancer. Patients with metastatic colorectal cancer received intravenous bevacizumab 7.5 mg/kg plus oxaliplatin 130 mg/m2 on day 1 followed by oral capecitabine 1,000 mg/m2 twice daily on days 1–14 every 3 weeks for six cycles. In the absence of disease progression, patients then received bevacizumab 7.5 mg/kg every 3 weeks plus oral erlotinib 150 mg once daily. The primary study endpoint was progressionfree survival. In the intention-to-treat population (n = 90), the median progression-free survival was 9.2 [95% confidence interval (CI): 7.9–11.9] months, and the median overall survival was 25.8 (95% CI: 18.0–30.9) months. In the patient subpopulation who received both induction and maintenance therapy (n = 52), median progression-free survival was 11.1 (95% CI: 9.0–15.7) months, and the median overall survival was 29.5 (95% CI: 23.7–36.7) months. KRAS status did not predict efficacy. The most common grade 3/4 adverse events were diarrhea, asthenia, and neutropenia. XELOX–bevacizumab for 6 cycles followed by bevacizumab–erlotinib maintenance therapy has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer. Key words: Bevacizumab; Capecitabine; Oxaliplatin; Metastatic colorectal cancer

INTRODUCTION Oxaliplatin is an effective and valuable cytotoxic agent for the treatment of metastatic colorectal cancer (1,2). However, a key issue for oncologists is how best to minimize oxaliplatin-related neurotoxicity while maintaining the efficacy of oxaliplatin-containing regimens. It has been observed that the median time to response with oxaliplatin-based chemotherapy is 2 to 5 months (1,3), whereas neurotoxicity occurs somewhat later (4 to 6 months) (2–4). Therefore, an abbreviated induction regimen with oxaliplatin-based chemotherapy followed by maintenance therapy seems to be a logical approach. OPTIMOX-1 and OPTIMOX-2 have recently documented the feasibility of

12 weeks of induction therapy with FOLFOX-7, followed by maintenance therapy with 5-fluorouracil/leucovorin for 24 weeks (5,6). The use of targeted agents as maintenance therapy, following oxaliplatin-based induction therapy, is currently being investigated in other several major trials (i.e., MACRO, DREAM, and OPTIMOX-3). The present phase II trial was conducted to assess the feasibility and efficacy of induction therapy with bevacizumab combined with capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib in patients with previously untreated metastatic colorectal cancer. The rationale for combining bevacizumab and erlotinib as maintenance therapy is to

Address correspondence to Dr. Alberto Muñoz, Hospital de Cruces, Plaza de Cruces, 12, 48903 San Vicente de Barakaldo, Vizcaya, Spain. Tel: +34-944-85-00-86; Fax: +34-944-99-29-45; E-mail: [email protected]

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block different routes of cell proliferation, that is, the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways. The validity of this approach has been confirmed clinically in other solid tumors (7–12). The predictive value of KRAS mutations was also investigated in the present study. MATERIALS AND METHODS Study Design This was an open-labeled, single-armed, nonrandomized, multicenter phase II trial. The study was performed in accordance with the Declaration of Helsinki. Approval of the protocol was obtained at each participating site from an ethics committee (Central Ethics Committee from Hospital General Yagüe, Burgos). All patients were required to provide informed consent prior to study enrolment (EudraCT No.: 2005-004662-169). Patient Population Outpatients aged 18 to 70 years with histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum, at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumours (RECIST), an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of at least 3 months were enrolled. Patients were required to have adequate hematological, hepatic, and renal function. No prior systemic therapy for metastatic disease, previous treatment with any study drug, or any other anti-EGFR or anti-VEGF agent was allowed. (Neo)adjuvant therapy was permitted if completed at least 6 months before initiating the study treatment. Radiotherapy or surgery for metastatic colorectal cancer was permitted if completed at least 4 weeks before enrolment. Exclusion criteria included known hypersensitivity to any of the study drugs; untreated cerebral metastasis, spinal cord compression, or primary brain tumors; CNS disease; clinically significant cardiovascular disease; confirmed peripheral neuropathy of grade 1 or greater; significant ophthalmologic anomalies; lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication; allogeneic blood transplantation; unhealed bone fractures, severe wounds, or ulcers; history of bleeding diathesis or coagulation disorders; recent or current use of full-dose anticoagulants or thrombolytic agents; and chronic daily treatment with high-dose aspirin (>325 mg/day) or nonsteroidal anti-inflammatory drugs. Pregnant or breast-feeding women were also excluded. Treatment Plan Induction therapy consisted of bevacizumab 7.5 mg/kg given as a 30- to 90-min intravenous infusion followed by oxaliplatin 130 mg/m2 given as a 2-h intravenous infusion on day 1 followed by oral capecitabine 1,000 mg/m2

