Epidermal Growth Factor Recep

Anti−Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today? Marc Peeters, Tim Price and Jean-Luc Van Laethem The Oncologist 2009, 14:29-39. doi: 10.1634/theoncologist.2008-0167 originally published online January 14, 2009

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Gastrointestinal Cancer Anti–Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today? MARC PEETERS,a TIM PRICE,b JEAN-LUC VAN LAETHEMc Department of Hepatogastroenterology, Digestive Oncology Unit, University Hospital Ghent, Gent, Belgium; Department of Haematology and Oncology, Queen Elizabeth Hospital, Woodville, Australia; cDepartment of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Brussels, Belgium

b

Key Words. Panitumumab • Cetuximab • EGFR • mCRC • Monotherapy Disclosures Marc Peeters: Honoraria: Amgen, Merck Serono; Research funding/contracted research: Amgen, Merck Serono; Tim Price: Consultant/advisory role: Amgen; Jean-Luc Van Laethem: None The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers.

ABSTRACT Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC). Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mouse– human chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy-refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitu-

mumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti-EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti-EGFR monotherapy is an effective treatment modality for patients with chemotherapy-refractory advanced CRC. The Oncologist 2009;14:29 –39

INTRODUCTION

excellent 5-year survival rate (90% for localized disease), approximately 20% of patients present with metastatic disease, and many patients diagnosed with stage II or III cancer will experience a recurrence and develop distant metastases. The 5-year survival rate for patients with metastatic disease is approximately 10% [3].

Colorectal cancer (CRC) is the fourth most common cancer worldwide with current predictions estimating that, in 2008, 1.2 million new cases of the disease would be diagnosed and 630,000 people would die as a result of the disease [1, 2]. While early-stage CRC is associated with an

Correspondence: Marc Peeters, M.D., Ph.D., Department of Hepatogastroenterology, Digestive Oncology Unit, University Hospital Ghent, De Pintelaan 185, B-9000 Gent, Belgium. Telephone: 32-9-332-23-81; Fax: 32-9-332-49-84; e-mail: marc.peeters@ ugent.be Received August 1, 2008; accepted for publication December 1, 2008; first published online in The Oncologist Express on January 14, 2009. ©AlphaMed Press 1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2008-0167

The Oncologist 2009;14:29 –39 www.TheOncologist.com


a

30

ANTI–EPIDERMAL GROWTH FACTOR RECEPTOR THERAPY IN THE TREATMENT OF CRC

and phase III clinical trials evaluating its safety and efficacy in the monotherapy setting. All registrational trials for the agents were included, although for the Bowel Oncology with Cetuximab Antibody (BOND) study of cetuximab plus irinotecan versus cetuximab monotherapy, only the monotherapy patients were analyzed [7]. Trials of cetuximab and panitumumab differed in study design and inclusion criteria, making direct comparisons of trial results difficult. This review, thus, provides an overview of the patient demographics, study designs, efficacy, and safety results of several of these key mCRC trials and discusses how study variations and differences may have influenced trial results. In addition, this paper provides an update on the recent retrospective analyses of mCRC clinical studies with anti-EGFR monotherapy suggesting that KRAS mutational status is an important predictor of resistance to EGFR-targeted therapy.

OVERVIEW OF 10 PANITUMUMAB AND CETUXIMAB MONOTHERAPY CLINICAL STUDIES In total, 10 studies consisting of data from eight phase II and two phase III trials were reviewed. Trials or arms of trials evaluating anti-EGFR antibodies in combination with chemotherapy were not included in the analysis. The phase II studies consisted of four cetuximab trials [7, 17–19] and four panitumumab trials, one of which was an open-label extension study of the phase III trial [20 –23], whereas the phase III studies consisted of one panitumumab trial [24] and one cetuximab trial [25]. The study designs of all of the trials are summarized in Table 1.

Overview of Subject Populations The patient demographics of the 10 trials are summarized in Table 2. The median age of the patients was similar across all trials (56 – 65 years) and represents a relatively young patient population compared with the majority of patients diagnosed with mCRC [26]. The studied populations consisted of slightly more men (54%– 69%) than women (31%– 46%). More than 90% of the phase II study subjects had good baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores (0 to 1), whereas some subjects with poorer baseline conditions (13%–23% had an ECOG PS score of 2) were included in the phase III studies. In comparing the phase III trials, the distribution of patients in regard to ECOG PS score was 23% for patients in the cetuximab versus best supportive care (BSC) study with a PS score of 2, compared with 13% of patients in the panitumumab study that were classified in this poorer performance category. For all the phase II and III studies, the enrolled pa-


