Current role of antibody therapy in patients with metastatic ... - Nature

Oncogene (2007) 26, 3661–3678

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REVIEW

Current role of antibody therapy in patients with metastatic colorectal cancer P Pfeiffer, C Qvortrup and JG Eriksen Department of Oncology, Odense University Hospital, Odense C, Denmark

In less than 10 years, the number and importance of nonsurgical treatment modalities in patients with colorectal cancer (CRC) have increased dramatically, both in the adjuvant and the advanced settings. However, despite the improvement of cytotoxic therapy in CRC, many patients still develop progressive disease and unfortunately in patients with disease resistant to 5-fluorouracil/folinic acid, irinotecan and oxaliplatin, no effective cytotoxic therapy is known. The rapidly expanding knowledge in tumor biology has encouraged optimism for the possibility to find and target tumor-specific mechanisms and thereby increase both efficacy and tolerance. A great number of ‘targeted drugs’ are being tested in clinical trials and some of these new drugs, like bevacizumab, cetuximab and panitumumab, are available for routine use in health care. These new targeted drugs will expand the therapeutic arsenal in CRC to a great extent, but they will also add to the complexity of treatment of CRC. In this review, we summarize the current status of antibody therapy in patients with CRC. Oncogene (2007) 26, 3661–3678. doi:10.1038/sj.onc.1210377 Keywords: metastatic colorectal cancer; antibodies; bevacizumab; cetuximab; panitumumab

tumor biology has encouraged optimism for the possibility to find and target tumor-specific mechanisms and thereby increase both efficacy and tolerance. A great number of ‘targeted drugs’ are being tested in clinical trials and some of these new drugs are already in the market and available for routine use in health care. In patients with metastatic CRC (mCRC), two antibodies were approved in USA and EU in 2004 and are now being used in daily practice; cetuximab (Cx) (Erbitux), a monoclonal antibody (mAb) blocking the epidermal growth factor receptor (EGFR), and bevacizumab (Bv) (Avastin) a mAb targeting angiogenesis. Very recently, panitumumab (Pa) (Vertibix), a new antibody against EGFR has been approved. These new targeted drugs expand the therapeutic arsenal in CRC to a great extent, but they will also add to the complexity of treatment of CRC. In this review, we summarize the current status of antibody therapy in patients with CRC. To better understand the clinical role of these antibodies, especially since they are to be combined with chemotherapy, we consider it necessary also to run through the current principles of chemotherapy in mCRC.

Principles for retrieval of data Introduction In less than 10 years, the number and importance of non-surgical treatment modalities in patients with colorectal cancer (CRC) have increased dramatically, both in the adjuvant and the advanced settings. A decade ago, treatment options were dominated by injections of 5-fluorouracil (FU) modulated by folinic acid (FA), but presently routinely combined with irinotecan or oxaliplatin. Despite the improvement of cytotoxic therapy in CRC, many patients still develop progressive disease; and unfortunately in patients with disease resistant to FU/FA, irinotecan and oxaliplatin no effective cytotoxic therapy is known. The rapidly expanding knowledge in Correspondence: Dr P Pfeiffer, Department of Oncology, Odense University Hospital, Sdr Boulevard 29, DK-5000 Odense C, Denmark. E-mail: [email protected]

To identify data on antibody therapy in patients with CRC, we searched the databases Medline and ClinicalTrials.gov for relevant publications using the search terms colon cancer, colorectal cancer, antibody therapy, monoclonal antibody, targeted therapy, cetuximab, bevacizumab, panitumumab and edrocolomab. Data on antibodies were also identified in relevant publications and from listings in recent overviews (Veronese and O’Dwyer, 2004; Nygren et al., 2005; Stern and Herrmann, 2005; Arnold et al., 2006; Saunders and Iveson, 2006; Van Cutsem et al., 2006). Full reporting of final results from important clinical trials often lags behind more preliminary reports in the abstract form. Therefore, we included data from abstracts to be able to present the most recent information on antibody therapy. Abstracts presented at the annual meetings of ASCO, ASCO GI, AACR, ECCO/ESMO from 2004 to 2006 were reviewed and included as applicable. In this review, we will summarize the clinical status of antibody therapy in mCRC but only antibodies that have been

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evaluated in large phase II or phase III studies or large observational studies.

Palliative chemotherapy in patients with mCRC FU and FA For almost 50 years, FU with or without FA has been the most extensively used chemotherapy regimen for patients with CRC, both as adjuvant and palliative treatment (Ragnhammar et al., 2001; Meyerhardt and Mayer, 2005). Untreated only half of the patients with mCRC will be alive after 6 months and survival past 2 years is rarely seen. FU/FA induced tumor regression (complete þ partial response) in 20% of patients, prolonged median survival from 6 to 12 months and improved quality of life (Ragnhammar et al., 2001). However, most patients developed progressive disease after median 4–6 months and there were no effective salvage therapies available for patients with progressive disease following FU/FA treatment. Many different schedules of FU with different doses of FA have been developed and numerous studies have been conducted to establish the optimal FU/FA regimen, but without reaching consensus. FU has been given as a continuous infusion, as prolonged infusion (24–48 h), as a bolus injection (1–5 consecutive days) or as a combination of both (Ragnhammar et al., 2001; Meyerhardt and Mayer, 2005). In the United States, the Mayo regimen (bolus on five consecutive days, repeated every 4 weeks) used to be the standard regimen for many years and served as comparison with newer regimens. Randomized trials have shown that infusional administration of FU/FA improves the tumor response rate (RR), increases time to tumor progression (TTP – in this review, we will make no distinction between TTP and progression-free survival) and marginally improves overall survival (OS) at reduced or similar toxicity (de Gramont et al., 1997; Ko¨hne et al., 2003), and the Mayo regimen should not be used anymore. In many parts of Europe, and increasingly in United States, modulated infusion regimens are preferred; the most commonly used approach is probably the ‘de Gramont’ regimen that combines FA, bolus FU and prolonged infusion FU (de Gramont et al., 1997; Ragnhammar et al., 2001; Meyerhardt and Mayer, 2005). Other bolus regimens are better tolerated than the Mayo regimen. The Nordic FU/FA bolus schedule (FU/ FA administered on days 1 and 2 every 2 weeks) can easily be combined with oxaliplatin (FLOXNordic) or irinotecan (FLIRINordic), and phase II (Sorbye et al., 2004) and III studies (Glimelius et al., 2005) have already shown that these regimens are valid alternatives to other combination regimens. Randomized studies have also shown that oral therapy with tegafur/uracil (UFT) and FA (Carmichael et al., 2002; Douillard et al., 2002) or capecitabine (Van Cutsem et al., 2004) is as effective as bolus FU/FA therapy and with comparable or less toxicity. Oncogene