Muñoz ET AL.

twice daily on days 1 to 14 every 3 weeks for a total of 6 cycles. If there was no evidence of disease progression, patients received maintenance therapy with bevacizumab 7.5 mg/kg once every 3 weeks and oral erlotinib 150 mg once daily until disease progression, unacceptable toxicity, withdrawal of patient consent, or physician decision. In case of adverse events, treatment delays or dose reductions were performed per the study protocol. If the study treatment was interrupted for more than 3 weeks because of toxicity, the patient was withdrawn from the study. Oxaliplatin alone could be interrupted for 1 cycle if a patient presented with paresthesia associated with pain or functional impairment. If the patient had not recovered by the following cycle, oxaliplatin was stopped. Administration of second-line therapy was permitted after the end of the study. Irinotecan monotherapy or  combination therapy with irinotecan and infusional 5-fluorouracil was recommended. Assessments Medical history, physical examination, routine blood analysis (hematology and chemistry), and urinalysis were performed within 7 days before study entry. During treatment, physical examination, hematology and biochemistry analyses, and urinalysis were repeated on day 1 of every treatment cycle. ECG measurements were taken within 21 days before study entry and, if clinically indicated, during treatment. Tumor assessments (CT scan, MRI, X-ray) and measurement of carcinoembryonic antigen (CEA) were performed within 28 days of starting study treatment and were repeated after every 9 weeks of therapy. The same imaging techniques were used at baseline and for later evaluations. RECIST guidelines (13) were used to define all responses. Confirmation of response was required after at least 4 weeks. After completion of study treatment, patients were followed-up every 12 weeks until disease progression, death, or initiation of a new anticancer treatment. KRAS mutational analysis was not a standard procedure to select therapy at the time of the study and was performed on tumor samples from 66 patients (73%). Testing was performed at each participating center using standard local procedures. Correlations with efficacy were performed centrally. Patients were evaluated for adverse events during therapy and until 30 days after the last dose of study medication. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3. Statistical Analysis The primary efficacy analysis was performed in the intention-to-treat population, which included all patients enrolled in the study. Tumor response was assessed in the

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XELOX–BEVACIZUMAB®BEVACIZUMAB–ERLOTINIB IN mCRC

evaluable population, defined as eligible patients without major protocol violations who had at least one evaluation after at least three treatment cycles. The safety population was defined as all patients who received at least one dose of the study treatment. Progression-free survival, the primary study endpoint, was defined as the time from the day of the study enrolment to disease progression or death because of progressive disease. Secondary study endpoints were overall response rate, overall survival (defined as the time from the study enrolment to the date of death), and safety. Patients lost to follow-up were censored on the date of the last follow-up visit. Time-to-event endpoints were analyzed using the Kaplan–Meier method and were presented as median values with 95% confidence intervals (CIs). An exploratory analysis of efficacy endpoints by KRAS mutation status was performed. The median progression-free survival for the XELOX regimen when given as first-line therapy in patients with metastatic colorectal cancer is 7.7 months (14). It was estimated that the addition of bevacizumab and erlotinib to XELOX would increase progression-free survival to at least 12 months (hazard ratio, 1.6). In order to prove this assumption, assuming an a error of 0.05 and a b error of 0.2, it was necessary to include at least 88 patients in the study. RESULTS Patient Population Ninety patients were enrolled from November 2006 to March 2008 from 10 Spanish centers and made up the intention-to-treat and safety populations. Baseline characteristics are shown in Table 1. All patients were Caucasian. A total of 84 patients were included in the population evaluable for response. Six patients were excluded for the following reasons: five patients received only 1 cycle of study therapy, and one patient was not eligible because he had received chemotherapy for metastatic disease. A total of 52 (58%) patients received maintenance therapy with bevacizumab–erlotinib after induction therapy and are referred to hereafter as the per-protocol population. Thirty-eight (42%) patients ended study treatment before starting maintenance therapy, 13 of them as they were considered for surgical resection per investigator criteria after induction therapy. Figure 1 depicts the different patient populations. Reasons for discontinuing the study treatment in each population are shown in Table 2. For the intention-to-treat population, the most common reason was disease progression (43%). At the study end, two patients remained on treatment. Treatment Exposure The median number of cycles of XELOX–bevacizumab combination therapy received was 6. Sixty-four (71%)

