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Erlotinib: applications in therapy and current status of research Expert Rev. Clin. Pharm. 2(1), 15–36 (2009)

Rachel E Sanborn† and Angela M Davies Author for correspondence Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan St, 2N35, Portland, OR 97213, USA Tel.: +1 503 215 6259 Fax: +1 503 215 6841 [email protected] †

Erlotinib, a small-molecule tyrosine kinase inhibitor targeted against the EGF receptor, has demonstrated survival benefit as a single agent in advanced non-small-cell lung cancer and in pancreatic cancer in combination with gemcitabine. Erlotinib has been studied extensively as a single agent as well as in combination with chemotherapy, radiation and other targeted agents. Despite its distinct target, biomarkers for selecting patients most likely to benefit from therapy are still under investigation. While EGF receptor mutations are present in approximately 10% of North American patients, that alone does not explain the benefit observed in patients with advanced non-small-cell lung cancer. With the therapeutic landscape becoming more crowded and challenging, the role of biomarkers to individualize therapy for patients is becoming increasingly more important. We summarize the current database of knowledge with regard to erlotinib pharmacology, clinical efficacy, toxicity and biomarkers. Keywords : cancer • EGF receptor • erlotinib • non-small-cell lung cancer • pancreatic cancer

The significant efficacy with agents targeted against the EGF receptors (EGFRs) has marked a new era in pharmacologic research and cancer care and has promised major breakthroughs to overcome the widely observed therapeutic plateaus in survival observed with conventional chemotherapeutic drugs [1–3] . This efficacy was first demonstrated in Her-2-amplified advanced breast cancer patients with the monoclonal antibody targeted against ErbB-2 (Her‑2), trastuzumab (Herceptin  ) [1] . Subsequent development of the murine monoclonal antibody targeted against ErbB-1 (EGFR), cetuximab (Erbitux ), resulted in survival benefit for patients with metastatic head and neck cancer, advanced colorectal cancer and most recently in patients with advanced non-small-cell lung cancer (NSCLC) [2–4] . Panitumumab (Vectibix), a fully humanized monoclonal antibody targeted against EGFR, has been shown to have activity as a monotherapy in KRAS wild-type (WT) patients with treatment-refractory metastatic colorectal cancer [5–7] . While most epithelial tumors have increased protein expression of the EGFR by immuno­ histochemistry (IHC), this has not been a useful biomarker for selection of patients. Although the initial studies of cetuximab in colorectal cancer were restricted to patients with tumor EGFR www.expert-reviews.com

10.1586/17512433.2.1.15

overexpression, activity has been demonstrated regardless of EGFR overexpression [8–10] . In fact, Kras mutation status may be a more useful biomarker to deselect patients for treatment with cetuximab [11] . Erlotinib (Tarceva, OSI-774) an oral smallmolecule tyrosine kinase inhibitor (TKI) targeted against the EGFR, has demonstrated survival benefit in advanced NSCLC and in combination with gemcitabine in advanced pancreatic cancer in an unselected population. We focus on the development of erlotinib, from preclinical studies to clinical trials and include a discussion of ongoing areas of research. EGF receptor

The EGFR was first purified and characterized in 1980 [12] . It was further defined as a member of a family of four transmembrane receptors: ErbB-1 (EGFR), ErbB-2 (Her-2), ErbB-3 and ErbB-4. EGFR is expressed on all epithelial and stromal cells, as well as some smooth muscle and glial cells [13] . It plays a crucial role in embryonic development. Homozygous mouse models genetically null for EGFR are primarily nonviable, demonstrating peri-implantation and mid-gestation lethality. Mice surviving gestation died within 3 weeks of birth, demonstrating gastrointestinal, renal, hepatic, cutaneous and CNS