First-line combination chemotherapy The new era of combination chemotherapy started when it was shown that irinotecan as single agent increases the median OS by 3 months in patients resistant to FU/FA (Cunningham et al., 1998; Rougier et al., 1998) compared with best supportive care (BSC) or infusional FU/FA. Comparable results can be obtained with a combination of FU/FA and oxaliplatin (Pitot et al., 2005). There is no strong rationale for combining FU/ FA and irinotecan in this setting as opposed to the strong synergy observed with oxaliplatin and FU/FA (Starling and Cunningham, 2005). The introduction of doublets (FU/FA or oral therapy in combination with irinotecan or oxaliplatin) as firstand second-line therapy has increased the life expectancy considerably, almost half of the patients are alive after 2 years and the chance of long-term survival still continues to increase (Ragnhammar et al., 2001; Rothenberg et al., 2003; Grothey et al., 2004; Meyerhardt and Mayer, 2005). First-line doublet (Tables 1 and 2) increases RRs (from 20 to almost 50%) and prolongs time to progression (TTP) from 4–6 months to 6–8 months (Ragnhammar et al., 2001; Meyerhardt and Mayer, 2005). In some studies, doublets increased RR rate and prolonged TTP, whereas significant prolongation of OS was not seen, probably due to crossover at the time of progressive disease (PD) and the use of effective secondline therapy (de Gramont et al., 2000; Giacchetti et al., 2000). Direct comparisons between combinations (Tables 1 and 2) with irinotecan (i.e. FOLFIRI or XELIRI) and oxaliplatin (i.e. FOLFOX or XELOX) show that most doublets are equally effective with respect to RR, median TTP and median OS (e.g. Grothey et al., 2003; Tournigand et al., 2004; Cassidy et al., 2006; Kubicka et al., 2006), however, only in studies in which identical fluoropyrimidenes were used (Goldberg et al., 2004). The general notion at present is that the choice of doublet is mainly a matter of the adverse effects profile that differs between these combinations, but IFL (bolus schedule of irinotecan in combination with fluorouracil and leucovorin primarily tested in North America) is too toxic and less active than other regimens and therefore obsolete and should not be offered anymore.

Table 1 Abbreviation of the most common chemotherapy regimens in patients with CRC FU/FA regimen

Oxaliplatin Irinotecan

Bolus

Infusion

Capecitabine

UFT/FA

FLOXnordic FLOXUS bFOL FLIRI IFL

FOLFOX FUFOX

XELOX or CAPOX

TEGAFOX

FOLFIRI

XELIRI or CAPIRI

TEGAFIRI

Abbreviations: CRC, colorectal cancer; FA, folinic acid; FU, 5fluorouracil.

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3663 Table 2 Important randomized studies evaluating chemotherapy in patients with mCRC Author (publication regimens)

No. of patients

RR (%)

Median TTP (months)

Median OS (months)

5-FU/FA vs combination with irinotecan Saltz et al. (2000) Bolus 5-FU/FA IFL

226 231

21 39a

4.3 7.0a

12.6 14.8a

Douillard et al. (2000) Infusion 5-FU/FA FOLFIRI

187 198

22 35a

4.4 6.7a

14.1 17.4a

Ko¨hne et al. (2003) Infusion 5-FU/FA FUFIRI

216 214

32 54a

6.4 8.5a

16.9 20.1a

5-FU/FA vs combination with oxaliplatin de Gramont et al. (2000) Infusion 5-FU/FA FOLFOX

210 210

22 51a

6.2 9.0a

14.7 16.2

Giacchetti et al. (2000) Infusion 5-FU/FA FOLFOX

100 100

12 34a

6.1 8.7a

19.9 19.4

Grothey et al. (2002) Bolus 5-FU/FA FUFOX

124 118

23 48a

5.3 7.9a

16.1 20.4a

Combination vs combination Tournigand et al. (2004) FOLFOX FOLFIRI

111 111

54 56

10.9 14.2

20.6 21.5

Grothey et al. (2003) CAPOX CAPIRI

82 79

51 43

7.9 7.9

>16 >16

Kubicka et al. (2006) FUFOX CAPOX

234 242

50 47

8.0 7.0

18.1 16.6

Goldberg et al. (2004) IFL FOLFOX

264 267

31 45a

6.9 8.7a

15.0 19.5a

Glimelius et al. (2005) FLIRINordic FOLFIRI

282 274

— —

9.5 9.0

18.2 17.8

Abbreviations: FA, folinic acid; FU, 5-fluorouracil; mCRC, metastatic colorectal cancer; OS, overall survival; RR, response rate; TTP, time to progression. aSignificant difference.

Duration of combination chemotherapy When FU/FA was the only treatment available, it was natural to continue therapy as long as the disease was controlled without any sign of progression. With the introduction of doublets, this strategy was maintained and chemotherapy was administered until tumor progression, but this strategy now has to be revised. One reason is the patients need for ‘drug holidays’ in light of the cumulative toxicity resulting from the above strategy. Another, and more important, reason is that recent studies have shown that an intermittent strategy compared with continuous use of chemotherapy does not compromise efficacy (Labianca et al., 2006; Maindrault-Goebel et al., 2006) and a final reason is a reduced cost of treatment. Thus, in patients with

non-progressive mCRC after, for example, 4 months of combination chemotherapy, a break in therapy can safely be recommended, assuming that a close surveillance is offered and followed by treatment re-introduction or change to another regimen upon tumor progression. Second-line therapy Second-line therapy after first-line doublet generates RRs of 5–20%, increases TTP to 4–6 months (Rothenberg et al., 2003; Grothey et al., 2004; Kemeny et al., 2004; Tournigand et al., 2004; Pfeiffer et al., 2006) and also adds to a prolonged OS. A recent review pointed out that OS was significantly correlated with the Oncogene

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percentage of patients who received all three drugs (Grothey et al., 2004). In a recent update, they demonstrated that a strategy of making all three active agents available was more important than the use of doublet upfront (Grothey and Sargent, 2005). Nevertheless, patients who received first-line chemotherapy doublets had a greater chance to receive all three agents in the course of their therapy and they concluded that in clinical practice doublet should remain the standard of care for first-line treatment of patients with advanced CRC. Third-line therapy Thus, many patients have received different combinations of FU/FA, irinotecan and oxaliplatin as first- and second-line (and occasionally third line) therapy for mCRC. Despite progressive disease, many patients are still in an excellent performance and there is definitely a need for further effective regimens with the capability to postpone further progression of the disease, induce remissions, prolong life and improve quality of life. Only very few studies on ‘third-line’ chemotherapy in patients pretreated with FU/FA, irinotecan and oxaliplatin have been published (Rosati et al., 2003; Lim et al., 2005). Rosati et al. (2003) treated 21 patients with raltitrexed and mitomycin-C but no patient had tumor regression, and median survival was only 5 months. Lim et al. (2005) also treated 21 patients but with a combination of capecitabine and mitomycin-C. Only one patient had tumor regression, TTP was 2.6 months and OS was 6.5 months and they concluded that the regimen did not add to increasing patients OS. Thus it seems as if the improvement in OS has reached a limit of around 18–21 months and even if all patients are exposed to all three drugs, either sequentially or concomitantly, it is not expected that the OS can be prolonged beyond 24 months (Grothey et al., 2004; Falcone et al., 2006; Souglakos et al., 2006).

Targeted drugs in CRC During the last decade, there has been major scientific progress in the understanding of cancer biology (Hanahan and Weinberg, 2000) and as a consequence, a large number of new potential targets for medical treatment have been identified. A number of approaches, from small molecules to antibodies (Nygren et al., 2005), can inhibit this signal transduction and thus slow down the growth of malignant cells. These new agents are often designated as ‘targeted drugs’ and very encouraging results have been obtained if administered with combination chemotherapy. The use of monoclonal antibodies have moved into the routine health care of patients with mCRC, and in recent years a huge number of patients have received antibodies often in combination with chemotherapy (Nygren et al., 2005; Arnold et al., 2006). At least five antibodies have been studied extensively in patients with CRC. Two antibodies – edrocolamab Oncogene

(Punt et al., 2002) and 3H1 (Chong et al., 2006) – were tested in the adjuvant and the metastatic settings, respectively, but without improvements of survival, and there is presently no indication for treatment with edrocolomab or 3HI outside clinical trials. Three antibodies – Bv, Cx and Pa – have shown clinical relevant efficacy in clinical trials and the following sections will summarize the data on their clinical efficacy and safety. Large clinical trials investigating their potential roles in the adjuvant setting are ongoing, but no data are yet available and therefore the following sections will only address patients with mCRC.