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Table 1.  Baseline Characteristics (Intent-to-Treat Population; N = 90) Characteristics Gender Male Female Age, years Median Range ECOG performance status 0 1 Primary tumor Colon Rectum Rectum–sigmoid colon Number of organs affected 1 2 ³3 KRAS mutational status Evaluable Wild type Mutation Not evaluable Previous therapy Surgery (Neo)adjuvant chemotherapy FOLFOX Fluoropyrimidine monotherapy Other

No. of Patients

Percentage

61 29

68 32 60.5 43–75

56 34

62 38

39 21 30

43 23 33

40 25 25

44 28 28

66 40 26 24

73 61 39 27

55 12 6 5

61 13 – –

1

–

Percentages subject to rounding error. ECOG, Eastern Cooperative Oncology Group; FOLFOX, 5-fluorouracil, folinic acid plus oxaliplatin.

patients received 6 cycles of induction therapy, 25 (28%) patients received £5 cycles, and 1 (1%) patient received 7 cycles. The median duration of XELOX–bevacizumab was 4.0 (range, 0.1 to 5.4) months. During induction therapy, capecitabine or oxaliplatin dose reductions were required in 31 (34%) patients and treatment delays in 44 (49%) patients. In the per-protocol population (n = 52), patients received a median of 6 (range, 1 to 43) cycles of maintenance therapy with bevacizumab–erlotinib for a median duration of 4.1 (range, 0.2 to 29.3) months. Erlotinib dose reductions were required in 12 (23%) patients, and treatment delays in 26 (50%) patients. Second-line antineoplastic therapy was given to 69 (77%) patients. Patients received bevacizumab-based therapy (n = 23), cetuximab-based therapy (n = 20), chemotherapy alone (n = 14), or both bevacizumab- and cetuximab-based therapy given sequentially (n = 12).

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Figure 1.  Patient populations. *One patient received 7 cycles of treatment.

Twelve patients underwent surgery: hepatectomy (n = 6), sigmoid resection (n = 3), resection of pulmonary metastases (n = 1), thoracotomy (n = 1), and colorectal resection/hepatectomy (n = 1). Efficacy A summary of the time-to-event endpoints by study population is provided in Table 3. At the time of database closure (May 18, 2010), the median follow-up time for the intention-to-treat population was 24.1 (95% CI, 18.0 to 26.1) months. The median progression-free survival, the primary study endpoint, was 9.2 (95% CI, 7.9 to 11.9) months in this population (Fig. 2a), and the median

overall survival was 25.8 (95% CI, 18.0 to 30.9) months (Fig. 2b). In the per-protocol population (i.e., patients who received maintenance therapy with bevacizumab–­ erlotinib), the median follow-up time was 26.3 (95% CI, 23.1 to 28.3) months. In this patient subpopulation, the median progression-free survival was 11.1 (95% CI, 8.9 to 15.7) months (Fig. 2a), and the median overall survival was 29.5 (95% CI, 23.7 to 36.7) months (Fig. 2b). In the population evaluable for response (n = 84), complete responses were documented in 3 (4%) patients and partial responses in 44 (52%) patients, giving an overall response rate of 56% (n = 47). Stable disease was

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Table 2.  Reasons for End of Treatment ITT Population (n = 90)* Reason

Induction Therapy Only (n = 38)

Induction + Maintenance Therapy (PP Population) (n = 52)*

No. of Patients

%

No. of Patients

%

No. of Patients

%

38 25 20 4 1

43 28 23 5 1

12 13 11 1 1

32 34 29 3 3

26 12 9 3 0

52 24 18 6 0

Disease progression Investigator judgment Adverse events Patient decision Death

Percentages calculated in relation to each population size. ITT, intention-to-treat; PP, per-protocol. *Two patients remained on treatment at the study end.