© 2009 Expert Reviews Ltd

ISSN 1751-2433

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Sanborn & Davies

abnormalities [14] . Heterozygous EGFR-null mice were viable but demonstrated abnormal eyelid formation, wavy coat and curly vibrissae, indicative of the role of EGFR expression in normal epithelial development [15] . The EGFR consists of an extracellular ligand-binding domain (the target of monoclonal antibodies), an intracellular tyrosine kinase domain (the target of the small-molecule inhibitors) and a transmembrane domain [12,16,17] (Figure 1) . When ligands (most commonly EGF or TGF-a) bind to EGFR, the receptor will heterodimerize or homodimerize with another receptor in the family (most commonly Her-2) [18,19] . Dimerization is followed by receptor endocytosis and internalization with resultant tyrosine kinase activation, autophosphorlyation and activation of intracellular downstream signaling cascades [20–22] . Activated signaling cascades include the ras and MAPK pathway as well as the PI3K and signal transducer and activator of transcription (STAT)-mediated pathways. This activation induces cellular proliferation, tumor invasion, angiogenesis and prevention of apoptosis [19,23–27] . The formation of heterodimers is associated with a more significant level of signal activation than that of EGFR homo­ dimerization [18,28] . Heterodimers of EGFR/Her-3 have an increased potency for activation of PI3K, the activation of which has antiapoptotic effects [29,30] . The combination of EGFR/Her-2 has been shown to have greater mitogenic potency relative to other heterodimers [30] . The EGFR may be associated with neoplastic activity through persistent receptor activation (either ligand-mediated or constitutive activation), receptor mutation or receptor overexpression. EGFR is overexpressed in a large number of epithelioid

Preclinical data

In colon, head and neck, breast and NSCLC cell lines the EGFRTKIs are primarily cytostatic through the induction of G1 arrest and the resultant inhibition of cell-cycle progression   48,49] . EGFR inhibition is not completely static in its effects, however. In a NSCLC cell line harboring an activating mutation of EGFR (discussed further in following sections), erlotinib therapy induced apoptosis [50] . Apoptosis was also demonstrated after treatment with erlotinib in colon cancer and head and neck cancer cell lines  [48] and in hepatocellular cell lines, erlotinib was shown to both induce dose-dependent G1/S arrest as well as apoptosis [51] . Erlotinib activity was studied in a comparative evaluation in chemosensitive, parental and chemoresistant cell lines (including cervical, breast, ovarian, head and neck, lung and colorectal cancers). Increasing sensitivity to EGFR inhibition was demonstrated with increasing chemotherapy resistance, with differences of two- to 20-fold relative sensitivity to EGFR inhibition between chemoresistant and parental cell lines. Increasing sensitivity corresponded to increasing levels of phosphorylated EGFR expression in the chemoresistant cell lines, a finding confirmed in a xenograft model utilizing cervical carcinoma cells. The authors concluded that increasing resistance to chemotherapy conferred increasing dependence upon the EGFR pathway, rendering tumors more susceptible to EGFR inhibition at lower drug concentrations [52] . In xenograft models (head and neck cancer and NSCLC), significant inhibition of tumor growth was observed with both erlotinib monotherapy and erlotinib in combination with chemotherapy [53,54] . EGFR Erlotinib’s efficacy as a radiosensitizer has Tyrosine kinase inhibitor also been demonstrated with enhanced radiation-induced apoptosis in vitro with NSCLC, prostate and head and neck cancer cell lines [55] . In xenograft models of human glioblastoma (GBM), erlotinib in combination with radiation demonstrated benefits Apoptosis in survival compared with monotherapy of either modality [56] .

HER1/EGFR extracellular Ligand-binding domain

HER1/EGFR tyrosine kinase Proliferation

Sensitive to chemotherapy

Invasion Metastasis Angiogenesis

Figure 1. Structure of the EGF receptor. EGFR: EGR receptor. Redrawn with permission from OSI Pharmaceuticals.

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malignancies, including squamous cell cancers of the head and neck (SCCHN), NSCLC, bladder, breast, colorectal and hepato­ cellular cancers (HCCs) [31–39] . Increased EGFR expression has been associated with poor overall prognosis, shorter disease-free survival and overall survival (OS) [34–36,40–47] .

