REVIEW URRENT C OPINION

Epidermal growth factor receptor-directed monoclonal antibodies in nonsmall cell lung cancer: an update Robert Pirker

Purpose of review The epidermal growth factor receptor (EGFR) is overexpressed in many nonsmall cell lung cancers (NSCLCs). Blockade of EGFR by monoclonal antibodies has been studied as a strategy to improve the outcome of first-line chemotherapy in patients with NSCLC. The present review updates the findings from phase III trials. Recent findings Cetuximab improved survival when combined with first-line chemotherapy and this benefit was limited to patients with high EGFR expression in their tumors. A Southwest Oncology Group study currently prospectively evaluates the predictive biomarkers for cetuximab. In the SQUIRE phase III trial, necitumumab added to cisplatin and gemcitabine increased the survival in patients with advanced squamous cell NSCLC. The INSPIRE trial studied chemotherapy with and without necitumumab in patients with nonsquamous NSCLC but was prematurely halted because of increased thromboembolic events with chemotherapy and necitumumab. Summary EGFR monoclonal antibodies improved the outcome including survival in selected patients with advanced NSCLC. Prospective validation of predictive biomarkers is ongoing. Keywords biomarker, cetuximab, EGF receptor, monoclonal antibody, necitumumab

INTRODUCTION Targeted therapies based on the molecular tumor features offer new opportunities for the treatment of patients with advanced nonsmall cell lung cancer (NSCLC) [1,2]. Growth factor receptor systems and angiogenesis have preferentially been studied as potential therapeutic targets. The epidermal growth factor receptor (EGFR) has been of major interest [3,4]. EGFR is a member of the ErbB family of transmembrane tyrosine kinase receptors and its ligands include EGF and transforming growth factor-alpha. EGFR is deregulated in many cancers. EGFR expression is detected in up to 85% of NSCLC and has been shown to be associated with poor prognosis. Thus, EGFR inhibition by EGFR-directed monoclonal antibodies or EGFR tyrosine kinase inhibitors has been anticipated to improve the outcome of patients with NSCLC. EGFR-directed tyrosine kinase inhibitors have shown efficacy in patients with advanced NSCLC, particularly in those who harbor EGFR-activating

mutations in their tumors [5]. Afatinib, erlotinib, and gefitinib have been approved for first-line therapy of patients with advanced EGFR mutationpositive NSCLC. Novel EGFR tyrosine inhibitors specifically targeting the EGFR mutations and sparing the wildtype are currently evaluated in phase III trials. The second strategy to block EGFR signaling is by means of monoclonal antibodies [6]. Anti-EGFR monoclonal antibodies bind to the EGFR on the surface of tumor cells and competitively block the binding of EGF. Antibody receptor complexes are internalized and degraded. This process leads to Department of Medicine I, Medical University of Vienna, Vienna, Austria Correspondence to Dr Robert Pirker, Professor, Department of Medicine I, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, 1090 Vienna, Austria. Tel: +43 1 40400 4422; fax: +43 1 40400 4461; e-mail: [email protected] Curr Opin Oncol 2015, 27:87–93 DOI:10.1097/CCO.0000000000000162

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KEY POINTS  High EGFR expression has been shown to be a predictive biomarker with regard to the outcome of firstline chemotherapy and cetuximab in patients with advanced NSCLC.  Necitumumab increased survival when added to firstline chemotherapy in patients with advanced squamous cell NSCLC.  Validation of predictive biomarkers is ongoing.

EGFR downregulation on the surface of tumor cells and inhibition of EGFR signaling. In addition to this inhibitory effect on EGFR signaling, monoclonal antibodies may also act via immunological mechanisms such as antibody-dependent cellular cytotoxicity [7]. EGFR-directed monoclonal antibodies include cetuximab, necitumumab, matuzumab, panitumumab, and others (Table 1). These monoclonal antibodies have been evaluated in clinical trials in patients with NSCLC, primarily in combination with first-line chemotherapy in patients with advanced NSCLC. This review provides an update on the current status of EGFR-directed monoclonal antibodies for the treatment of patients with advanced NSCLC.

