TheOncologist®
`
`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
`
`Key Words. EGFR · Tyrosine kinase inhibitor · Quinazoline · Paclitaxel · Letrozole · Capecitabine · Trastuzumab · HER-2
`
`LEARNING OBJECTIVES
`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.
`
`CMECME
`
`Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
`
`ABSTRACT
`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 sur-
`vival 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 toxic-
`ity (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 corre-
`lates 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. The Oncologist 2004;9(suppl 3):10-15
`
`INTRODUCTION
`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 heterodimer-
`
`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@tnonc.com Received
`March 26, 2004; accepted for publication April 15, 2004. ©AlphaMed Press 1083-7159/2004/$12.00/0
`
`The Oncologist 2004;9(suppl 3):10-15 www.TheOncologist.com
`
`Ex. 1116-0001
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`

`Burris
`
`Figure 1. ErbB signal transduction
`cascade. Abbreviations: HB = heparin-
`binding; AR = androgen receptor;
`Epi = epiregulin
`
`ization, resulting in receptor auto-
`phosphorylation and activation;
`ErbB-2 (HER-2) has no known lig-
`ands but is a heterodimerization
`partner for EGFR and other mem-
`bers of the ErbB receptor family,
`with transactivation of ErbB-2
`occurring following heterodimer-
`ization. Autophosphorylation acti-
`vates 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 phos-
`phatidylinositol 3′ kinase (PI3K)/AKT pathways (Fig. 1) [1-
`3]. Overexpression or constitutive activation of the EGFR or
`ErbB-2 receptors results in cell transformation and is associ-
`ated 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 recep-
`tor and agents that inhibit receptor TKs; for example, cetux-
`imab (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 over-
`coming 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 implicat-
`ing 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 investiga-
`tions, providing support for a dual inhibitor approach in can-
`cer therapy.
`
`LAPATINIB PROPERTIES
`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
`
`11
`
`inhibitor gefitinib plus the anti-erbB-2 (HER-2) receptor
`monoclonal antibody trastuzumab produced a greater apop-
`totic effect than either inhibitor alone in the ErbB-2-overex-
`pressing 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-α) than antagonists targeting either
`EGFR or ErbB-2 alone [7].
`Lapatinib is a large head group quinazoline, distinguish-
`ing 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
`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 signifi-
`cant 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.
`
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`12
`
`Dual EGFR/ErbB-2 Inhibitor Lapatinib
`
`Table 1. Preliminary toxicity data by grade in 43 solid tumor patients receiving lapatinib in study EGF10003
`
`Lapatinib dose (mg)
`
`n of patients
`
`n with adverse events (%)
`
`Common toxicity criteria grade, n adverse events (% at dose level)
`
`175
`375
`675
`900
`1,200
`1,600
`1,800
`900 bid
`Total
`
`2
`4
`4
`5
`6
`10
`9
`3
`43
`
`0 (0)
`4 (100)
`4 (100)
`4 (80)
`3 (50)
`8 (80)
`9 (100)
`2 (67)
`34 (71)
`
`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
`
`Table 2. Preliminary data on adverse events in 43 solid tumor
`patients receiving lapatinib in study EGF10003
`
`Adverse event
`Rash, including acneiform rash
`
`Diarrhea
`
`Nausea
`
`Vomiting
`
`Constipation
`
`Fatigue
`
`Anorexia
`
`Grade
`1
`2
`1
`2
`3
`1
`2
`1
`2
`1
`2
`1
`2
`1
`
`n of patients
`7
`1
`6
`6
`2
`7
`2
`2
`1
`4
`1
`8
`1
`5
`
`Table 3. Patients on study EGF10003 for ≥4 months
`
`Diagnosis
`Adenocarcinoma, lung
`Adenocystic/salivary
`Breast cancer
`Nasopharyngeal cancer
`Unknown primary site
`Colorectal cancer
`Colorectal cancer
`Head and neck cancer
`Unknown primary site
`
`Lapatinib dose (mg)
`675/900/1,200/1,600
`1,200/1,600
`1,600
`1,800
`1,200/1,600/1,800
`675/900/1,200/1,600
`1,600
`1,250
`1,250
`
`1
`0 (0)
`11 (79)
`15 (100)
`2 (40)
`11 (79)
`4 (57)
`14 (78)
`0 (0)
`57 (76)
`
`2
`0 (0)
`3 (21)
`0 (0)
`3 (60)
`3 (21)
`3 (43)
`4 (22)
`0 (0)
`16 (21)
`
`3
