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The Oncologist, Vol. 9, Suppl 3, 10–15, June 3, 2004
© 2004 AlphaMed Press

Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib

Howard A. Burris, III

Sarah Cannon Cancer Center and Tennessee Oncology, Nashville, Tennessee, USA

Correspondence: Howard A. Burris III, M.D., F.A.C.P., Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 110, Nashville, Tennessee 37203, USA. Telephone: 615-986-4300; Fax: 615-986-0029; e-mail: hburris{at}tnonc.com


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Identify the rationale for the development of dual ErbB receptor inhibitors.
  2. Describe safety data from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib.
  3. Describe evidence of biologic and clinical activity from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
 References
 
Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for >=4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.

Key Words. EGFR • Tyrosine kinase inhibitor • Quinazoline • Paclitaxel • Letrozole • Capecitabine • Trastuzumab • HER-2


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
 References
 
The ErbB family of cellular type I receptor tyrosine kinases (TKs) plays a central role in normal cell proliferation, survival, and differentiation in a variety of tissues. Ligand binding to the epidermal growth factor receptor (EGFR, ErbB-1) induces receptor homodimerization or heterodimerization, resulting in receptor autophosphorylation and activation; ErbB-2 (HER-2) has no known ligands but is a heterodimerization partner for EGFR and other members of the ErbB receptor family, with transactivation of ErbB-2 occurring following heterodimerization. Autophosphorylation activates receptor TKs, resulting in activation of signaling pathways involved in cell proliferation, survival, and transformation, including the well-characterized mitogen-activated protein kinase (MAPK) (Erk1/2) and phosphatidylinositol 3' kinase (PI3K)/AKT pathways (Fig. 1Go) [1–3]. Overexpression or constitutive activation of the EGFR or ErbB-2 receptors results in cell transformation and is associated with poor clinical outcome in a number of malignancies [4, 5]. The potential roles of the EGFR and ErbB-2 receptors in tumor cell proliferation and survival have prompted the development of monoclonal antibodies that inhibit the receptor and agents that inhibit receptor TKs; for example, cetuximab (Erbitux®; ImClone Systems, Inc.; New York, NY) and trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) are monoclonal antibodies to the ErbB-1 and ErbB-2 receptors, respectively, and gefitinib (Iressa®; AstraZeneca Pharmaceuticals; Wilmington, DE) inhibits the ErbB-1 TK. There is considerable rationale for combined receptor/kinase inhibition, including the potential for overcoming redundancy in cell signaling pathways with the use of broader inhibition and the potential application to a wider range of patients based on epidemiologic evidence implicating EGFR and ErbB-2 receptors in a variety of tumor types. Lapatinib (GlaxoSmithKline; Research Triangle Park, NC) is a novel dual EGFR/ErbB-2 TK inhibitor that has shown promising activity in preclinical and early clinical investigations, providing support for a dual inhibitor approach in cancer therapy.



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  		Figure 1. ErbB signal transduction cascade. Abbreviations: HB = heparin-binding; AR = androgen receptor; Epi = epiregulin

 

   LAPATINIB PROPERTIES
Top
 Learning Objectives
 Abstract
 Introduction
 Lapatinib Properties
Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
 References
 
Part of the rationale for the development of lapatinib was provided by preclinical findings of synergistic cell growth inhibition with simultaneous targeting of EGFR and ErbB-2 receptor TKs. For example, treatment with the ErbB-1 TK inhibitor gefitinib plus the anti-erbB-2 (HER-2) receptor monoclonal antibody trastuzumab produced a greater apoptotic effect than either inhibitor alone in the ErbB-2-overexpressing breast cancer cell lines SKBR-3 and BT-474 [6]. Lapatinib was shown to exhibit greater growth inhibition of colon cancer cells activated by the EGFR ligand transforming growth factor alpha (TGF-{alpha}) than antagonists targeting either EGFR or ErbB-2 alone [7].