Monoclonal antibodies for treatment of mCRC Efficacy and safety of Bv in mCRC Angiogenesis plays an important role in cancer because tumor growth beyond 1–2 mm depends on new blood vessels for supply of nutrients and oxygen. Vascular endothelial growth factors (VEGF’s), pro-angiogenic factors, are the most important regulators of angiogenesis and has been detected in a range of malignant tumors, including CRC. Excess VEGF from tumor or normal stromal cells leads to activation of endothelial cell proliferation, migration and survival but also to increased vascular permeability and increased interstitial pressure. Bv is a humanized mAb which prevents binding of VEGF-A to the VEGF receptors. The terminal elimination half-life is approximately 21 days and does not induce antibodies to Bv (Ferrara, 2004). Inactivation of VEGF will lead to normalization of tumor vessels, decreased interstitial pressure and allow a more efficient delivery of chemotherapy to tumor cell (Ferrara, 2004; Willett et al., 2004; Hicklin and Ellis, 2005). First-line therapy In a small randomized phase II study (AVF 0780) with 104 patients (Table 3), the goal was to investigate efficacy and safety of Bv in combination with FU/FA (Kabbinavar et al., 2003). Three groups of patients received FU/FA alone, FU/FA in combination with low-dose Bv (5 mg/kg every 2 weeks) or high-dose Bv (10 mg/kg every 2 weeks). Patients receiving low-dose Bv had the highest RR (40%) and longest TTP (9.0 months) and logically low-dose Bv was recommended for further studies. A retrospective analysis of this trial (Kabbinavar et al., 2005) suggested that Bv was particularly effective in patients with poor prognostic features ((performance status (PS) 1–2, age >65 years, and low serum albumin). In contrast, retrospective analyses of studies demonstrating the benefit of adding irinotecan to FU/FA (Douillard et al., 2000; Saltz et al., 2000) suggested that the benefit derived from irinotecan might be limited to patients with a good performance status. In addition, there was a tendency to increased toxicity in elderly patients, poor performance, low serum albumin or prior

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3665 Table 3 Most important studies with Bv in patients with mCRC Author First-line therapy Kabbinavar et al. (2003) AVF 0780 Hurwitz et al. (2004) AVF 2107 Kabbinavar et al. (2005) AVF 2192 Hochster et al. (2006) TREE-1 TREE-2 Fuchs et al. (2006) BICC-C period 1 BICC-C period 2 Cassidy et al. (2006) NO 16966 Second-line therapy Giantonio et al. (2005) E3200

Regimen FUFA FUFA+BvLD FUFA+BvHD IFL IFL+BvLD FL+BvLD FUFA FUFA+BvLD mFOLFOX bFOL mXELOX mFOLFOX+BvLD bFOL+BvLD mXELOX+BvLD FOLFIRI mIFL XELIRI FOLFIRI+BvLD mIFL+BvLD XELOX or FOLFOX XELOX or FOLFOX+BvLD FOLFOX FOLFOX+BvHD

Phase

n

RR (%)

TTP (months)

OS (months)

II

36 35 33 411 402 (110)

17 40a 24 35 45a (40)

5.2 9.0a 7.2 6.2 10.6a (8.8)

13.8 21.5 16.1 15.6 20.3a (18.3)

105 104 50 50 50 75 74 74 144 141 145 57 60 700 700

15 26 43 22 35 53 41 48 47 42 38 54 53 — —

5.5 9.2a 8.7 6.8 5.9 9.9 8.3 10.3 7.6a 5.8 5.5 9.9 8.3 8.0 9.4a

12.9 16.6 19.2 17.9 17.2 26.0 20.7 27.0 23.1 17.5 18.9 NRa 18.7 — —

292 293

9 22a

4.8 7.2a

10.8 12.9a

III

II II II II II III

III

Abbreviations: Bv, bevacizumab; BvHD, high-dose Bv (10 mg/kg); BvLD, low-dose bevacizumab (5 mg/kg); mCRC, metastatic colorectal cancer; NR, not reached yet; OS, overall survival; RR, response rate; TTP, time to progression. aSignificant difference.

pelvic radiotherapy. Therefore, two subsequent randomized trials (Table 3) of Bv were planned and conducted. In the pivotal phase III trial, AVF2107 (Hurwitz et al., 2004) Bv was added to IFL (standard combination chemotherapy in US when the study was launched) in good performance patients (PS 0 or 1). A supportive randomized, phase II trial (AVF 2192) was run concurrently in patients considered non-optimal candidates for first-line irinotecan-containing regimens (Kabbinavar et al., 2005). In AVF2107, 925 patients were randomized to bolus FU/FA and irinotecan (IFL) or IFL in combination with low-dose Bv (Hurwitz et al., 2004). Initially a third arm with FU/FA þ Bv was included but terminated after inclusion of 110 patients following a planned safety analysis. Patients were allowed to receive further chemotherapy, but not to crossover to Bv. Approximately half the patients in both treatment groups (Hedrick et al., 2004) received second-line therapy but nonetheless OS was significantly prolonged (from 15.6 to 20.3 months). This improvement was observed in the subgroup receiving oxaliplatin as second-line treatment (25 vs 22 months) as well as in patients who did not receive oxaliplatin (20 vs 16 months). In AVF 2192 (Kabbinavar et al., 2005), 209 patients who were not suitable for irinotecan received FU/FA and placebo or FU/FA combined with low-dose Bv (Table 3). The addition of Bv significantly prolonged TTP (from 5.5 to 9.2 months) but RR (15 vs 26%) and OS (12.9 vs 16.6 months) were not improved

significantly. The lack of difference in median OS may be due to the small number of patients but postprogression therapy, which hampers the interpretation of OS, might be another explanation. TTP is unaffected by second-line therapy and for that reason TTP may be a more representative measurement of the clinical benefit provided by new regimens. OS was significantly prolonged only in AVF 2107, but the overall impression from the published phase II and III studies (Table 3) was that addition of Bv to FU/FA alone as well as to doublet prolong TTP with 3–4 months and OS with 4–6 months. Although addition of Bv constantly improved outcome in first-line treatment, data are only coming from what might be called ‘mediocre chemotherapy regimen’. The question therefore is whether Bv also will add to the efficacy of ‘optimal chemotherapy regimens’. Two recently randomized phase II studies (TREE and BICC-C) were presented at the oral session of the 2006 colorectal ASCO program (Table 3). Both studies were initiated to establish the optimal combination of chemotherapy but they were cut short secondary to the availability of Bv. In TREE-1 (Hochster et al., 2006), three different fluoropyrimidine–oxaliplatine regimens (FOLFOX, bFOL or XELOX) were compared. Only 150 patients were randomized and no major differences in activity were observed but bFOL was the least efficacious (in relation to RR and TTP). In TREE-2 (Hochster et al., 2006), low-dose Bv was added to the three regimens. In a cross-trial comparison with the Oncogene