Adhesion

Erlotinib: pharmacology & pharmacokinetics Pharmacology, dosing & practical issues

Erlotinib is a quinazolinamine derivative that competitively and reversibly binds to the catalytic domain of the ATP-binding Expert Rev. Clin. Pharmacol. 2(1), (2009)

Erlotinib: applications in therapy & current status of research

Table 1. Major CYP3A4 inducers and inhibitors. CYP3A4 inducers

CYP3A4 inhibitors

Aminoglutethimide

Amprenavir, fosamprenavir

Bosentan

Atazanavir

Carbamazepine

Clarithromycin

Efavirenz

Delavirdine

Fosphenytoin

Diclofenac

Nafcillin

Enoxacin

Nevirapine

Imatinib

Oxcarbazepine

Indinavir

Pentobarbital

Isoniazid

Phenobarbital

Itraconazole

Phenytoin

Ketoconazole

Primidone

Miconazole

Rifabutin

Nefazodone

Rifampin

Nelfinavir

Rifapentine

Nicardipine Propofol Quinidine Ritonavir Telithromycin

CYP: Cytochrome P450. Data from [61].

pocket of the tyrosine kinase and thus impairs the ability of the receptor to activate downstream signaling cascades. In vitro, erlotinib inhibits the EGFR tyrosine kinase at an IC50 of 2 nmol/l. The potency of erlotinib for inhibition of the EGFR receptor is 1000-fold greater than for other intracellular tyrosine kinases [48] . Erlotinib oral dosing is recommended 1 h before and 2 h after meals. Erlotinib has an oral bioavailability of approximately 60%  [57] . The bioavailability increases with fatty food intake and meal ingestion by approximately 33%; however, there is significant intrapatient variability [58,59] . Erlotinib is metabolized primarily through hepatic cytochrome P450 3A4 (CYP3A4) and excreted through the biliary system with a small amount eliminated in the urine [60] . Thus, metabolism and elimination of erlotinib can be affected by CYP3A4 inducers or inhibitors, with increased or decreased drug clearance, respectively (Table 1) [61] . It is recommended that patients avoid such medications while receiving erlotinib. Patients receiving erlotinib that have unexpected toxicity should be questioned regarding administration with food and other medications (both prescribed and over the counter). Elevations in the international normalized ratio have been documented in patients taking erlotinib concurrently with warfarin (Coumadin). Regular monitoring of the international normalized ratio has been recommended for patients taking warfarin or other coumarin-derived anticoagulants while taking erlotinib [62] . www.expert-reviews.com

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Hepatic & renal dysfunction

In a Phase I study involving patients with hepatic and renal dysfunction, Miller and associates recommended dose reductions to 75 mg daily for patients with hepatic dysfunction (defined as aspartate transaminase ≥ three-times the upper limit of normal or serum albumin less than 2.5 g/dl; or direct bilirubin of 1.0–7.0 mg/dl with any AST and normal creatinine) owing to increased toxicity. Patients with hepatic dysfunction receiving higher doses of erlotinib experienced dose-limiting toxicities (DLTs) including increases in direct and total bilirubin, grade 4 diarrhea and dehydration and grade 3 hypotension [63] . O’Bryant and colleagues reported from their ongoing Phase I pharmacokinetic (PK) study in which a single dose of erlotinib was administered to patients with advanced solid tumors and normal or moderately impaired hepatic function (normal hepatic function defined as total bilirubin ≤ the upper limit of normal and AST/ALT ≤ 1.5-times the upper limit of normal; moderate hepatic impairment defined as Child–Pugh score of 7–9). Serial PK and plasma protein binding studies were conducted over 96 h after ingestion of the single dose. Of the 29 patients enrolled, eight had moderate hepatic impairment, with six of those having PK data available. Patients with hepatic impairment demonstrated an increase in systemic exposure to erlotinib, although increases in plasma protein binding were not observed. No grade 3 or 4 toxicities were observed in patients with hepatic impairment [64] . Patients with bilirubin above the upper limit of normal should be monitored closely while on therapy with erlotinib due to potential increased risk of toxicity. In addition for such patients, starting at a lower dose and dose escalating in the absence of toxicity should be considered. Acute and severe hepatitis has been reported to occur sporadically even in patients with previously normal hepatic function, thus regular monitoring of hepatic enzymes is recommended for all patients taking erlotinib [65] . In patients with serum creatinine between 1.5 and 5.0 mg/dl enrolled in the Phase I study by Miller and associates, the standard dose of 150 mg/day was tolerable and dose adjustments were not recommended [63] . Given the small amount of erlotinib eliminated in the urine, no dose reductions were required for patients with renal impairment. Pharmacodynamic measurements & rash