Colorectal neoplasms are a subgroup of epithelial malignancies that overexpress the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase whose activation leads to aberrant signaling and cell proliferation [4]. EGFR expression levels in CRC tumors correlate with disease progression, metastatic spread, and poorer prognosis [5]. Two monoclonal antibodies (mAbs) that bind and block EGFR signaling are currently approved for the treatment of metastatic CRC (mCRC). The first drug approved in this class was cetuximab (Erbitux威; ImClone Systems, New York, Merck-Serono, Geneva, Switzerland, and Bristol-Myers Squibb, New York), an IgG1 human–mouse chimeric mAb. Cetuximab was approved both as a monotherapy and in combination with irinotecan by the U.S. Food and Drug Administration (FDA) in February 2004 and by the European Medicines Agency in June 2004 for the treatment of refractory mCRC based on the results of a phase II study of cetuximab monotherapy versus cetuximab combined with irinotecan [6 – 8]. Cetuximab has also recently been approved for use in combination with chemotherapy in the European Union (EU) for the treatment of patients with EGFR-expressing, wild-type KRAS mCRC [8]. Panitumumab (Vectibix威, ABX-EGF; Amgen, Thousand Oaks, CA) is an IgG2 fully human mAb directed against the EGFR. Panitumumab was approved for use as monotherapy by the U.S. FDA in September 2006 and is indicated for the treatment of EGFR-expressing mCRC that has progressed on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [9]. Panitumumab was also granted approval in the EU in December 2007 for the treatment of patients with chemotherapy-refractory, EGFR-expressing mCRC with wild-type KRAS [10]. Preclinical studies have shown that both cetuximab and panitumumab bind to the extracellular domain of the EGFR, blocking ligand-induced receptor signaling, which results in inhibition of tumor growth [6, 9, 11, 12]. Preclinical data also suggest that cetuximab may induce antibodydependent cellular cytotoxicity (ADCC) [13–15]. However, a recent report failed to demonstrate cetuximab-induced ADCC and this phenomenon has not yet been shown to be clinically relevant [16]. Both panitumumab and cetuximab have been extensively studied as single agents for the treatment of mCRC in a number of phase II and III trials. Although cetuximab is also approved for use and commonly used in combination with irinotecan, for the purpose of this review it seemed appropriate to focus only on relevant phase II

EGFR Monotherapy for mCRC

Peeters, Price, Van Laethem

31

Table 1. Study designs and methods Cetuximab

Panitumumab Van Cutsem et al. (2008) [23]

Berlin et al. (2006) [20]

Hecht et al. (2008) [21]

Hecht et al. (2007) [22]

Cunningham et al. (2004) [7]

Lenz et al. (2006) [17]

Jonker et al. (2007) [25]

Wierzbicki et al. (2008) [19]

57

111

346

287

85

231

176

93

203a

148

Phase

II

II/III

II

III

II

III

II

II

II

II

Dose schedule

400 mg/m2 loading dose, 250 mg/m2 weekly





6 mg/kg every 2 wks

6 mg/kg every 2 wks

6 mg/kg every 2 wks

6 mg/kg every 2 wks

2.5 mg/kg weekly

Duration of infusion

Loading, 2 hours; weekly, 1 hour




Loading, 2 hours; weekly, 1 hour L

1 hour

1 hour

1 hour

1 hour

1 hour

Premedication drugs per protocol

Diphenhydramine, 50 mg

Antihistamine

Diphenhydramine, 50 mg

Antihistamine

NR

NA

NA

NA

NA

NA

Response assessment

RECIST, central review

RECIST, local review; WHO, central review

WHO, central review


Local review


RECIST, local review

WHO, central review

WHO, central review


Tumor cells stained by IHC for membrane EGFR-b, %

Positive ⱖ1

Positive

9 (2.6%) were undetectable, others had IHC 1⫹ to 3⫹

Detectable by IHC

Negative

ⱖ1%

ⱖ1%

ⱖ10%

Negative (⬍1%) or low (1%– 9%)

High or low

n of patients (treatment arm)

a Includes patients with no evaluable EGFR staining. Abbreviations: EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; NA, not applicable; NR, not reported; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization.

Table 2. Demographics Cetuximab

Panitumumab

Saltz et al. (2004) [18]


Lenz et al. (2006) [17]



Van Cutsem et al. (2007) [24]



Hecht et al. (2008) [21]

Hecht et al. (2007) [22]

n of patients (treatment arm)

57

111

346

287

85

231

176

93

203

148

Phase

II

II/III

II

III

II

III

II

II

II

II

Male

35 (61)

63 (57)

185 (54)

186 (65)

59 (69)

146 (63)

111 (63)

51 (55)

114 (56)

83 (56)

Female

22 (39)

48 (43)

161 (46)

101 (35)

26 (31)

85 (37)

65 (37)

42 (45)

89 (44)

65 (44)

56 (28, 80)

58 (39, 84)

59 (29, 85)

63 (29, 88)

65.4 (40–86)

62 (27, 82)

62 (32, 83)

59 (31, 82)

61 (20,85)