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former TREE-1 trial (identical oxaliplatin regimens without Bv), the RRs were higher and OS was prolonged from 18.2 to 24.4 months. The BICC-C (Fuchs et al., 2006) was a parallel study. In the first part, patients were randomized to three different fluoropyrimidine–irinotecan regimens (FOLFIRI, modified IFL or XELIRI with a second randomization to plus/minus celecoxib). TTP was superior for FOLFIRI compared with either of the other two regimens, there was a trend in OS in favour of FOLFIRI, and toxicity also favored the FOLFIRI arm. In the second part of the trial, OS was significantly prolonged for FOLFIRI plus low-dose Bv compared to IFL plus low-dose Bv (Table 3). Cross-trial comparison between part 1 and 2 of BICC-C suggested that addition of low-dose Bv prolonged OS. However, these data must be interpreted with some precaution due to the method of a cross-trial comparison, and therefore final results of NO16966 (FOLFOX vs XELOX, with or without Bv) and a US trial (mFOLFOX6 with or without Bv) are awaited with impatience and the first data were recently presented (Cassidy et al., 2006). NO16966 (Table 3) was initiated to compare FOLFOX and XELOX and from June 2003 to May 2004, 614 patients were randomized. After approval of Bv, it was very difficult to continue with chemotherapy alone and therefore the protocol was amended to a two-bytwo placebo-controlled study where patients were randomized to XELOX or FOLFOX4 and low-dose Bv or placebo (additionally 1400 patients). The main end point was TTP and the two primary objectives were to establish that XELOX was not inferior to FOLFOX and that chemotherapy plus Bv was superior to chemotherapy plus placebo. In more than 2000 patients, XELOX was not inferior to FOLFOX (TTP 8.0 vs 8.5 months) and the safety profiles were balanced. In the second part of the study, the first evidence that Bv adds benefit to first-line oxaliplatin-based chemotherapy was presented. The overall safety profile was in line with previous studies. TTP was significantly prolonged (TTP 8.0 vs 9.4 months). Hopefully, this improvement will translate into a clinically meaningful improvement in OS but before making final conclusions we must await data on OS.

High-dose Bv and FOLFOX significantly improved RR, TTP and OS (Table 3). The survival benefit was observed in subgroups defined by age (o65 vs >65 years) and gender. The combination of FU/FA and low-dose Bv was also evaluated in patients progressing after irinotecan and oxaliplatin-based regimens (third-line therapy), but an investigator RR of only 4% (independent confirmed 1%) and an median TTP of 3.7 months indicated very limited activity of this combination in this setting (Chen et al., 2006). On 26 February 2004, FDA (US Food and Drug Administration) approved Avastin (Bv) in combination with intravenous (i.v.) fluorouracil-based chemotherapy as a first-line treatment for patients with mCRC and on 20 June 2006, FDA granted approval for a labeling extension for Avastin, with i.v. FU-based chemotherapy, for the second-line treatment of mCRC. In Europe, Bv was granted marketing authorization by the European Medicines Agency (EMEA) on 13 January 2005 with the approved indication ‘Avastin (bevacizumab) in combination with intravenous 5fluorouracil/folinic acid or intravenous 5-fluorouracil/ folinic acid/irinotecan is indicated for first-line treatment of patients with mCRC’.

Second-line therapy After publication of the Saltz study (Saltz et al., 2000), IFL became the standard treatment in US for first-line treatment. In a phase III study (Rothenberg et al., 2003), it was established that FOLFOX added to OS as secondline therapy after first-line therapy with irinotecan. It was therefore natural to assess second-line oxaliplatin in combination with Bv. In the important ECOG E3200 phase III study, 829 patients previously treated with FU/FA and irinotecan were randomized to receive FOLFOX alone, FOLFOX in combination with highdose Bv or high-dose Bv alone (Giantonio et al., 2005). The Bv alone arm was closed by the data monitoring committee after an interim analysis in 244 patients suggested low activity (RR 3% and TTP 2.7 months).

Toxicity to Bv Treatment with Bv is generally well tolerated and does not enhance the specific chemotherapy toxicity. The most dangerous adverse events associated with Bv are thrombo-embolic complications, gastro-intestinal perforation and wound healing complications, but bleeding, hypertension and proteinuria are also seen. Initial evaluation of toxicity suggested an increased risk of any thrombo-embolic event, but detailed analysis of data from the randomized studies (Novotny et al., 2004) and from large observation studies with over 3800 patients (Kozloff et al., 2006; Van Cutsem et al., 2007) showed a two- or three-fold increase but only in arterial thrombo-embolic events. These figures were confirmed in a pooled analysis of data from five randomized trials

Oncogene

Do the prognostic characteristics of patients included in trials reflect those of patients in routine health care? In a large, observational study (BRiTE) of almost 2000 patients (Kozloff et al., 2006), the objective was to estimate TTP and OS in less-selected patients receiving Bv plus first-line chemotherapy at the physician’s discretion (63% oxaliplatin regimens, 24% irinotecan regimens). Estimated TTP (10.2 months) was comparable to that observed in AVF2107 with no difference between irinotecan and oxaliplatin regimens, but OS was not yet estimable. In a parallel community-based study enrolling almost 2000 patients (First BEAT), the safety profile of Bv in combination with first-line chemotherapy regimens at physician’s choice (48% oxaliplatin regimens, 33% irinotecan regimens) was also found to be consistent with that observed in other studies (Kozloff et al., 2006; Van Cutsem et al., 2007a).

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in patients with lung cancer, breast cancer or CRC (Skillings et al., 2005). The addition of Bv to chemotherapy increased the risk of arterial thromboembolic complications (from 1.7 to 3.8%) – especially in patients with cardiovascular risk factors and age X65 years. GI-perforation is a life-threatening but fortunately uncommon complication observed in around 1% of patients (often within the first 60 days of treatment) treated with Bv (Hurwitz et al., 2004; Kozloff et al., 2006; Kretzschmar et al., 2006; Sugrue et al., 2006). The risk of bleeding is twofold increased (approximately 4 vs 2%), but Bv did not increase hemorrhagic complications in patients receiving low-dose aspirin (Hambleton et al., 2005) or even full-dose anticoagulation (Hambleton et al., 2004). A common side effect is hypertension. In the randomized studies (Kabbinavar et al., 2003, 2005; Hurwitz et al., 2004), severe hypertension grade 3/4 occurred in approximately 10% of patients but was easily managed with oral medication in most cases. Proteinuria may be seen but grade 3 or 4 is unusual. What is the optimal dose and what is the optimal duration of therapy with Bv? No published study has been adequately powered to conclude a dose–response relationship (Lyseng-Williamson and Robinson, 2006). In AVF 0780, patients receiving low-dose Bv (5 mg/kg every 2 weeks) had the highest RR (40%) and longest TTP (9.0 months) and logically lowdose Bv was recommended for further studies. A few studies have used Bv 10 mg/kg in patients with mCRC (Giantonio et al., 2005, 2006a) but, to our knowledge, without substantial argument for this doubling of dose. Interestingly, in E3200, a sizeable number of patients needed protocol-specified dose reductions of Bv to 5 mg/kg, and TTP and OS were not compromised for patients who underwent dose reduction (Giantonio et al., 2006b). In a small breast cancer study, patients received (not randomized) Bv monotherapy at three different dose levels: 3 mg/kg (18 patients: RR 5.6%, OS 14.0 months), 10 mg/kg (41 patients: RR 7.3%, OS 12.8 months) or 20 mg/kg (16 patients: RR 6.3%, OS 7.6 months) every 2 weeks. The optimal dose of Bv was determined to be 10 mg/kg but this type of data does not allow any comparison or conclusion (Lyseng-Williamson and Robinson, 2006). In most studies, patients continued Bv until progression or unacceptable toxicity. No data have been presented yet justifying the continued use of Bv beyond PD in combination with some other chemotherapeutic regimen. Since the introduction of Bv in phase I studies, the first dose of Bv had been given over 90 min; the second dose over 60 min and subsequent doses over 30 min. At MSK Cancer Center, non-protocol infusion times of Bv were gradually reduced and since November 2005, Bv at 5 mg/kg was given over 10 min without serious hypersensitivity reactions (Saltz et al., 2006).