Lapatinib is a large head group quinazoline, distinguishing it from the small head group quinazolines erlotinib and gefitinib. It demonstrates high cell potency (50% inhibitory concentration <0.2 µM), has been shown to inhibit EGFR and ErbB-2 phosphorylated (phospho)-tyrosine, phospho-Erk1/2, phospho-AKT, and cyclin D in tumor cell lines and xenograft models, and has been shown to be efficacious in inhibiting cell growth in xenograft models [8, 9]. The drug exhibited a favorable toxicity profile in rodents and dogs and no evidence of cardiac toxicity during high exposure over 6 and 9 months, respectively.


   PHASE I STUDIES OF LAPATINIB
Top
 Learning Objectives
 Abstract
 Introduction
 Lapatinib Properties
 Phase I Studies of...
Ongoing Studies of Lapatinib...
 Conclusion
 References
 
Oral lapatinib was administered to 135 healthy volunteers in four studies at doses of 10–250 mg and was found to be safe and well tolerated. In phase I studies in cancer patients, the drug was administered at doses of 175–1,800 mg once daily or 500–900 mg twice daily (bid) in 92 patients, with no significant toxicities observed to date. Pharmacokinetic data from these studies are under analysis; pharmacodynamic data derived from skin biopsies and buccal smears taken in all phase I patients are also being analyzed.

The maximum-tolerated dose study, EGF10003, enrolled 39 cancer patients with no ErbB receptor status requirement [10]. All patients are to receive lapatinib at doses of 175–1,800 mg once daily. Additional patients are receiving doses of 900 mg bid (n = 6), 1,250 once daily to assess food effect (n = 6), 500 mg bid (n = 13), and 750 mg bid (n = 22). Preliminary data in 43 of those patients indicate no grade 4 toxicities; most toxicities were grade 1 or 2, with two cases of grade 3 diarrhea observed at the 900-mg bid dose level (Table 1Go and Table 2Go). Rash, diarrhea, nausea, and fatigue were the most common adverse events. Some evidence of clinical activity has been observed. As shown in Table 3Go, patients with a variety of tumors have had stable disease for up to 13 months; one patient exhibited a minor response, and one patient with a head and neck tumor had a complete response and remained on study after 19 months. Preliminary pharmacokinetic data indicate that the lapatinib serum concentrations were above the in vitro 90% inhibitory concentration at the 1,200-mg once-daily dose, and pharmacokinetics appear to be linear over the tested dose range (up to 1,800 mg).


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  		Table 1. Preliminary toxicity data by grade in 43 solid tumor patients receiving lapatinib in study EGF10003
 

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  		Table 2. Preliminary data on adverse events in 43 solid tumor patients receiving lapatinib in study EGF10003
 

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  		Table 3. Patients on study EGF10003 for >=4 months
 