60 (21, 88)

Gender, n (%)

Median (min, max) age, yrs ECOG score, % 0

Median, 0;

KS: ⬍80,

42

25

33 (39)

46

30

33

50

25

1

range, 0–2

13.5%;

57

52

52 (61)

41

48

59

43

75

80–100, 86.5%

0.9

23

0 (0)

13

22

8

6

0

2

Abbreviations: ECOG, Eastern Cooperative Oncology Group; KS, Karnofsky score.

tients had failed prior fluoropyrimidine-based chemotherapy. Table 3 provides an overview of the trial subjects’ disease characteristics and prior exposure to chemotherapy. In all the reviewed studies, ⱖ93% of the patients were refractory to fluoropyrimidine- and irinotecan-containing therapy. For the phase III studies of both cetuximab and panitumumab, patients were re-

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quired to have failed or have contraindications to treatment with oxaliplatin, irinotecan, and a fluoropyrimidine, whereas criteria were less stringent for some of the phase II studies [24, 25]. Across most of the phase II studies ⱖ92% of patients’ tumors were exposed to all three agents, with the exception of two phase II studies of cetuximab [7, 18] and one phase II study of panitumumab [22], which had rel-


Saltz et al. (2004) [18]



32

Table 3. Disease characteristics Cetuximab

Panitumumab

Saltz et al. Cunningham Lenz et al. Wierzbicki Van Cutsem Van Cutsem (2004) et al. (2004) (2006) Jonker et al. et al. et al. (2007) et al. (2008) Berlin et al. Hecht et al. Hecht et al. [18] [7] [17] (2007) [25] (2008) [19] [24] [23] (2006) [20] (2008) [21] (2007) [22] n of patients

57

111

346

287

85

231

176

93

203

148

Phase

II

II/III

II

III

II

III

II

II

II

II

Colon cancer

77

NR

74

59.6

NR

66

64

75

73

72

Rectal cancer

23

NR

26

22.0

NR

34

36

25

26

28

Fluoropyrimidine

100

100

100

100

100

100

100

100

100

100

Irinotecan

100

100

100

96.5

93

100

100

100

100

95

Oxaliplatin

14

64

100

97.9

92

100

100

100

100

49

Primary diagnosis, %

Previous exposure to chemotherapeutic agents, %

atively lower percentages of patients previously treated with oxaliplatin (Table 2). Dosing was consistent across the five cetuximab trials, with patients receiving a loading dose of cetuximab (400 mg/m2 infused over 1 hour) and weekly maintenance doses (250 mg/m2 infused over 1 hour). All patients received an antihistamine prior to cetuximab infusion as prophylaxis against infusion reactions. A weekly dose of 2.5 mg/kg was also tested in the panitumumab trial reported by Hecht et al. [22], but patients receiving panitumumab in the other four studies were given a less frequent dosing schedule of 6 mg/kg infused over a 1-hour period every 2 weeks (Table 1). Subjects in the panitumumab studies did not require any pretreatment prior to infusions. EGFR testing by immunohistochemistry (IHC) is currently required for both cetuximab and panitumumab [6, 9]. The last row of Table 1 summarizes subjects’ EGFR status across the 10 trials. In most cases, positive EGFR (ⱖ1%) by IHC was required for enrollment into these studies. Earlier studies, such as two phase II trials of panitumumab reported by Berlin et al. [20] and Hecht et al. [21], required that patients have a high percentage of tumor cells staining positive (ⱖ10%). Patients in the Hecht et al. [21] study were further delineated into strata defined as high EGFR (intensity of staining of ⫹2 or ⫹3 in ⱖ10% of cells) or low EGFR (intensity of staining of ⫹2 or ⫹3 in ⬍10% of cells). Similarly, in a cetuximab trial reported by Lenz et al. [17], patients were stratified by intensity of EGFR staining as determined by IHC into undetectable, ⫹1, ⫹2, and ⫹3 subgroups. The phase II trial of panitumumab reported by Hecht et al. [21] at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in 2008 examined pa-

tients with tumors that had either low (⬍1%) or negative EGFR expression. A more recent study conducted by Wierzbicki et al. [19] evaluated the safety and efficacy of cetuximab in patients with EGFR⫺ tumors. While the inclusion criteria based on EGFR status differed among the trials, these studies demonstrated that EGFR staining by IHC does not seem to be a predictive factor of response to anti-EGFR therapy in the treatment of mCRC. Furthermore, patients with no detectable EGFR expression in their tumors demonstrated a positive response to antiEGFR therapy with similar efficacy results [17, 19, 21].