Predicting efficacy of Bv Treatment with Bv is cost-intensive and thus, it is very imported to identify predictive factors (clinical, serological or tissue). For patients treated in AVF 2107, subgroup analysis showed prolonged OS for patients treated with IFL plus Bv regardless of clinical characteristics at baseline (Fyfe et al., 2004). Patients with an increased level of baseline plasma-VEGF had a shorter median OS, but the survival benefit of treatment with Bv was independent of baseline plasma-VEGF (Holden et al., 2005). Other subset analysis evaluated microvessel density (MVD) and expression of VEGF and thrombospondin2 on archival tumor tissue from almost 300 patients, but Bv improved survival regardless of the level of VEGF, thrombospondin-2 or MVD (Jubb et al., 2006). Finally, tumor tissue from 295 patients was analysed for mutations in k-ras, b-raf or p-53 and expression of p53, but none of these factors could predict median OS and Bv improved survival in all subgroups (Ince et al., 2005).

Antibodies against EGFR Malignant cells have an increased activity in a variety of signal transport systems compared with normal cells. Growth factors and their receptors are important for normal cellular functions as cellular growth, proliferation, differentiation, angiogenesis and cell death. Several subclasses of tyrosine kinase receptors and their ligands have been isolated and among these are the EGFR and ligands (epidermal growth factor and transforming growth factor-a). Once a ligand binds to the extracellular domain of EGFR, receptor dimerization occurs and down-stream signalling cascades are activated. Antibodies bind to EGFR with high affinity and prevent the binding of the natural ligands. This results in reduced receptor activated tyrosine kinase activity and subsequently to, for example, reduced cell proliferation, cell survival and cell invasion.

Efficacy and safety of Cx in mCRC Cx is a chimeric IgG1 mAb that binds to the extracellular ligand-binding domain of the EGFR with a 5- to 10-fold greater affinity than its natural ligands. The efficacy of Cx has been proven in third-line therapy, but phase III studies are not yet mature in the first- and second-line line setting and therefore, we will begin our review with third-line data. Second- or third-line therapy Preclinical and clinical studies have shown that Cx has activity as a single-agent and synergistic activity in combination with chemotherapy (Veronese and O’Dwyer, 2004; Nygren et al., 2005; Stern and Herrmann, 2005; Arnold et al., 2006; Saunders and Iveson, 2006; Van Cutsem et al., 2006). In a phase II Oncogene

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study of 57 patients with irinotecan-refractory mCRC, Cx alone produced a RR of 8.8% (Saltz et al., 2004), but in combination with irinotecan the RR was as high as 22.5% (Saltz et al., 2001). These encouraging results were confirmed in the pivotal randomized BOND I trial (Cunningham et al., 2004). In BOND I, 329 patients whose disease had progressed during or within 3 months after treatment with an irinotecan-based regimen and whose tumors expressed any level of EGFR were randomized to receive either Cx (400 mg/m2 loading dose, followed by 250 mg/m2 weekly) alone (111 patients) or Cx (as above) in combination with irinotecan (same schedule as before; 218 patients). The combination significantly increased RR from 11 to 23% and prolonged TTP from 1.5 to 4.5 months, but significant prolongation of OS was not seen, perhaps because the study was not designed to show a survival difference or perhaps due to crossover and use of CxIri as salvage therapy at the time of PD. In 56 patients progressing on Cx alone, the addition of irinotecan resulted in two partial responses. Subgroup analyses indicated preserved efficacy for the combination for patients having prior oxaliplatin treatment (65% of patients). One of the criticisms of the BOND I study was the lack of a control group. Therefore, a large phase III study (NCIC-CO.17) was conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) in collaboration with the Australasian Gastro-Intestinal Trials Group (AGITG). A total of 572 patients pretreated with irinotecan and oxaliplatin were randomized to the BSC or Cx monotherapy. No data have been presented yet, but a press release on 6 November 2006 stated that Cx did improve OS. The multinational MABEL study was designed to investigate irinotecan and Cx in a larger community practice (Wilke et al., 2006). More than 1100 patients with EGFR-detectable and irinotecan refractory mCRC (69% also pretreated with oxaliplatin) received Cx in combination with three different irinotecan schedules (125 mg/m2 weekly for 4/6 weeks, 180 mg/m2 every 2 weeks or 350 mg/m2 every 3 weeks). For all irinotecan regimens, comparable RR, TTP, OS and toxicity were seen. Overall RR was 20%, median TTP was 3.3 months and median OS was 9.2 months, clearly confirming in a wider setting the efficacy and safety of CxIri. Since January 2005, third-line therapy with CxIri in patients with mCRC resistant to FU/FA, irinotecan and oxaliplatin (EGFR status was not mandatory) has been offered at four departments in Denmark. The efficacy and toxicity in the first 65 consecutive patients (Pfeiffer et al., 2007b) treated at three departments were registered and it was confirmed in a general population that salvage therapy with Cx and irinotecan is effective in patients pretreated with irinotecan and oxaliplatin. Almost identical results were found in an Italian study with 55 patients (Vincenzi et al., 2006c). A combination of Cx and oxaliplatin has been investigated in patients having progressed on oxaliplatin and on Cx plus irinotecan, but due to lack of response in the first 12 patients, the study was prematurely terminated (Vincenzi et al., 2006b). Oncogene

A randomized second-line study (EXPLORE) compared FOLFOX with or without Cx. This study was also prematurely stopped after inclusion of 102 patients of the planned 1100 patients due to recent change in clinical practice resulting in the replacement of irinotecan with oxaliplatin in the first-line setting in many institutions. Safety analysis has been presented, but there was no relevant therapeutic benefit (Jennis et al., 2005). As a result of the BOND I study, the combination of CxIri was approved for patients with irinotecanresistant disease in US in February 2004. In June 2004, Erbitux was approved by EMEA for the following indication: ‘Erbitux in combination with irinotecan is indicated for the treatment of patients with EGFRexpressing metastatic colorectal cancer after failure of irinotecan-including cytotoxic therapy’ (Nygren et al., 2005). First-line therapy Several small and preliminary reported phase II trials (Rougier et al., 2004; Dittrich et al., 2006; Folprecht et al., 2006; Andre et al., 2007) have shown a promising activity for chemotherapy–Cx combinations, but there are not yet mature and reliable data available from phase III studies. In these single-arm phase II studies, combinations with irinotecan- or oxaliplatin-based chemotherapy are well tolerated and active with RR ranging from 45 to 81% and OS ranging from 23 months to more than 30 months (Table 4). At the ASCO 2006 annual meeting, a two-by-two randomized study from the CALGB group (randomizing chemonaive patients to either FOLFOX or FOLFIRI, with or without Cx) was presented (Venook et al., 2006). This trial was also prematurely closed (after Bv registration), but 238 patients were evaluable for efficacy. There was no difference in RRs for FOLFOX vs FOLFIRI. Chemotherapy in combination with Cx significantly increased RR from 33 to 49%. Prelimary data from two small randomized phase II studies (Borner et al., 2006; Heinemann et al., 2006) were also presented. One study showed that addition of Cx to XELOX increased RR (from 27 to 43%) and another study showed that the combination of XELOX and Cx increased RR from 42 to 66% compared with XELIRI and Cx. Efficacy results from randomized phase III trials comparing FOLFIRI (CRYSTAL) or FOLFOX with or without Cx in first-line setting have to be awaited for a definitive conclusion.