documented in a further 31 (37%) patients, giving a disease control rate of 93% (n = 78). Four patients, who achieved a partial response during treatment, underwent surgery and subsequently achieved a complete response. Efficacy by KRAS Mutational Status Of the 66 patients who were evaluable for KRAS analysis, 40 (61%) had KRAS wild-type tumors, and the remaining 26 (39%) had tumors with KRAS mutations. In the per-protocol population, 38 patients were evaluable for KRAS gene analysis, of whom 25 had KRAS wild-type tumors, and the remaining 13 had tumors with KRAS mutations. Of the 40 KRAS wild-type patients, 32 received second-line antineoplastic therapy: bevacizumab-based therapy (n = 5), cetuximab-based therapy (n = 13), chemotherapy alone (n = 4), or sequential bevacizumab- and cetuximab-based therapy (n = 10). Of the 26 KRAS-mutated patients, 24 received second-line antineoplastic therapy: bevacizumab-based therapy (n = 15), cetuximab-based therapy (n = 4), or chemotherapy alone (n = 5). Ten patients (eight KRAS wild-type and two with KRAS mutations) did not receive second-line therapy. In the intention-to-treat population, there was a trend to longer progression-free survival and overall survival

in patients with KRAS wild-type tumors compared with patients carrying tumors with KRAS mutations; however, the differences between the two populations were not statistically significantly different for either endpoint (Table 3). A similar result was observed in the per-protocol population who received bevacizumab–erlotinib maintenance therapy (Fig. 3). Safety In the safety population (n = 90), the most common treatment-related adverse events reported in association with the induction phase were asthenia (70%), diarrhea (50%), and nausea (42%) (Table 4). The most common grade 3/4 treatment-related adverse events were diarrhea (17%), asthenia (11%), and neutropenia (8%). Eight grade 4 events were reported in total (diarrhea, n = 2; vomiting, intestinal obstruction, intestinal perforation, pneumonia, tumor perforation, and pulmonary embolism, 1 each). Paresthesia, neurotoxicity, or dysesthesia occurred in approximately 23% to 33% of patients and were generally grade 1 or 2 in severity; no grade 3 dysesthesia was reported in the induction phase. Adverse events of interest to bevacizumab in the induction phase were hemorrhage (n = 15), epistaxis (n = 10),

Table 3.  Progression-Free Survival and Overall Survival by Study Population Progression-Free Survival Population Intention-to-treat Per-protocol† Intention-to-treat KRAS wild-type KRAS mutation Per-protocol† KRAS wild-type KRAS mutation

Overall Survival

No. of Patients

Median (Months)

95% CI

p Value*

Median (Months)

95% CI

p Value*

90 52

9.2 11.1

7.9–11.9 9.0–15.7

– –

25.8 29.5

18.0–30.9 23.7–36.7

– –

40 26

10.2 8.2

7.8–13.3 7.2-13.8

0.6945

26.4 25.8

17.9–NR 14.6–36.7

0.8274

25 13

11.3 11.1

8.4–15.9 7.2–17.5

0.2287

29.5 27.9

18.1–NR 13.6–36.7

0.6729

CI, confidence intervals; NR, not reached. *Log-rank test. †Patients who received maintenance therapy with bevacizumab–erlotinib.

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Figure 2.  (a) Progression-free survival and (b) overall survival in the intention-to-treat (n = 90) and per-protocol (n = 52) populations. The per-protocol population included patients who received XELOX–bevacizumab followed by maintenance therapy with bevacizumab plus erlotinib.

other hemorrhage (n = 5), hypertension (n = 11), venous thromboembolic events (n = 4), proteinuria (n = 4), and gastrointestinal perforation (n = 1). In the per-protocol population (n = 52), the most common treatment-related adverse events associated with maintenance therapy were asthenia (56%), diarrhea (56%), and rash (71%) (Table 4). The most common grade 3/4 adverse events were rash (12%), diarrhea (8%),

and hypertension (6%); all but one of these events were grade 3 in severity. Two grade 4 events were reported in total (ischemic colitis and hypertension, one each). Adverse events of interest to bevacizumab in the maintenance phase were hemorrhage (n =  24), epistaxis (n = 10), other hemorrhage (n = 14), hypertension (n = 6), proteinuria (n = 6), and venous thromboembolic events (n = 1). There were no treatment-related deaths in this study.