Overview of Clinical Efficacy With the exception of the Cunningham et al. [7] registrational trial of cetuximab plus irinotecan versus cetuximab, all the reviewed phase II studies were single-arm monotherapy trials, whereas the phase III trials were randomized studies of cetuximab or panitumumab versus BSC. The major difference between the two phase III studies based on the crossover options was the chosen primary endpoint—progression-free survival (PFS) for the panitumumab study and overall survival (OS) in the cetuximab study. In the panitumumab versus BSC trial, patients were given the opportunity to cross over to receive panitumumab in the extension study, whereas crossover was not included in the cetuximab study design [24, 25]. Radiological responses to treatment were identified using either the Response Evaluation Criteria in Solid Tumors or the World Health Organization criteria, and a majority of the studies analyzed response using a central review (Table 1). Rates of response and stable disease (SD) were similar across all studies of both agents, with response rates in the range of 8%–11.6% and


Abbreviation: NR, not reported.


33

Table 4. Clinical efficacy data Cetuximab

Panitumumab

Saltz et al. (2004) [18]


Lenz et al. (2006) [17]






Hecht et al. (2008) [21]

Hecht et al. (2007) [22]

n of patients

57

111

346

287

85

231

176

93

203

148

Phase

II

II/III

II

III

II

III

II

II

II

II

Complete response

0

0

0

0

0

1

0c

0

0

Partial response

8.8

10.8

11.6

8.0

8.2

10

11

8c

4

11

Stable disease

36.8

21.6

31.8

31.4

42.3

27

33

21c

32

36

Disease progression

NR

53.2

46.2

NR

41.2

NR

37

49c

50

47

Unevaluable/not done

NR

14.4

10.4

NR

NR

NR

18

23c

14

6

Response rate, %

8.8

10.8

11.6

8.0

8.2

10

11.6

8c

4

11

Disease control, %

45.6

32.4

43.4

39.4

50.6

36

44

29c

36

Objective response, %

3.7

d

6.1

47 d

18.2

Median duration of response (mos)

NR

4.2

4.2

NR

NR

3.9

Median PFS/TTP (mos)

Median TTP, 1.4

Median TTP, ⬃1.5

1.4

1.9

Median TTP, 2.6

1.8d

2.1d

1.7d

2d

3.2d

Median OS (mos)

6.4

6.9

6.6

6.1 (versus 4.6 for BSC)a

NR

⬃6.2 (versus 6.2 for BSC)b

6.3d

NR

10.4d (low), 9.4d (high)

8.6d

a

No crossover to cetuximab allowed. Crossover of BSC patients to panitumumab was allowed. c Data based on efficacy data set (n ⫽ 39). d Data are presented in weeks in the original publication. Abbreviations: BSC, best supportive care; NR, not reported; OS, overall survival; PFS, progression-free survival; TTP, time to progression. b

SD rates of 21%– 42.3% (Table 4). One complete response was reported in the panitumumab extension study, as determined by local review [23]. The median PFS times were similar across studies (reported as time to progression in three phase II cetuximab studies), in the range of 1.4 –3.2 months for the phase II studies and 1.8 –1.9 months for the phase III studies for both agents (Table 4). The median OS times were similar across most cetuximab studies and in the panitumumab extension study, in the range of 6.3– 6.9 months in the phase II studies (Table 4). Two phase II studies of panitumumab demonstrated a slightly longer median OS time of 8.6 –10.2 months, compared with the other studies analyzed [21, 22]. The phase III trials of cetuximab or panitumumab versus BSC exhibited very similar median OS times of 6.1 and 6.2 months, respectively, for patients in the treatment arms. However, a difference was observed in the BSC arms of the trials, where median OS times of 4.3 and 6.2 months were reported for the cetuximab and panitumumab trials, respectively [23–25]. While only 7% of BSC patients eventually received cetuximab, 76% of the patients crossed over from BSC to receive panitumumab, and thus lived about as long


as patients in the panitumumab alone arm (6.2 months for both groups) [23, 25]. These data suggest that the differences in the trial design, such as the inclusion of crossover of patients in the BSC arm, may account for differences in the OS durations of patients treated in the two phase III studies.

Overview of Safety Data Skin toxicities were the most commonly reported adverse event (AE) in all cetuximab and panitumumab studies, likely as a result of inhibition of EGFR signaling in the epidermal tissues, which express high levels of EGFR. Unfortunately, skin toxicities were reported differently across the 10 studies, making direct comparisons difficult. The classic papulopustular rash was often described as “acne-like” or “acneiform” in the study reports (Table 5). Grade 3 or 4 papulopustular rashes were reported in 3%–16% of patients and were different in patients treated with cetuximab or panitumumab (Table 5). Furthermore, the onset of skin rash typically occurred within 1–3 weeks following initiation of therapy with either cetuximab or panitumumab (Table 5). In several studies, the severity of skin toxicity was associated with clinical benefit from EGFR-inhibitor treatment


d


34

Table 5. Grade 3 or 4 reported AEs Cetuximab Cunningham et al. (2004) [7]

Lenz et al. (2006) [17]



n of patients

57

115

346

287

85

Any AE, n (%)