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`2 (100)
`2 (3)
`
`4
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`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 indi-
`cate 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 1 and Table 2). Rash, diarrhea, nau-
`sea, and fatigue were the most common adverse events.
`Some evidence of clinical activity has been observed. As
`shown in Table 3, patients with a variety of tumors have
`had stable disease for up to 13 months; one patient exhib-
`ited 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).
`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
`
`Disease status
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`Complete response
`Minor response
`
`Duration on study (months)
`12+
`9+
`7+
`13+
`6+
`6+
`4+
`19+
`8+
`
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`Burris
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`13
`
`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 conse-
`quences 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 clin-
`ical 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%), ovar-
`ian cancer (15%), head and neck cancer (12%), adenocarci-
`noma 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 pul-
`monary 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 can-
`cer (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 4. That patient had received previous adjuvant ther-
`apy, hormonal therapy, and chemotherapy in addition to
`trastuzumab. Decreases in phospho-erbB-1 and phospho-
`erbB-2, phospho-Erk index, cyclin D, and TGF-α 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 pacli-
`taxel, 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 4). 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 util-
`ity of the other correlates is currently being evaluated.
`Figure 2 shows that a ≥75% inhibition of phospho-erbB-1,
`phospho-erbB-2, phospho-Erk1/2, or phospho-AKT expres-
`sion was reliably achieved at lapatinib doses of 650 mg
`and greater.
`
`Table 4. Biologic correlates in select metastatic breast cancer patients with or without response on lapatinib in study EGF10004
`
`EGFR
`
`Phospho-
`EGFR
`
`ErbB-2
`
`Phospho-
`erbB-2
`
`Phospho-
`Erk index
`
`Cyclin D
`
`Phospho-
`AKT
`
`TGF-αα
`
`TUNEL
`
`35
`32
`-9
`
`7
`2
`-71
`
`5
`1
`-80
`
`11
`5
`-54
`
`Patient A:
`partial response (900 mg)
`Day 0
`Day 21
`% change
`Patient B:
`partial response (1,200 mg)
`Day 0
`Day 21
`% change
`Patient C:
`progressive disease (900 mg)
`Day 0
`14
`16
`44
`3
`Day 21
`19
`3
`32
`3
`% change
`+35
`-81
`-27
`0
`Phospho-Erk index: (% positive cells) × (OD reading); OD = optical density
`
`70
`65
`-7
`
`50
`41
`-18
`
`29
`5
`-83
`
`8
`8
`0
`
`2,397
`760
`-68
`
`378
`10
`-97
`
`1,081
`0
`-100
`
`28
`12
`-57
`
`20
`4
`-80
`
`42
`10
`-76
`
`20
`20
`0
`
`48
`30
`-37
`
`36
`33
`-8
`
`54
`21
`-61
`
`38
`25
`-34
`
`49
`23
`-53
`
`3
`72
`+2,400
`
`4
`34
`+850
`
`0
`0
`0
`
`Ex. 1116-0004
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`

`

`Dual EGFR/ErbB-2 Inhibitor Lapatinib
`
`gressed 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 estro-
`gen/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
`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.
`
`ACKNOWLEDGMENTS
`from
`support were
`Grants
`and
`research
`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.
`
`75
`
`80
`
`66.67
`
` 60
`
`25
`
`500
`
`650
`900
`1,200
`Lapatinib dose (mg)
`
`1,600
`
`14
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Frequency (%)
`
`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-contain-
`ing regimens, and disease stabilization was observed in
`patients with a variety of other tumor types. Lapatinib inhib-
`ited signaling pathways implicated in tumor growth and sur-
`vival. Data in this regard suggest that, although inhibition of
`phospho-Erk1/2, phospho-AKT, or cyclin D may be neces-
`sary 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
`The activity of lapatinib against breast cancer in preclin-
`ical models and its safety and activity in initial clinical expe-
`rience 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 pro-
`
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`Ex. 1116-0006
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