Study EGF10004 is a phase IB study of lapatinib in heavily pretreated metastatic cancer patients with disease that can be biopsied, and EGFR or ErbB-2 overexpression on immunohistochemistry, erbB-2 gene overexpression on gene amplification, or evidence of activated EGFR and ErbB-2 receptors on immunohistochemistry [11]. Patients are randomized to receive lapatinib at doses of 500, 650, 900, 1,200, or 1,600 mg once daily. The biologic consequences of treatment on growth and survival pathways are being assessed in tumor biopsy samples obtained prior to and 21 days after the start of treatment, and safety and clinical activity are being evaluated. Thus far, 33 patients have been entered in the study, seven at the 500-mg dose, eight at the 650-mg dose, five at the 900-mg dose, six at the 1,200-mg dose, and seven at the 1,600-mg dose; tumor types in these patients consist of breast cancer (33%), ovarian cancer (15%), head and neck cancer (12%), adenocarcinoma of unknown primary site (12%), colorectal cancer (12%), lung cancer (6%), and others (9%). Treatment has been well tolerated, with no grade 4 and one grade 3 toxicity (gastroesophageal reflux). The most common adverse events (all grade 1 or 2) have been diarrhea (27%), rash (25%), and nausea/vomiting (21%). No treatment-related cardiac or pulmonary toxicity has been observed. Partial responses were observed in three patients (10%) at the 1,200-mg (n = 2) and 900-mg (n = 1) doses, with those patients having received therapy for a median of 23 weeks (20 to >25 weeks). Each of the three patients had breast cancer and exhibited both EGFR and ErbB-2 overexpression. Stable disease was observed in 12 patients (36%) at the 500-mg (n = 4), 650-mg (n = 3), 900-mg (n = 1), 1,200-mg (n = 2), and 1,600 mg (n = 2) doses, with a median treatment duration of 19 weeks (14 to >34 weeks) in those patients. Of the 12 patients, 10 had EGFR overexpression and six had ErbB-2 overexpression, including all breast cancer patients with stable disease. Overall, the tumor types responding to treatment (partial response or stable disease) have consisted of trastuzumab-refractory breast cancer (n = 7), colorectal cancer (n = 2), ovarian cancer (n = 2), lung cancer (n = 1), adenocarcinoma of unknown primary site (n = 1), granular cell carcinoma (n = 1), and head and neck cancer (n = 1).

Biologic correlates in a patient (patient A) with trastuzumab-refractory inflammatory breast cancer who had a rather dramatic partial response to lapatinib are shown in Table 4Go. That patient had received previous adjuvant therapy, hormonal therapy, and chemotherapy in addition to trastuzumab. Decreases in phospho-erbB-1 and phospho-erbB-2, phospho-Erk index, cyclin D, and TGF-{alpha} were observed, with a dramatic increase in tumor cell apoptosis using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay. Patient B also exhibited a partial response to lapatinib after progression of metastatic breast cancer following treatments with paclitaxel, carboplatin, and trastuzumab, and with vinorelbine and trastuzumab. Biologic correlates in that patient also indicate a marked increase in apoptosis on the TUNEL assay (Table 4Go). In contrast, correlates in a patient (patient C) with progressive disease on lapatinib after failing two previous courses of chemotherapy plus trastuzumab indicate an absence of effect on apoptosis. In patients assessed thus far, clinical responses have been observed only in those with a positive effect on the TUNEL assay. The prognostic utility of the other correlates is currently being evaluated. Figure 2Go shows that a >=75% inhibition of phospho-erbB-1, phospho-erbB-2, phospho-Erk1/2, or phospho-AKT expression was reliably achieved at lapatinib doses of 650 mg and greater.


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  		Table 4. Biologic correlates in select metastatic breast cancer patients with or without response on lapatinib in study EGF10004
 


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  		Figure 2. Frequency of achieving a >=75% inhibition of phospho-EGFR, phospho-ErbB-2, phospho-Erk1/2, or phospho-AKT expression in tumors at day 21 compared with baseline according to lapatinib dose in study EGF10004.

 
In summary, preliminary findings from the EGF10003 trial indicate that lapatinib was well tolerated at all doses tested. Clinical responses were observed at a variety of doses in these heavily pretreated patients with metastatic disease. Partial responses were observed in ErbB-2-expressing breast cancer that had progressed on previous trastuzumab-containing regimens, and disease stabilization was observed in patients with a variety of other tumor types. Lapatinib inhibited signaling pathways implicated in tumor growth and survival. Data in this regard suggest that, although inhibition of phospho-Erk1/2, phospho-AKT, or cyclin D may be necessary for clinically detectable antitumor effects, they are not sufficient for producing such effects; induction of tumor cell apoptosis, as reflected in TUNEL assay measurements, appeared to correlate with clinical response.