NR

50 (43.5)

NR

226 (78.5)

81 (95.3)

Phase

II

II/III

II

III

II

Type, n (%)

Acne, 16; asthenia, 4; atrial fibrillation, 2; hypokalemia, 2; rash, 2; vomiting, 2; confusion, 2; diarrhea, 2; headache, 2

Dyspnea, 13.0; asthenia, 10.4; acne-like rash, 5.2; abdominal pain, 5.2; nausea/vomiting, 4.3; anemia, 2.6; diarrhea, 1.7; thrombocytopenia, 0.9; stomatitis, 0.9

Acne, 4.9; asthenia, 2.0; headache, 1.2; diarrhea, 1.2; nausea, 0.6; dry skin, 0.6; fever, 0.3

Fatigue, 33.0; dyspnea, 16.3; abdominal pain, 13.2; pain–other, 14.9; infection without neutropenia, 12.8: rash or desquamation, 11.8; hypomagnesemia, 5.8; edema, 5.2; anorexia, 8.3; constipation, 3.5; nausea, 5.6; vomiting, 5.6; confusion, 5.6

Dermatitis, 4.7; hypomagnesemia, 4.7; dyspnea 2.4; headache, 1.2

Onset of skin toxicity

1–3 wks

1–3 wks

8–19 days

NR

NR

Infusion reactions, type, n (%)

Allergic reactions, 3 (5)

Hypersensitivity reaction, 4 (3.5)



Infusion reaction grade ⱖ3, (3.5)

Panitumumab Van Cutsem et al. (2007) [24]



Hecht et al. (2008) [21]

Hecht et al. (2007) [22]

n of patients

229

176

93

203

148

Any AE, n (%)

79 (35)

32 (18)

23 (25)

88 (42)

18 (12)

Phase

III

II

II

II

II

Type, n (%)

Acneiform rash, 7.4; abdominal pain, 7.4; erythema, 5.2; dyspnea, 4.8; fatigue, 4.4; anorexia, 3.5; asthenia, 3.1; constipation, 2.6; pruritus, 2.2; skin exfoliation, 2.2; vomiting, 2.2; hypomagnesemia, 3.0; back pain, 1.7; paronychia, 1.3; diarrhea, 1.3; nausea, 0.9; rash, 0.9; skin fissures, 0.9; edema, 0.9; cough 0.4

Acne, 6.2; erythema, 5.1; rash, 4.5; other skin manifestations, 2.3; paronychia, 1.7; pruritus, 1.1; skin exfoliation, 0.6; diarrhea, 0.6; conjunctivitis, 0.6

Acneiform rash, 9.9; erythema, 6.6; rash, 3.3; pruritus, 2.2; paronychia, 2.2; hypokalemia, 2.2; exfoliation, 1.1; skin fissures, 1.1; vomiting, 1.1; anorexia, 1.1; hypomagnesemia, 1.1

Acneiform rash, 6; erythema, 5; pruritus, 3; rash, 3; exfoliation, 3; nausea/vomiting, 2; fatigue/asthenia, 2; diarrhea, 2; dyspnea, 1; infections, 6

Rash, 3; fatigue, 3; vomiting, 1; pruritus, 1; nausea, 1; diarrhea, 1; dyspnea, 1

Onset of skin toxicity

12–15 days

NR

6–13 days

NR

9–14 days

Infusion reactions, type, n (%)

Infusion reaction, 0 (0); only one grade 2 reaction

Moderate hypersensitivity, 1 (0.6)

Infusion reaction, 1 (1)

Infusion reaction, grade 3 or 4, 7 (3)


Abbreviations: AE, adverse event; NR, not reported.

and has been demonstrated to serve as a marker of clinical efficacy [23–25]. In addition to skin toxicities, grade 3 or 4 asthenia or fatigue in the range of 1%–10.4% was observed in most studies, with the exception of the phase III trial of cetuximab, in which it was found in 33% of patients (Table 5). This phase III cetuximab study also reported grade 3 or 4 infection without neutropenia in 12.8% of cetuximab-treated patients, whereas other studies of cetuximab and panitumumab had no reports of that AE. Grade 3 or 4 hypomagnesemia occurred in 5.8% of patients in the cetuximab phase III study and in 3% of patients in the panitumumab phase III study. Although magnesium was prospectively monitored in both trials, the management of low-grade hypomagnesemia may have differed among the

trials, possibly affecting the grade 3 or 4 incidence. EGFR inhibition has been previously shown to be associated with hypomagnesemia, which can be difficult to treat and may require a high dose of magnesium supplementation in this small subset of patients [27]. Despite pretreatment with antihistamines, severe (grade 3 or 4) infusion reactions were reported in 3.5%–7.5% of patients receiving cetuximab, thus requiring immediate interruption and permanent discontinuation of therapy (Table 5). Rare fatal infusion reactions have also been reported with cetuximab therapy, although none were observed in the studies reviewed here [6, 8]. Because of the risk for infusion reactions, safety guidelines suggest a 1-hour observation period following cetuximab administration [6, 8]. In all patients across all doses, the incidence of severe infusion