Efficacy and safety of Pa in mCRC Pa is a fully human anti-EGFR IgG2 mAb. In contrast to IgG1 antibodies (e.g., Cx), Pa does not stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Clinical trials have documented efficacy of Pa as monotherapy (Malik et al., 2005; Peeters et al., 2006). In a large phase II study, 148 pretreated patients with

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3669 Table 4 Most important studies with Cx in patients with mCRC Author Third-line therapy Cunningham et al. (2004) BOND I Lenz et al. (2006) Saltz et al. (2005) BOND II Pfeiffer et al. Acta Oncol (2007b) Vincenzi et al. (2006) Wilke et al. (2006) MABEL Van Cutsem, ASCO GI (2007) EVEREST Not presented yet

Regimen Cx CxIri Cx Cx+Bv Iri+Cx+Bv CxIri CxIri CxIri

Phase

n

RR (%)

TTP (months)

OS (months)

II

111 218 346 35 39 65 55 1147

11 23a 12 23 39 20 25 20

1.5 4.1a 1.5 6.9 8.5 5.4 4.7 —

6.9 8.5 6.6 — — 10.4 9.8 9.2

77 44 45 285 287

22 30 13 — —

— — — — —

— — — — —

650 650 52 50

— — — —

— — 4.1 4.4

— — — —

II II II II Open

Classic CxIri Escalating CxIri Classic CxIri BSC Cx

II III

Second-line therapy Abubakr et al., ASCO (2006) EPIC Jennis et al. (2005) EXPLORE

Iri CxIri FOLFOX FOLFOX+Cx

III

First-line therapy In combination with irinotecan Rougier et al. (2004) Folprecht et al. (2006)

FOLFIRI+Cx AIO/Iri+Cx

I/II I/II

42 21

45 67

— 9.9

23 33 30

NCIC-CO.17

III

III

In combination with oxaliplatin Dittrich et al. ASCO GI (2007) ACROBAT Dittrich et al. (2006)

FOLFOX+Cx

II

42

81

12.3

FUFOX+Cx

II

49

57

—

30.6

Randomized studies Borner et al. (2006) SAKK Heinemann et al. (2006) AIO Venook et al., ASCO (2006) CALGB 80203

XELOX XELOX+Cx XELOX+Cx XELIRI+Cx FOLFOX/FOLFIRI FOLFOX/FOLFIRI+Cx

II

37 37 41 43 121 117

27 43 66 42 38 52a

— — — — — —

— — — — — —

II III

Abbreviations: Cx, cetuximab; OS, overall survival; RR, response rate; TTP, time to progression. aSignificant difference.

known EGFR overexpression were treated with Pa 2.5 mg/kg i.v. weekly (Malik et al., 2005). A partial response was observed in 9% of patients and disease control in 29%, median TTP was 3.1 months and median OS was 8.7 months. Pa was well tolerated, only 7% had skin toxicity grade III and only 3% had to discontinue treatment due to toxicity. Only one patient experienced infusion reaction, but it was possible to retreat the patient in subsequent cycles. A subsequent phase III trial was conducted to compare efficacy and safety of Pa plus BSC to BSC alone in 463 patients with mCRC resistant to oxaliplatin and irinotecan (Peeters et al., 2006). As in the BOND I study, one of the inclusion criterias was EGFR positive tumors (EGFR expression in X1% of tumor cells). Patients received Pa 6 mg/kg every 2 weeks until PD and cross-over was allowed for patients, who progressed on BSC. Patients treated with Pa obtained PR of 8% and disease stabilization in 28%. Treatment with Pa resulted in 46% decrease in progression rate (e.g., TTP was increased from 30% to 49% at week 8). The significant

improvement in TTP was demonstrated in all subgroups, and the improvement was independent of EGFR status (Hecht et al., 2006b). The rate (174 of 232 patients or 75%) and timing (median 7 weeks) of crossover from the BSC arm to receiving Pa, and the antitumor activity observed after crossover (RR 10%), likely confounded the ability to demonstrate a treatment effect on OS. Preliminary data have shown that a combination of FOLFIRI with Pa was well tolerated and had activity as first-line treatment (Hecht et al., 2006a). Based on these data, Pa (Vectibix) was approved by FDA on 27 September 2006 for the treatment of patients with mCRC resistant to FU/FA, oxaliplatin and irinotecan. Toxicity of Cx and Pa Side effects are in general related to abundant amounts of EGFR in normal tissues like the skin, mouth and gastrointestinal tract (GI tract), but in addition, administration of antibodies also may give rise to immunologic reactions. Oncogene

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The most frequently encountered side effect to treatment with Cx (Saltz et al., 2004) and Pa (Gibson et al., 2006) is a generally mild to moderate acne-like rash in more than 80% of the patients. It consists of a folliculitis often associated with pruritus. It is predominantly located to seborrheic areas in the face (like the nose, cheek, chin and forehead) and the upper chest and back. However, depending on the severity of the rash it can be located anywhere but not in the palms and soles (Busam et al., 2001; Robert et al., 2005). Typically, the rash appears within 1–2 weeks after onset of therapy with spontaneous improvement within the next 4–5 weeks (Busam et al., 2001; Cunningham et al., 2004; Saltz et al., 2004). The skin reactions are fully reversible within a couple of weeks after cessation of therapy (Robert et al., 2005). There are no evidence-based recommendations for treatment of cutaneous side effects, but systemic antibiotics like tetracycline or steroids, topical retinoids and vitamin K have been used successfully on an empirical basis (Yamamoto et al., 2004; Agero et al., 2006; Perez-Soler et al., 2006). Another problematic, but less frequent, dermatological side effect is paronychia often seen after 2–4 months of Cx therapy (Saltz et al., 2004). Curly, fine or more brittle hair on the scalp and extremities and slow growth of beard has been reported (Van Doorn et al., 2002). In contrast, extensive growth of both eyelashes and eyebrows has been reported after long-time treatment with Cx (Bouche´ et al., 2005; Robert et al., 2005). Affection of EGFR in the GI tract may cause nausea and diarrhea (Cunningham et al., 2004; Vincenzi et al., 2006a) as well as oral aphthous ulcers (Busam et al., 2001). EGFR is strongly expressed in the kidney, particularly in the ascending limb of the loop of Henle where 70% of filtered magnesium is reabsorbed and as a result, EGFR blockade may trigger hypomagnesemia. Grade 3–4 hypomagnesemia has been observed in as many as 25% of patients (Carson et al., 2005; Schrag et al., 2005; Fakih et al., 2006) and may augment nausea and fatigue. Oral supplementation may be ineffective, then i.v. magnesium sulpfhate will easily normalize the condition (Fakih et al., 2006). No study has compared side effects of Cx and Pa, but crosstrial comparison (Saltz et al., 2004; Saif and Cohenuram, 2006) showed that the spectrum of side effects are equivalent, but anaphylactic reactions are probably more rarely seen with Pa. Comparison of Cx and Pa RR for Cx and Pa single agents (8–11%) are very similar in pretreated patients (Cunningham et al., 2004; Malik et al., 2005; Lenz et al., 2006; Peeters et al., 2006). There was no improvement in median OS, neither in the Peeters study nor in the BOND I study, but this lack of difference may be caused by the fact that many patients in both studies received salvage therapy upon PD. Indirectly, data from these randomized studies and data from studies evaluating efficacy of third-line Oncogene