The PK evaluation of erlotinib in a Phase I dose-escalation study demonstrated that 150 mg daily resulted in plasma levels anticipated to have EGFR inhibition (estimated from animal pharmacodynamic studies). Patients with skin rash had significantly higher AUC0–24 when compared with patients without skin rash (p = 0.02), suggesting skin rash may be a pharmacodynamic marker of treatment effect [66] . Subsequent large randomized trials in both NSCLC and pancreatic cancer have supported the correlation between grade of rash and efficacy with erlotinib [67] . Skin biopsies from patients enrolled in a Phase I study demonstrated decreases in phosphorylated EGFR (phospho-EGFR) after the first cycle of treatment although the degree of phospho-EGFR 17

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Sanborn & Davies

reduction did not correlate with drug dosing. Expression of p27, a cell-cycle inhibitor upregulated upon EGFR inhibition, had a dose-related response to erlotinib [68] . PK issues

While subset analyses from the BR.21 study in advanced NSCLC demonstrate benefit in all patient subsets [69] , the magnitude of benefit in current smokers is lower. Molecular differences may explain this difference; however, PK interactions may also be at play, given that smoking is an inducer of CYP1A1/2 [70] . In a Phase I dose-escalation study of erlotinib in current smokers with NSCLC the maximum-tolerated dose (MTD) was 300 mg daily with a similar toxicity profile to 150 mg daily in nonsmokers [71] . In addition, erlotinib plasma concentrations were decreased in current smokers compared with nonsmokers or former smokers. A larger ana­lysis of erlotinib PK collected from multiple single-agent studies confirmed a 23.5% increase in erlotinib plasma clearance in smokers compared with nonsmokers [72] . Currently, studies evaluating the optimal dosing of erlotinib in smokers are ongoing. The concurrent administration of enzyme-inducing antiepileptic drugs (EIAEDs) increases erlotinib clearance at least threefold, via CYP3A4 hepatic enzyme induction. In order to achieve an equivalent exposure, patients taking EIAEDs required erlotinib 500 mg daily in a PK and comparative study of GBM patients with and without EIAEDs [73] . It is preferable that patients taking EIAEDs be switched to noninducing antiepileptic agents when initiating erlotinib therapy. As a small molecule, erlotinib can cross the blood–brain barrier in low concentrations; whether these are clinically relevant concentrations is unclear. In preclinical primate studies,

simultaneous measurements of plasma and cerebrospinal fluid (CSF) levels of erlotinib and its active metabolite, OSI-420, were obtained after intravenous administration of erlotinib. Although the CSF penetration was less than 5% relative to total plasma concentration, CSF drug exposure was calculated to be approximately 30% of plasma free-drug exposure [74] . In patients with GBM, CSF penetration of erlotinib was 6.9 and 8.6% for OSI-420  [75] . Occasional partial responses in recurrent GBM have been reported in Phase II trials of single-agent erlotinib [76,77] . In addition, multiple case reports of NSCLC patients with brain metastases responsive to erlotinib therapy exist in the literature [78–82] . Clinical data: single-agent studies Phase I: solid tumors

The MTD of erlotinib in solid tumor Phase I trials was oral 150 mg once daily. The primary DLTs were diarrhea (responsive to loperamide) and skin rash [66] . Weekly dosing schedules have been evaluated although a MTD was not reached (maximum dose evaluated was 2000 mg). On a twice-weekly schedule, a MTD of 1000 mg was identified with a DLT of grade 3 rash [83] . NSCLC

Based upon response rates (RRs) in Phase II studies similar to those of second-line chemotherapy, erlotinib was evaluated in a randomized Phase III international trial in previously treated advanced NSCLC patients (BR.21 study) (Table 2) . In a 2:1 randomization, patients received erlotinib (150 mg/day) and best supportive care, or placebo and best supportive care (Figure 2) . In this study, 65% of patients had an Eastern Cooperative Oncology

Table 2. Erlotinib in selected single-agent non-small-cell lung cancer studies. Study

Design

Phase n

RR (%) PFS/TTP

Shepherd et al. Erlotinib vs (2005) BSC; second/ third line

III

731

8.9

Giaccone et al. (2006)

First line

II

53

Jackman et al. (2007)

First line, ≥70 years of age

II

Hesketh et al. (2007)

First line, PS2

Lilenbaum et al. (2008)

p-value

OS

HR

p-value

PFS: 2.2 vs 1.8 months