Saltz et al. (2004) [18]


35

reactions is rare in patients receiving panitumumab without antihistamine premedication. Grade 3 infusion reactions were reported in 0%–3% of patients receiving panitumumab, and no grade 4 reactions were reported. No fatal infusion reactions were reported with panitumumab; however, a fatal case of angioedema occurring several days after drug administration was recently reported [9]. In addition, several case reports have demonstrated that patients who discontinued cetuximab treatment because of the severity of infusion reactions could safely receive panitumumab therapy [28 –30]. One possible explanation for some of these differences was suggested in the recent report by Chung and colleagues [31]. Their study of patient samples from several institutions located in the southern U.S. showed that cetuximab hypersensitivity reactions are associated with IgE antibodies against galactose-␣-1,3-galactose present in patients prior to treatment [31]. This oligosaccharide is attached to cetuximab during its production in the mouse cell line SP2/0, which expresses the gene for ␣-1,3-galactosyltransferase. Panitumumab is produced in a Chinese hamster ovary cell line that lacks expression of this enzyme [6, 8 –10]. There are, however, other mechanisms that may contribute to antibody-related infusion reactions, and further research is needed to determine if there are other re-


gions in the world where patients experience high rates of infusion reactions.

OVERVIEW OF DATA ON KRAS MUTATIONAL STATUS IN ANTI-EGFR MCRC MONOTHERAPY The role of a patient’s tumor KRAS mutational status in the treatment of mCRC with anti-EGFR agents has recently become an emerging area of research and interest. The KRAS oncogene is a signal transducer modulated by the EGFR pathway, and mutations within the KRAS gene resulting in constitutive protein activity are found in approximately 30%–50% of all CRCs [32, 33]. Mutations of the K-RAS protein activate signaling to the downstream RAF/mitogenactivated protein kinase/extracellular signal–related kinase (ERK) kinase/ERK pathway, resulting in increased proliferation, tumor angiogenesis, metastasis, and inhibition of apoptosis, which support continued cancer cell survival, even in the presence of EGFR inhibition (Fig. 1). The impact of KRAS mutational status on the treatment of mCRC with anti-EGFR therapies has been analyzed via retrospective analyses of several mCRC clinical studies. Since KRAS analyses were not available from all of the clinical trials reviewed above, the results of seven retrospective analyses in which KRAS status was studied in patients treated with antiEGFR monotherapy were compared (Table 6) [32–37]. In


Figure 1. Mutated K-RAS is active in the presence of EGFR inhibition by anti-EGFR mAbs. In wild-type KRAS tumors, antiEGFR mAbs, such as panitumumab or cetuximab, inhibit binding of the ligands EGF and TGF-␣ to EGFR and inhibit signaling of the RAS pathway. Mutant K-RAS is constitutively active and can promote downstream signaling in the presence of EGFR inhibition, leading to activation of genes that promote cell proliferation, survival, metastasis, and angiogenesis. Abbreviations: EGFR, epidermal growth factor receptor; ERK, extracellular signal–related kinase; mAb, monoclonal antibody; MEK, mitogen-activated protein kinase/extracellular signal–related kinase kinase; TGF, transforming growth factor.


36

Table 6. Activity of panitumumab or cetuximab therapy in patients based on KRAS mutation status Median PFS OR with with monon of monotherapy therapy, monotherapy n (%) wksa patients Study Treatment (WT:MT) WT MT WT MT c

Median OS with monotherapy mosb WT

MT

pmab or cmab or cmab ⫹ CTd

37 (24:13)

6 (25)

1 (8)

NR

NR

NR

NR

Khambata-Ford et al. (2007) [32]

cmab

80 (50:30)

5 (10)

(0)

8.7a

8.4a

NR

NR

De Roock et al. (2008) [37]

cmab or cmab ⫹ irinotecand

28 (18:10)

5 (28)

0 (0)

12

12

6.8

6.3b

Hecht et al. (2008) [21]

pmab

171 (94:77)

8 (9)

0 (0)

15

7.1

13.5b

7.3b

Freeman et al. (2008) [34]

pmab

59 (38:21)

6 (16)

0 (0)

16.2

7.4

10.7b

5.6b

Amado et al. (2008) [33]

pmab

208 (124:84)

21 (17)

0 (0)

12.3

7.4

8.1

4.9

9.5

4.5

Karapetis et al. (2008) [35]

cmab

198 (117:81)

13 (12.8)