CETUXIMAB Cetuximab is a chimeric human–murine monoclonal IgG1 antibody. It inhibits EGFR signaling through binding to the external domain of the EGFR and may also act via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity [7]. Cetuximab combined with first-line chemotherapy has been studied in phase II and III trials in patients with advanced NSCLC (Table 2) [8,9 ,10,11 ,13–15]. Cetuximab has also been &&

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Table 1. Epidermal growth factor receptor-directed monoclonal antibodies in advanced nonsmall cell lung cancer Clinical development Monoclonal antibody

Phase

Status

Cetuximab

Phase III

Completed

Matuzumab

Phase II

Completed

Panitumumab

Phase II

Completed

Necitumumab

Phase III

Completed

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assessed in combination with chemoradiotherapy in patients with locally advanced NSCLC. Cetuximab is usually administered concurrently with chemotherapy and continued as single agent after the end of chemotherapy. Following an initial loading dose of 400 mg/m2, cetuximab is intravenously infused at weekly doses of 250 mg/m2 until disease progression or unacceptable toxicity. Acne-like skin rash, diarrhea and rare hypersensitivity reactions are the clinically relevant side-effects of cetuximab. These side-effects can be managed by prophylactic or therapeutic measures. Skin rash is managed by the application of creams and, in more severe cases, topical or systemic administration of corticosteroids or antibiotics. Antiallergic premedication is required before the first infusion and recommended for subsequent infusions.

Phase II trials Several single-arm phase II trials evaluated cetuximab in combination with different platinum-based doublets in the first-line setting of advanced NSCLC [13–15]. Two randomized phase II trials suggested improved efficacy of chemotherapy and cetuximab compared with chemotherapy alone [16,17]. Chemotherapy consisted of cisplatin and vinorelbine or platin and gemcitabine. Another randomized phase II trial found similar outcomes for the concurrent and the sequential administration of chemotherapy and cetuximab [18]. The promising results of these phase II trials led to two randomized phase III trials in patients with advanced NSCLC: the First-Line ErbituX in lung cancer (FLEX) trial [8,9 ] and the Bristol-Myers Squibb (BMS) 099 trial [10]. &&

Phase III trials Two randomized, open-label, phase III trials compared chemotherapy and cetuximab with chemotherapy alone in patients with advanced NSCLC (Table 2) [8,10]. The FLEX trial demonstrated improved overall survival for cetuximab added to chemotherapy, whereas the BMS099 trial failed to demonstrate an improvement in the progressionfree survival. The FLEX trial compared cetuximab added to first-line chemotherapy consisting of cisplatin and vinorelbine with the same chemotherapy alone in patients with advanced EGFR-expressing NSCLC [8]. The primary endpoint of this trial was overall survival. Secondary endpoints included progressionfree survival, response rate, safety, and quality of life. Eligibility criteria were stage IV or stage IIIB with malignant effusion, age at least 18 years, Volume 27  Number 2  March 2015

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EGFR antibodies in nonsmall cell lung cancer Pirker Table 2. First-line chemotherapy with or without epidermal growth factor receptor monoclonal antibodies in advanced nonsmall cell lung cancer: phase III trials Survival Trial

Treatment

No.

RR

Hazard ratio

0.87 (0.76–0.99)

Median

1-Year

P-value

0.04

FLEX [8,9 ] &&

ITT

CT þ cetuximab

557

36%

CT

568

29%

High EGFR score

CT þ cetuximab

178

44%

CT

167

28%

Low EGFR score

CT þ cetuximab

377

33%

CT

399

30%

CT þ cetuximab

338

26%

CT

338

17%

CT þ cetuximab

1003

32%

CT

1015

24%

CT þ necitumumab

545

31%

CT

548

29%

0.73 (0.58–0.93) 0.99 (0.84–1.16)

11.3

47%

10.1

42%

12.0

50%

9.6

37%

9.8

40%

10.3

40%

0.01 0.88

BMS099 [10] ITT

0.89 (0.75–1.05)

9.7

40%

8.4

40%

10.3

45%

9.4

40%

0.17

Meta-analysis [11 ] &

ITT

0.88 (0.79–0–97)

0.009

SQUIRE [12 ] &&

Squamous

0.84 (0.74–0.96)

11.5

48%

9.9

43%

0.012

BMS, Bristol-Myers Squibb; CT, chemotherapy; EGFR, epidermal growth factor receptor; FLEX, First-Line ErbituX in lung cancer; ITT, intent-to-treat; RR, response rate.

Eastern Cooperative Oncology Group (ECOG) performance status 0–2, adequate organ functions, the presence of at least one bidimensionally measurable tumor lesion, and EGFR expression on tumor cells. EGFR expression was determined by immunohistochemistry (IHC). In order to be eligible for inclusion into the FLEX trial, patients had to have at least one positively stained tumor cell in their tumors. Exclusion criteria were known brain metastases, previous exposure to EGFR-targeted therapy or monoclonal antibodies, major surgery within 4 weeks or chest irradiation within 12 weeks prior to study entry, active infection, pregnancy, and symptomatic peripheral neuropathy. Eligible patients were randomized to chemotherapy and cetuximab or chemotherapy alone. Chemotherapy consisted of cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 of 3-week cycles. Patients in the cetuximab arm received cetuximab with a loading dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2. Chemotherapy was planned for a maximum of six cycles, but cetuximab was planned to be continued after the end of chemotherapy until disease progression or unacceptable toxicity. At baseline, patients (n ¼ 1125) had the following characteristics: 70% men; median age 60 (range 18–83 years); ECOG performance status 0–1 and 2 in 83 and 17% of the patients, respectively; 47% adenocarcinoma, 34% squamous cell carcinoma,