   ONGOING STUDIES OF LAPATINIB IN ADVANCED BREAST CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
Conclusion
 References
 
The activity of lapatinib against breast cancer in preclinical models and its safety and activity in initial clinical experience have prompted the initiation of phase II and phase III trials in the setting of advanced breast cancer. In an open-label, multicenter, single-arm phase II trial (EGF20002/ EGF20008), lapatinib is to be used as single-agent therapy in patients with advanced or metastatic breast cancer who progressed while receiving trastuzumab-containing regimens. A phase III randomized, open-label, multicenter trial (EGF100151) is comparing lapatinib plus capecitabine with capecitabine alone in patients with refractory advanced or metastatic breast cancer. EGF30001 is a randomized, double-blind, placebo-controlled, two-arm, multicenter phase III trial of lapatinib plus paclitaxel versus paclitaxel alone in previously untreated patients with advanced or metastatic disease. EGF30008 is a randomized, double-blind, placebo-controlled, multicenter phase III trial comparing lapatinib plus letrozole with letrozole alone in patients with estrogen/progesterone-receptor-positive advanced metastatic breast cancer. Findings in these trials should help to clarify the potential roles of this new dual EGFR/ErbB-2 inhibitor in the treatment of advanced breast cancer.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
References
 
Lapatinib is a novel dual EGFR/ErbB-2 receptor TK inhibitor being studied in patients with advanced and metastatic cancer. Phase I data indicate good tolerability, with grade 1 or 2 rash and gastrointestinal effects being the most common observed toxicities, and evidence of clinical activity in patients with a variety of tumor types. Phase II and III trials have been initiated in patients with advanced breast cancer to assess lapatinib used alone or combined with agents such as capecitabine, a taxane, or hormonal therapy, and include previously treated and untreated patients. Preliminary assessment of biologic correlates in patients treated with lapatinib suggests that induction of tumor cell apoptosis as measured by the TUNEL assay correlates with clinical response.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
 References
 
Grants and research support were from GlaxoSmithKline, Bristol-Myers Squibb, Genentech, Vion, Sonus, DTI, Lilly, and Novartis. HB receives grant support and honoraria and is on the advisory boards for GlaxoSmithKline, Bristol-Myers Squibb, Aventis, and Genentech.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Lapatinib Properties
 Phase I Studies of...
 Ongoing Studies of Lapatinib...
 Conclusion
 References
 

  1. Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 1998;20:41–48.[CrossRef][Medline]
  2. Amundadottir LT, Leder P. Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes. Oncogene 1998;16:737–746.[CrossRef][Medline]
  3. Okano J, Gaslightwala I, Birnbaum MJ et al. Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation. J Biol Chem 2000;275:30934–30942.[Abstract/Free Full Text]
  4. Olayioye MA, Neve RM, Lane HA et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000;19:3159–3167.[CrossRef][Medline]
  5. Klapper LN, Kirschbaum MH, Sela M et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000;77:25–79.[Medline]
  6. Moulder SL, Yakes FM, Muthuswamy SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001;61:8887–8895.[Abstract/Free Full Text]
  7. Zhou Y, Brattain M. A novel strategy of colon cancer therapy: targeting both EGFR and ErbB2 receptors. Proc Am Assoc Cancer Res 2003;1267. Abstract 5529.
  8. Rusnak DW, Affleck K, Cockerill SG et al. The characterization of novel, dual erbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 2001;61:7196–7203.[Abstract/Free Full Text]
  9. Xia W, Mullin RJ, Keith BR et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002;21:6255–6263.[CrossRef][Medline]
  10. Burris HA, Taylor C, Jones S et al. A phase I study of GW572016 in patients with solid tumors. Proc Am Soc Clin Oncol 2003;22:258.
  11. Spector N, Raefsky E, Hurwitz H et al. Safety, clinical efficacy, and biologic assessments from EGF10004: a randomized phase IB study of GW572016 for patients with metastatic carcinomas overexpressing EGFR or erbB2. Proc Am Soc Clin Oncol 2003;22:193.
Received March 26, 2004; accepted for publication April 15, 2004.




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