1 (1.2)

a

14.8

b

a

7.2

a

All indicated values were converted to weeks. All indicated values were converted to months from weeks. c 25 pmab monotherapy (predominantly third or fourth line), 12 cmab monotherapy (predominantly first line), 11 cmab ⫹ CT. d Only monotherapy results are shown here. Abbreviations: cmab, cetuximab; CT, chemotherapy; MT, mutant; NR, not reported; OR, objective response; OS, overall survival; pmab, panitumumab; PFS, progression-free survival; TTP, time to progression; WT, wild-type. b

Table 6, the patients treated with either panitumumab monotherapy or cetuximab monotherapy are highlighted. Across the seven studies, tumor KRAS mutations were consistently found in 35%– 45% of all patients as determined via allele-specific, reverse transcription-polymerase chain reaction and/or direct sequencing, with the remaining 55%– 65% of patients’ tumors determined to have a wild-type KRAS gene status. Of the patients with tumors bearing KRAS mutations across all studies, objective responses were observed in two patients [35, 36]. In contrast, objective responses were observed in 9%–28% of patients’ tumors bearing a wild-type KRAS gene status (Table 6). Reports by Benvenuti et al. [36] and Khambata-Ford et al. [32] were among the first to demonstrate a superior response rate with anti-EGFR monotherapy among CRC patients with wild-type KRAS tumors. However, those studies did not report, or failed to demonstrate, a longer median PFS time or OS time. The first study to analyze KRAS as a predictive marker to anti-EGFR therapy in a randomized phase III trial setting was reported by Amado et al. [33]. In that retrospective analysis, KRAS status was assessed in 427 (92%) tumor samples from patients treated in the phase III registrational trial of panitumumab versus BSC. This study demonstrated that patients whose tumors harbored mutations within the KRAS gene failed to respond to panitumumab monotherapy [33]. A statistically significant longer median PFS duration was observed among panitumumab-treated patients with

wild-type KRAS tumors than among patients with mutant KRAS tumors (12.3 weeks versus 7.4 weeks, respectively; p ⬍ .001) (Table 6). The OS time was also longer in patients with wild-type KRAS tumors, 8.1 months, versus 4.9 months. Similar findings in terms of the response rate and PFS time among patients with wild-type KRAS tumors were observed in a retrospective analysis of the phase III trial of cetuximab versus BSC [35]. In that study, 394 (68.9%) patient samples were available for KRAS testing analysis. The median PFS time was significantly longer in patients with wild-type KRAS tumors than in patients with mutant KRAS tumors (14.8 weeks versus 7.2 weeks, respectively; p ⬍ .001) (Table 6) [35]. That study also demonstrated a significant benefit in terms of OS in patients with wild-type KRAS tumors treated with cetuximab when compared with patients with mutant KRAS tumors (9.5 months versus 4.5 months, respectively; p ⫽ .01). Of note, a clear lack of prognostic value for KRAS was observed through analysis of patients treated in the BSC arm of that study. No survival benefit was observed in patients with wild-type KRAS tumors compared with patients with mutant KRAS tumors in the BSC arm (4.8 versus 4.6 months, respectively) [35]. This suggests that the longer survival duration in patients with wild-type KRAS tumors was a result of benefit from anti-EGFR therapy rather than a more favorable overall prognosis for this subset of patients. Studies evaluating the predictive value of KRAS mutational status on anti-EGFR therapy typically examine pa-


Benvenuti et al. (2007) [36]


DISCUSSION The results of monotherapy trials with anti-EGFR mAbs in the treatment of advanced mCRC have produced consistent efficacy and safety results after failure of standard chemotherapy combinations. Panitumumab and cetuximab monotherapy differ mostly in their AE profiles and current dosing schedules. Panitumumab is approved for use on a biweekly dosing schedule and cetuximab is approved for a weekly infusion regimen with a loading dose, and these remain the standard. Some recent reports suggest the possibility of a simplified cetuximab monotherapy regimen dosed every 2 weeks, whereas other studies have demonstrated the clinical activity of cetuximab biweekly regimens when used in combination with irinotecan [42– 44]. Furthermore, clinical studies have demonstrated efficacy in patients treated with panitumumab using a 3-week dosing schedule [45, 46].