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Figure 3.  (a) Progression-free survival and (b) overall survival among patients with KRAS wild-type (n=25) and KRAS mutant tumors (n=13) in the per-protocol who received induction therapy with XELOX–bevacizumab followed by maintenance therapy with bevacizumab–erlotinib.

DISCUSSION The present phase II study demonstrates the feasibility and activity of induction chemotherapy with XELOX– bevacizumab for 6 cycles followed by maintenance therapy with bevacizumab–erlotinib in patients with previously untreated metastatic colorectal cancer. In the intent-to-treat population, which included patients who received induction chemotherapy with or without maintenance therapy, we observed a median progression-free survival of 9.2 months and a median overall survival of 25.8 months. Improved efficacy outcomes were evident in the patient

subpopulation who received both induction chemotherapy and maintenance therapy as planned; in this patient subgroup, the median progression-free survival was 11.1 months, and the median overall survival was 29.5 months. The validity of using targeted agents, without chemotherapy, as maintenance therapy in metastatic colorectal cancer has recently been tested in the phase III MACRO trial (15). In the MACRO study, patients were randomized to receive either XELOX–bevacizumab until disease progression or XELOX–bevacizumab for 6 cycles followed by maintenance therapy with bevacizumab alone.

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Table 4.  Treatment-Related Adverse Events (>10% of Patients) by Grade National Cancer Institute Common Toxicity Criteria Grade [No. of Patients (%)] Safety Population, Induction Phase (n = 90) Adverse Event Total with at least one event Asthenia Diarrhea Nausea Vomiting Anorexia Paresthesia Hand–foot syndrome Neurotoxicity Neutropenia Dysesthesia Abdominal pain Mucosal inflammation Anemia Pyrexia Leucopoenia Hypertension Epistaxis Stomatitis Constipation Proteinuria Rash

Per-Protocol Population, Maintenance Phase (n = 52)*

All Grades

Grade 3/4

All Grades

Grade 3/4

89 (99) 63 (70) 45 (50) 38 (42) 34 (38) 31 (34) 30 (33) 28 (31) 27 (30) 24 (27) 21 (23) 19 (21) 15 (17) 15 (17) 13 (14) 12 (13) 11 (12) 10 (11) 10 (11) 7 (8) 4 (4) 1 (1)

35 (39) 10 (11) 15 (17) 2 (2) 4 (4) 0 (0) 0 (0) 1 (1) 0 (0) 7 (8) 0 (0) 1 (1) 2 (2) 1 (1) 1 (1) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

52 (100) 29 (56) 29 (56) 4 (8) 4 (8) 10 (19) 12 (23) 6 (12) 13 (25) 9 (17) 8 (15) 14 (27) 6 (12) 2 (4) 5 (10) 2 (4) 6 (12) 10 (19) 2 (4) 7 (13) 6 (12) 37 (71)

23 (44) 2 (4) 4 (8) 0 (0) 0 (0) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) 0 (0) 0 (0) 1 (2) 0 (0) 0 (0) 3 (6) 0 (0) 0 (0) 0 (0) 0 (0) 6 (12)

*Patients who received maintenance therapy with bevacizumab–erlotinib.

In patients who received XELOX–bevacizumab followed by bevacizumab maintenance therapy, the preliminary median progression-free survival was 10.3 months with a preliminary median overall survival of 20.7 months; the efficacy of this regimen was noninferior to the control group. It is of interest that the data from patients in the present study who received maintenance therapy with bevacizumab–erlotinib compare favorably with the bevacizumab maintenance arm of the MACRO trial. Preliminary data from the phase III randomized CAIRO 3 study have been recently reported (16). Patients treated with capecitabine– bevacizumab maintenance after 18 weeks of induction with XELOX–bevacizumab achieved a median overall survival of 21.7 months over observation (17.9 months; HR, 0.77; p = 0.02). Interestingly, the median overall survival achieved in the CAIRO 3 study with the maintenance therapy was somehow shorter than the approximately 26-month overall survival achieved in our study with or without maintenance therapy, although comparison is not possible by differences in the study design. The precise contribution of erlotinib to maintenance therapy is currently being investigated in the ongoing Double Reintroduction with Erlotinib and Avastin