chemotherapy in patients with oxaliplatin and irinotecan resistant disease (Rosati et al., 2003; Lim et al., 2005) indicate that a combination of irinotecan and Cx increase median OS from 5–6 to 9–10 months in heavily pretreated patients. There is apparently no difference in the incidence or grade of rash but there are some differences in rare instances. Development of interstitial lung disease (0.5%) and human antihuman antibodies have only been reported in patients receiving Cx. Pa has a higher affinity for EGFR, but antibodies with high affinities for target receptors may bind stably to the first-encountered receptor (including normal tissues) and thus have impaired tumor penetration properties (Adams et al., 2001). Only Cx induce antibody-dependent cellmediated cytotoxicity that may add to efficacy. Pa can be administrated without hypersensitivity premedication, and it is routinely administrated every 2 (or perhaps 3) weeks, which makes Pa an excellent partner for combination chemotherapy. However, a pharmacokinetic and pharmacodynamic study showed no major differences between Cx standard dose weekly and Cx double dose every second week (Tabernero et al., 2006), and since November 2005, we have routinely administered simplified CxIri as thirdline treatment every second week to patients with mCRC (Pfeiffer et al., 2007a). In 40 consecutive patients, efficacy and toxicity were similar to results obtained with standard CxIri. Several ongoing trials are actual evaluating the efficacy of both Cx and Pa in combination with chemotherapy and other targeted agents as first-line treatment, and as adjuvant therapy. Cx and Pa have not been compared directly, but the two antibodies seem to have comparable efficacy and toxicity as single agent and in combination with chemotherapy in chemorefractory patients. Predicting efficacy of Cx and Pa Costs of targeted therapies warrant the selection of patients that actually benefit from the therapy. To date, no predictive markers are in routine use, but several promising candidates have been identified. Among these are immunohistochemistry (IHC) and fluorescence in situ hybridization in pre-treatment tumor biopsies, the development of skin rash, changes of biomarkers in the skin or mutations in EGFR. Correlation of survival with rash. In BOND I, patients treated with CxIri and developing severe skin rash, RR was 55%, TTP was 8.2 months and median OS was 13.7 months, respectively, and the degree of rash as a predictive marker for RR and OS has been confirmed in many studies (Lenz et al., 2006; Pfeiffer et al., 2007b). IHC and FISH in pre-treatment tumor biopsies. Approximately 75% of all colorectal carcinomas stain positive for the EGFR (Salomon et al., 1995). In BOND I, efficacy for both CxIri and Cx alone was unrelated to percentage of EGFR-expressing cells and staining intensity.

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Before approval of Cx, a multicenter study was initiated to determine the activity of Cx in mCRC refractory to both irinotecan and oxaliplatin (Lenz et al., 2006). The aim of the study was to obtain more information on the toxicity, but also to relate efficacy to EGFR gene mutations and gene amplification. The RR in 346 patients was 12%, TTP was 1.4 months and OS was 6.6 months. RR and OS were strongly related to skin rash. Interestingly, out of nine erroneously EGFR-negative patients enrolled, two had partial remissions. Recent retrospective studies (Chung et al., 2005; Hebbar et al., 2006) confirmed activity of CxIri or Cx alone in EGFR negative mCRC, and the practice of testing EGFR status by IHC to select for Cx (or Pa) therapy is clearly inappropriate and other predictive tests are needed (Meropol, 2005; Nygren et al., 2005; Hecht et al., 2006b). Furthermore, the expression in primary tumors does not necessarily reflect or predict the expression in metastatic sites (Scartozzi et al., 2004). Perhaps the level of activated, phosphorylated EGFR is more important than the total EGFR level (Ciardiello and Tortora, 2003; Luo et al., 2005). In a small study, with just 23 patients with irinotecan-resistent mCRC, high expression of phosphorylated EGFR was a predictive factor for high RR after to Cx (Personeni et al., 2005). Then, why does IHC not predict for activity of Cx? First of all, EGFR positivity is relative and highly dependent of the antibody used, the type of tissue fixation and the duration of storage (Grabau et al., 1998). Secondly, tumor heterogeneity may play a role, and finally the general assumption that an increased number of receptors may lead to a greater degree of clinical activity may be wrong. It is necessary to look in greater detail at the target: activated EGFR, activation of the downstream cascade, co-activation of other related receptors or gene amplification of the receptors in question (Shia et al., 2005). In a small study with 31 patients receiving Cx or Pa, eight of nine responders had amplification of EGFR, whereas this was only the case in one of 21 non-responders (Moroni et al., 2005). Mutations. With the discovery of the prognostic importance of mutations in the kinase domain of EGFR for the efficacy of kinase inhibitors in lung cancer (Lynch et al., 2004; Paez et al., 2004), it was reasonable to assume the same influence in colorectal carcinomas. However, the presence of mutations in exon 18, 19 and 21 of the kinase domain (Barber et al., 2004; Moroni et al., 2005; Tsuchihashi and Khambata-Ford, 2005; Lenz et al., 2006) and mutation in the external part of EGFR (Azuma et al., 2006) is very rare in CRCs suggesting that EGFR mutations are not critical for efficacy of EGFR inhibition. Other biomarkers. The absence of predictive markers has increased the focus of other parts of signaling pathways related to the EGFR system. No clinical data are available, but at a preclinical level, it was found that

high gene expression of VEGF was associated with resistance to EGFR inhibition (Vallbohmer et al., 2005). In line with these data, long-lasting reduced levels of serum VEGF was found upon treatment with Cx (Vincenzi et al., 2006b). These preliminary data might be important for the future combination of targeted drugs like Bv, Cx and Pa. Optimal dosage and schedule of Cx Phase I studies (Baselga et al., 2000; Humblet et al., 2005) have established the standard dose of Cx (loading dose 400 mg/m2 followed by weekly doses of 250 mg/m2) used in the majority of clinical trials. Cx is administered weekly but preliminary data suggest that Cx 500 mg/m2 can be safely and effectively be administered every second week (Tabernero et al., 2006; Pfeiffer et al., abstract accepted for ASCO GI 2007a). In the EVEREST study, all patients received standard dose CxIri for 3 weeks. Patients with no or mild rash (grade 0 or 1) were then randomized to continue standard CxIri or CxIri with increasing dose of Cx. The higher dose of Cx (up to 500 mg/m2 weekly) was generally well tolerated with slightly increased skin toxicity as the only extra side effect and these data seems to be supported by preliminary data from a phase I study in multiple tumor types (Ho et al., 2006). Recently, the first efficacy data for the EVEREST study was presented (Van Cutsem et al., 2007b). Patients treated with an increased dose of Cx had a doubling of RRs (30 vs 13%), but data on TTP and OS are awaited before this strategy can be recommended in routine practice.

Combination of targeted therapies Inhibition of the EGFR is a promising concept and it is tempting to combine inhibition of the extracellular part of EGFR with inhibition of the tyrosine kinase domain – that is, combine antibody therapy with tyrosine kinase inhibitors. Some preclinical studies (Huang et al., 2004; Matar et al., 2004) but not all (Cunningham et al., 2006) showed synergistic effect, but solid clinical data are lacking. There is a reliable rationale for combining VEGF and EGFR inhibitors (Vallbohmer et al., 2005; Vincenzi et al., 2006b). Preclinical studies confirmed a synergistic growth inhibition (Morelli et al., 2006; Tonra et al., 2006) and preliminary clinical data have already verified efficacy of the combination (Saltz et al., 2005). The BOND II trial was a randomized phase II trial (combination of Cx and Bv with or without irinotecan), but it was sadly preliminary stopped due to poor accrual after inclusion of only 74 patients with irinotecanresistent mCRC (Table 3). High RR (23 and 39%) and long TTP (6.9 and 8.5 months) without any unexpected toxicity are very encouraging in these pretreated patients, especially if results are weighed against BOND I data (Table 4). These promising data are the basis for Oncogene

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large ongoing phase III trials evaluating efficacy of modern chemotherapy in combination with Cx or Pa and Bv.