While promising, these regimens require further studies evaluating efficacy in a larger cohort of patients. The role of KRAS gene mutation status in the treatment of mCRC with anti-EGFR therapies should be considered for a personalized approach to therapy and incorporated into the final analysis of studies evaluating anti-EGFR mAbs. It is important to note that, in the enriched wild-type KRAS tumor population, response rates are higher than previously reported in nonenriched populations. For example, the response rate for patients treated with panitumumab in the phase III trial of panitumumab versus BSC was 10% (Table 4), but the retrospective analysis of patients with wild-type KRAS tumors from that trial demonstrated a response rate to panitumumab of 17% (Table 6) [33, 47]. These results are comparable with those from the phase III trial of cetuximab versus BSC, with response rates of 8% for all patients receiving cetuximab (Table 4) and 12.8% for patients with wild-type KRAS tumors receiving cetuximab (Table 6) [25, 35]. These data demonstrate the utility of KRAS mutation as a negative predictive marker of response to anti-EGFR therapy. However, the lack of response observed in KRAS mutant tumor patients treated with cetuximab monotherapy raises a question about the significance of cetuximab-induced ADCC as a mechanism of action in advanced disease. ADCC is mediated through KRAS-independent pathways, and future clinical studies, particularly in earlier lines of therapy or the adjuvant setting, are needed to further test the role of ADCC in cetuximab-mediated antitumor activity. These new findings raise an important point for the future treatment of CRC. Patients who have progressed following several lines of therapy traditionally have low response rates to additional cytotoxic agents, which are associated with additional toxic events. Often in this setting, the goal of the physician is to increase survival with minimal toxicity. In an era in which the physician can now prospectively select for a wild-type KRAS tumor patient population, anti-EGFR monotherapy could become an effective alternative in this subset of patients. The response rates observed with anti-EGFR monotherapy in wild-type KRAS populations are approaching the rates observed with anti-EGFR therapy in combination with chemotherapy in unselected populations. For example, the response rate to the combination of irinotecan and cetuximab in KRAS unselected patients in a study by Cunningham et al. [7] was 22.9%, compared with 17% in wild-type KRAS patients treated with panitumumab [33]. Although prospective trials need to be conducted to determine the role of combinations of irinotecan and anti-EGFR agents in wild-type KRAS patients, these new data may have implications in altering the line of therapy in which patients are treated with anti-EGFR monotherapy.


tients treated in the chemotherapy-refractory setting. An updated biomarker analysis reported by Cervantes et al. [38] examined the efficacy of cetuximab in previously untreated mCRC patients. That study evaluated the safety and efficacy of weekly and biweekly administration of cetuximab monotherapy tested at escalating doses. This was followed by a combination therapy phase with cetuximab and 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI), and efficacy for both phases of the trial was analyzed according to KRAS mutational status [38]. A biomarker analysis demonstrated that patients with wild-type KRAS tumors exhibited a 27.6% response rate in the cetuximab monotherapy phase of the trial whereas patients with mutant KRAS tumors did not respond to cetuximab monotherapy [38]. These results demonstrate that KRAS mutational testing can serve as an effective biomarker to predict response to antiEGFR therapy in the first-line setting. Patients treated with combination anti-EGFR therapy plus chemotherapy were not reviewed here in order to assess the impact of tumor KRAS status directly on anti-EGFR therapy without the influence of concurrent chemotherapy. However, data presented at the 2008 ASCO Annual Meeting and the 2008 European Society for Medical Oncology Congress clearly demonstrate the added predictive value of KRAS status in the tumors of patients treated with antiEGFR therapy in combination with chemotherapy [39 – 41]. Across all studies reviewed here, it appears that the clinical efficacy of panitumumab or cetuximab monotherapy is restricted to patients with wild-type KRAS tumors. In light of the results of these studies, KRAS genotyping of tumors should be strongly considered for patients being treated with panitumumab or cetuximab monotherapy.

37


38

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AUTHOR CONTRIBUTIONS Conception/design: Marc Peeters, Jean-Luc Van Laethem Provision of study materials: Marc Peeters Data analysis: Tim Price, Jean-Luc Van Laethem Manuscript writing: Tim Price, Jean-Luc Van Laethem Final approval of manuscript: Marc Peeters, Tim Price, Jean-Luc Van Laethem The authors take full responsibility for the content of the paper but thank William Fazzone, Ph.D., from MediTech-Media, Ltd., supported by Amgen, for his assistance in organizing the published literature, preparing the initial draft of the manuscript, and collating the comments of authors.

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Errata

An erratum has been published regarding this article. Please see next page or: http://theoncologist.alphamedpress.org/content/14/3/307.full.pdf


ERRATUM

Anti–Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today? MARC PEETERS, TIM PRICE, JEAN-LUC VAN LAETHEM The Oncologist 2009;14:29 –39; doi: 10.1634/theoncologist.2008-0167 The inclusion criteria for the phase III studies of cetuximab and panitumumab were not described correctly. On page 31, the third sentence should read as follows: For the phase III studies of both cetuximab and panitumumab, patients were required to have failed oxaliplatin, irinotecan, and a fluoropyrimidine (or have contraindications to treatment with these agents; for the cetuximab study only), whereas criteria were less stringent for some of the phase II studies [24, 25].


The information in Table 5, which reported the incidence of infusion reactions in the Hecht et al. (2008) [21] study, was reported incorrectly, as the original reference reported infusion reactions of any grade, not grade 3/4. As a result, the first complete sentence on page 35 should read as follows: Grade 3 infusion reactions were reported in 0%–1% of patients receiving panitumumab, and no grade 4 reactions were reported.