19% other NSCLC; 84% Caucasians, 11% Asian ethnicity; and 22% never-smokers. The two treatment arms were well balanced with regard to these baseline patient characteristics. Patients receiving chemotherapy and cetuximab had longer survival compared with those receiving chemotherapy alone. The hazard ratio was 0.87 [95% confidence interval (CI) 0.762–0.996; P ¼ 0.044]. The median survival times were 11.3 and 10.1 months, and 1-year survival rates were 47 and 42%, respectively. The survival benefit was seen across all major subgroups. In Caucasian patients (n ¼ 946), the hazard ratio was 0.8 (95% CI 0.69–0.93), and the median survival times were 10.5 and 9.1 months, respectively. For patients with adenocarcinomas (n ¼ 413), the hazard ratio was 0.94 (95% CI 0.77–1.15), and the median survival times were 12.0 and 10.3 months. For patients with squamous cell carcinomas (n ¼ 347), the hazard ratio was 0.80 (95% CI 0.64–0.10), the median survival times were 10.2 and 8.9 months, respectively. The overall response rates were 36 and 29%, respectively (P ¼ 0.01). Progression-free survival times were not significantly different, but time-to-treatment failure favored the chemotherapy–cetuximab arm with a hazard ratio of 0.86 (95% CI 0.76–0.97; P ¼ 0.015). EGFR expression based on an IHC score has been found to be a predictive biomarker [9 ]. Acne-like rash as the main cetuximab-related side-effect occurred in about two-thirds of the

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patients, but grade 3 was seen in only 10% of the patients. Infusion-related reactions were seen in only 4% of the patients. The BMS099 phase III trial compared cetuximab in combination with carboplatin and a taxane (paclitaxel or docetaxel) with chemotherapy alone in unselected patients (n ¼ 676) with advanced NSCLC [10]. The primary endpoint was progression-free survival determined by a blinded Independent Radiology Review Committee. Progression-free survival was not different between the two treatment arms. The hazard ratio was 0.90 (P ¼ 0.2), and the median progression-free survival times were 4.4 and 4.2 months, respectively. However, the response rate was higher in the chemotherapy and cetuximab arm compared with the chemotherapy-alone arm (26 vs. 17%, P ¼ 0.007). Although the trial was not powered for survival, the hazard ratio of death was 0.89 in favor of chemotherapy and cetuximab. In both phase III trials, cetuximab was administered concurrently with chemotherapy and continued as single agent after the completion of chemotherapy. The fact that response rates have been higher with chemotherapy and cetuximab in all trials indicates that cetuximab is active during the chemotherapy phase. The exact impact of cetuximab maintenance on the overall outcome, however, remains to be determined.

Meta-analysis of randomized trials A meta-analysis based on the four randomized trials was performed in order to determine the benefit and risk for the addition of cetuximab to the first-line platinum-based chemotherapy [11 ]. The metaanalysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients. The meta-analysis demonstrated a survival benefit for chemotherapy and cetuximab compared with chemotherapy alone. The hazard ratio was 0.88 (95% CI 0.79–0.97; P ¼ 0.009). The median survival times were 10.3 and 9.4 months, and 1-year survival rates were 45 and 40% for chemotherapy plus cetuximab and chemotherapy alone, respectively. Progression-free survival was also improved by the addition of cetuximab. The hazard ratio was 0.90 (95% CI 0.82–1.00; P ¼ 0.045). Median progression-free survival time was 4.7 vs. 4.5 months, and 1-year progression-free survival rates were 8.8 vs. 5.9% for chemotherapy plus cetuximab and chemotherapy alone, respectively. With regard to response, the odds ratio was 1.46 (95% CI 1.2–1.78; P < 0.001). The response rate was 32% for chemotherapy plus cetuximab and 24% for chemotherapy alone. &

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A subgroup analysis revealed no differences in the treatment effects in relation to histology, age (

Epidermal growth factor receptor-directed monoclonal antibodies in nonsmall cell lung cancer: an update.

The epidermal growth factor receptor (EGFR) is overexpressed in many nonsmall cell lung cancers (NSCLCs). Blockade of EGFR by monoclonal antibodies ha...
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