Surgery and antibody therapy Presently liver-resection offers the best chance of cure in patients with resectable liver metastases, and nonrandomized studies indicate that comparable results can be obtained following neo-adjuvant chemotherapy in patients with initially unresectable liver metastases (Adam et al., 2004). In phase III studies evaluating doublets, a resection rate of 5–10% is often found. An improved RR will hopefully result in even more curative intended resections. Compared to historical data, addition of antibodies to chemotherapy has increased the resection rate (Rougier et al., 2004; Folprecht et al., 2006; Andre et al., 2007), but presently it is not known for sure whether the higher resection rate is caused by more effective therapy or simply a matter of selection and more experienced surgeons. In an excellent review (Folprecht et al., 2005), it was found that 24–54% of patients with non-resectable liver metastases became resectable following chemotherapy, compared with 1– 26% of patients in trials that included non-selected patients with mCRC. A strong correlation was found between RRs and the resection rate and ‘resectability’ as a novel end point in mCRC was suggested. However, in several of the above-mentioned small phase II studies, a doubling of resection rate has been observed. If these data can be confirmed in large studies, there is a real chance that not only median survival but also long-term survival will be influenced. EGFR therapy in conjunction with surgery must be considered very carefully as it is demonstrated that EGFR regulates multiple facets of wound healing, including inflammation, wound contraction, proliferation, migration and angiogenesis (Repertinger et al., 2004). In head and neck cancer, a small study with eight patients (Harari et al., 2003) receiving elective neck dissection after curative intended radiotherapy in combination with Cx, the length of hospital stay was not prolonged and no postoperative complications was found. In phase II studies in mCRC, a number of patients had R0 liver-resection after neo-adjuvant therapy without extra comlications reported (Rougier et al., 2004; Tabernero et al., 2004; Folprecht et al., 2006). Preclinical studies have shown that inhibition of angiogenesis may impair wound healing (Howdieshell et al., 2001). In clinical trials/observational studies wound healing complication is reported to occur in 0.3–5.6% of patients receiving chemotherapy and Bv (Van Custsem et al., 2007a; Hochster et al., 2006; Kozloff et al., 2006). A pooled analysis of AVF 2107 and AVF 2192 (Scappaticci et al., 2005) assessed wound healing complications in patients who underwent surgery 28– 60 days before study treatment (patients who had Oncogene

undergone major surgery within 28 days were not eligible for enrolment). The risk of wound healing complications was not significantly increased in patients receiving Bv at least 4 weeks after surgery. In addition, surgical complications in patients who underwent major surgery (5.6% of patients receiving chemotherapy alone, but 12% of patients receiving Bv) during study treatment were evaluated. Wound healing complication was increased from 3.4 to 13% in patients receiving treatment with Bv if surgery was performed within 60 days after last treatment. In accordance with these data, it was recommended waiting at least 8 weeks after last dose of Bv based on pharmacokinetic data (Ellis et al., 2005). In a pilot study, eight of nine patients receiving neoadjuvant XELOX and Bv underwent liver resection for synchronous liver metastases (Gruenberger et al., 2006). Therapy with Bv was discontinued 5 weeks before surgery and restarted 5 weeks after surgery. The authors found no extra complications compared with their previous data evaluating chemotherapy alone before surgery. Yet this pilot study included a small number of patients, and therefore, more clinical data are needed before any final conclusion can be made. Implantation of venous access device shortly before starting Bv did not increase the risk of wound healing/ bleeding (Van Cutsem et al., 2007a)

Cost More progress has been made in increasing the duration of survival of patients with mCRC in the past 5 years than in most other cancers. We have seen approval of irinotecan, oxaliplatin, Cx, Bv and recently Pa, and these newer therapies are much more expensive than FU/FA (Schrag, 2004; Paramore et al., 2006). In a recent study (Paramore et al., 2006), the mean monthly disease-related cost almost tripled from 1998 ($4200) to 2004 ($11 100). Monthly disease-related costs were similar in the diagnostic phase ($12 200) and death phase ($12 300), but were significantly lower in the treatment phase ($4700). Patients with longer survival thus have a lower average monthly cost. The study points out that the economic impact of mCRC is substantial and increasing over time and that monthly cost almost tripled from 1998 to 2004. Because of substantial increase in costs, questions and discussions about cost-effectiveness of new therapies are needed. Cost-effectiveness analysis is a tool that can help to shift away from or avoid therapies that produce too little benefit at too high cost. Presently, there is no consensus regarding the appropriate threshold value, but a range of $50 000–100 000 per gained life year is commonly used in the United States (Hillner et al., 2005) and in UK, a threshold of d30 000 (approximately $55,000) has been suggested (Miners et al., 2005). N9741 demonstrated that FOLFOX was superior to the previous standard of care in the United States, IFL (Goldberg et al., 2004). Compared to IFL a post hoc

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analysis revealed that FOLFOX increased average cost of almost $30 000 corresponding to approximately $80 000 per life year gained and $110 000 per qualityadjusted life year (Hillner et al., 2005). The authors concluded that FOLFOX provided considerable benefits, however, the substantial additional costs fell into the upper range of commonly accepted oncology interventions. In August 2006, the UK’s National Institute of Clinical Excellence decided not to recommend the use of Bv and Cx in mCRC based on the cost-effectiveness, arguing that both drugs are too expensive. The decision prompted outcries from charities and oncologists and appeals have already been launched before the finalstage draft guidance comes into effect. Final remarks Medical treatment of mCRC has changed dramatically in the past 5 years. Which patient should receive targeted therapy in combination with chemotherapy taking into account efficacy, toxicity and costs? There is no clear-cut answer that may differ from department to department or from country to country. Both the ‘new’ targeted drugs and the ‘old’ cytotoxic agents have contributed to a substantial improved outcome for our patients. Presently, there are several appropriate treatment options without any single optimal regimen and this has made the treatment decision more complex, but at the same given room for individualized treatment. The best choice for a given patient must take into account, for example, age, performance status, symptoms, co-morbidity and whether the tumor is potential resectable after neo-adjuvant therapy:

The contribution from antibodies is important but still small in absolute terms and at a price that will be difficult to handle in some health-care systems. Therefore, selection of patients with a higher chance of responding to a specific treatment is very important and tumor, serum and plasma must be collected prospectively along with clinical data to look for predictive markers. Randomized studies have consistently shown that addition of Bv to chemotherapy prolongs TTP with 3–4 months and OS with 4–6 months in the first-line treatment and if a drug prolongs median survival for 4–6 months, patients should definitely be offered this treatment. It remains to be proven that Bv also will add 4–6 months to the efficacy of ‘optimal chemotherapy regimens’. However, for many patients, Bv should be integrated into the standard first-line therapy but ‘best chemotherapy’ (e.g., FOLFOX or FOLFIRI) may be a reasonable alternative. Presently, it is not known whether Bv should be continued in combination with second-line chemotherapy, but this question is currently being investigated. The high RR, resection rate and very long OS of selected patients receiving Cx and chemotherapy in first line phase II trials are very promising, but confirmatory randomized trials must be awaited before final conclusions. There is strong evidence for treatment of patients with Cx (or Pa) and irinotecan after failure of irinotecan- and oxaliplatin-based therapies. The high RR and long OS in first-line phase II trials are very promising, but confirmation in randomized trials are required. The practice of testing EGFR status by IHC to select for EGFR antibody therapy is clearly inappropriate and should no longer be used.

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