in Metastatic Colorectal Cancer (DREAM) study (17) in which patients are being randomized to maintenance therapy with bevacizumab ± erlotinib following 6 cycles of XELOX or FOLFOX7 plus bevacizumab. The findings of strong activity with combined EGFRand VEGF-targeted therapies in our trial are of interest given the outcomes of the recent PACCE and CAIRO-2 trials (18,19). These trials examined the effect of adding anti-EGFR antibodies (panitumumab or cetuximab) to an anti-VEGF antibody (bevacizumab) plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer. Both studies showed that the addition of an anti-EGFR antibody had a significantly detrimental effect on progression-free survival compared with no added anti-EGFR antibody (18,19). Data from both studies also suggested a potential negative interaction between anti-EGFR and antiVEGF therapy and oxaliplatin-based chemotherapy. The positive outcome of our study suggests that bevacizumab can be combined with an EGFR tyrosine kinase inhibitor to give an effective combination, although whether this is because of mechanistic differences between erlotinib and the anti-EGFR antibodies or because the administration of targeted therapy and chemotherapy was sequential,

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rather than concurrent, is unknown. The final results of the DREAM study (17) will help to better understand the efficacy of dual-targeted therapy. The KRAS genotype appears to influence the response to anti-EGFR antibody therapy in patients with metastatic ­colorectal cancer: only patients with wild-type KRAS tumors will be benefited from anti-EGFR treatmentin mono­ therapy (20,21) or as a dual approach (22), although KRAS genotype as a prognostic factor is still the subject of some debate (23,24). In the present study, we observed that KRAS mutational status was not statistically associated with the efficacy of the study treatment regimen, although a trend to longer survival was observed in patients with KRAS wildtype tumors compared with patients with KRAS-mutated tumors. The trend toward improved survival for the wildtype group may be explained with the proportion of patients with KRAS wild-type versus mutation-positive patients who went on maintenance therapy (2:1) compared with those who started the induction phase (1:1) and with the number of EGFR-based regimen (cetuximab) received in second or subsequent lines of treatment. KRAS mutational status has been associated with outcome following erlotinib-based therapy in some studies in patients with non-small cell lung cancer (25–27), although this has not been a consistent observation (12,28). Larger patient numbers are required to assess more accurately the relevance of this biomarker to erlotinib-containing therapy in colorectal cancer. The predominant toxicity associated with the regimen we studied was diarrhea; about 20% of patients reported grade 3/4 events. Rash was also common in patients receiving maintenance therapy, although no grade 4 events were reported. This profile is in keeping with the interim safety analysis from the DREAM study, which studied an identical regimen (17). Neurotoxicity was observed in about 23% to 33% of patients in the present trial and was generally mild to moderate in severity. A single case of grade 3 dysesthesia was documented. This compares with the considerably higher rates of grade 3/4 events (17% to 24%) reported with XELOX with or without bevacizumab when given until disease progression (14,29,30). This suggests that an abbreviated induction regimen markedly reduced the severity and occurrence of oxaliplatin-related neurotoxicity in our study population. A limitation of the present study is that almost 40% of the patient population stopped the study treatment before receiving maintenance therapy with bevacizumab–­ erlotinib, limiting the accuracy of the estimates of efficacy. However, it should be noted that, of the 38 patients who stopped treatment prior to maintenance therapy, 12 (13%) patients showed disease progression and were therefore not eligible for maintenance therapy, and 13 stopped treatment because of investigator decision (usually to assess patient eligibility for surgery). However, some selection bias might not be excluded.

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In conclusion, XELOX–bevacizumab for 6 cycles followed by maintenance therapy with bevacizumab–erlotinib until disease progression has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer. These findings support the use of an induction chemotherapy regimen followed by maintenance therapy with targeted agents in patients with metastatic colorectal cancer. Further phase III clinical trials evaluating this approach appear to be warranted. ACKNOWLEDGMENTS: This work was sponsored by Roche Farma, S.A., Spain. Support for third-party writing assistance for this article, furnished by Miller Medical Communications and PIVOTAL S.L., was provided by Hoffmann-La Roche Spain. The authors declare no conflict of interest.

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