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Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer

Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line... Annals of Oncology 22: 2610–2615, 2011 doi:10.1093/annonc/mdr021 original article Published online 17 March 2011 Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer 1 2 3 1 1 4 S. Iqbal *, B. Goldman , C. M. Fenoglio-Preiser , H. J. Lenz , W. Zhang , K. D. Danenberg , 5 6 S. I. Shibata & C. D. Blanke 1 2 3 Division of Medical Oncology, University of Southern California, Los Angeles; Southwest Oncology Group Statistical Center, Seattle; Department of Pathology, 4 5 University of Cincinnati, Cincinnati; Response Genetics, Inc., Los Angeles; Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA; Department of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada Received 2 July 2010; revised 14 January 2011; accepted 17 January 2011 Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%–45% of gastric cancers, making them potential targets. Patients and methods: The primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days. Results: The study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6–3.1) months and OS was 4.8 (3.2–7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS. Conclusions: Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation. Key words: EGFR, gastric cancer, HER2, lapatinib One potential therapeutic target is the epidermal growth introduction factor receptor (EGFR). Both the EGFR and human epidermal In 2010, there were an estimated 21 000 new cases of gastric growth factor receptor 2 (HER2) genes are amplified and cancer in the United States with 10 570 deaths and an overall overexpressed in a variety of solid human cancers and are 5-year survival rate of 22% [1]. Only 20% of cases are associated with a poor prognosis in patients with gastric cancer. diagnosed at an early, potentially curable, stage. Preclinical studies have shown a significant number of gastric Many chemotherapeutic drugs have single-agent activity in cancer cell lines express EGFR, which grow in response to EGF advanced disease, including fluoropyrimidines, platinums, and transforming growth factor-a and show a greater degree of irinotecan, taxanes, and adriamycin. Combination regimens gastric wall invasion and lymph node metastasis, representing have been shown to be more effective, with response rates greater malignant potential [3–5]. Additionally, EGFR ranging from 30% to 50%. However, there can be significant expression is significantly higher in gastric carcinoma than in toxicity associated with these combinations and historically, adjacent normal gastric mucosa, with greater EGFR levels median survival has been 6–9 months. There are more recent found in more advanced tumors [6]. Yasui et al. [7] evaluated phase II and III studies that have reported longer survival, some gastric carcinoma samples for EGFR by 125-labeled EGF >1 year [2]. Nevertheless, there remain limitations of binding, with EGFR expression immunoreactivity detected in traditional therapies and promising preliminary data with novel 33 (34%) of the 96 advanced gastric cancers. Similarly, targeted therapeutics, newer agents are being investigated. evaluation by He et al. [8] of 104 specimens of gastric cancer revealed that 42% demonstrated expression of EGFR. *Correspondence to: Dr S. Iqbal, Division of Medical Oncology, Norris Comprehensive Simultaneous EGF and EGFR expression was noted in 15% of Cancer Center, University of Southern California, 1441 Eastlake Avenue, Room 3457, gastric cancers, suggesting that these tumors may grow in an Los Angeles, CA 90033, USA. Tel: +1-323-865-3907; Fax: +1-323-865-0061; E-mail: iqbal@usc.edu Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. original article Annals of Oncology original article not surgically curable; measurable disease by RECIST criteria; 2-week autocrine fashion. Twelve percent of specimens in this study period between any surgery and study entry; completion of prior were found to be positive for c-ErB2 [9]. chemotherapy, hormonal therapy, immunotherapy, radiation therapy (to HER2 has also been associated with poor prognosis, and <25% of bone marrow), or chemoradiotherapy as neoadjuvant or adjuvant expression of HER2 assessed in many trials and tissue series in treatment at least 6 months before documented recurrence or advanced/ gastric cancer specimens have shown conflicting results. This metastatic disease; Zubrod’s performance status from 0 to 1; ability to may be due to the differing methodology used in measuring swallow and/or receive enteral medications via gastrostomy feeding tube HER2 status [6]. In fact, evaluations of both EGFR and HER2 (including ability to absorb medication); adequate bone marrow reserve as have revealed varying expression, which may relate to the evidenced by absolute granulocyte count ‡1500/ll and platelets ‡100 000/ methods used to evaluate these markers [10–12]. Most recently, ll; adequate hepatic function as evidenced by serum bilirubin £ HER2 expression was noted to be 22% in the ToGA institutional upper limit of normal (IULN), serum transaminases [serum trial, carried out by both FISH and immunohistochemistry glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic (IHC) [13]. transaminase (SGPT)] £2.5 · (IULN) [if liver metastasis were present, In the laboratory, the combination of anti-EGFR and anti- SGOT or SGPT had to be £5 · (IULN)]; measured or calculated creatinine ErB2 mAbs results in additive antiproliferative effects, clearance of >60 ml/min (utilizing G–K equation); cardiac ejection fraction suggesting a potential benefit of this combined therapy in the within the institutional range as measured by echocardiogram or Multi treatment of cancers stimulated by EGFR and HER2 signals. Gated Acquisition (MUGA) scan. Patients must not have received previous Lapatinib was approved by the Food and Drug treatment of metastatic disease or received any prior therapy with EGFR Administration in March 2007 for use in patients only in targeting therapies. Human immunodeficiency virus-positive patients were combination with capecitabine for HER2-positive breast cancer excluded because of possible pharmacokinetic interactions with patients, who have completely responded to previous antiretroviral therapy. HER2 amplification was not an entry criterion for chemotherapy with anthracycline, taxanes, and trastuzumab this study. All patients must have signed the informed consent in accordance with institutional and federal guidelines. [14]. Preclinical data have shown that lapatinib, an ErbB1 (EGFR) and ErB2 (HER2) inhibitor, may down-regulate thymidylate synthase in vitro. study design The antitumor effect of lapatinib in gastric cancer cell lines This was a phase II, open-label, multicenter trial administered and has been reported to have the greatest effects in HER2- monitored by SWOG. The primary objective of this study was to assess the amplified cells [15]. Lapatinib inhibited phosphorylation of response rate of lapatinib in patients with advanced/metastatic gastric cancer. Secondary objectives included (i) assessment of overall survival HER2, EGFR, and downstream signaling proteins resulting in (OS) in these patients; (ii) quantitative and qualitative toxic effects of this G1 arrest and induction of apoptosis [16]. regimen; (iii) preliminary assessment of the relationship of protein Lapatinib, a dual tyrosine kinase inhibitor of both EGFR and expression and gene expression of EGFR, HER2, markers of angiogenesis HER2/erbB2, is thought to react with the ATP binding site of [cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), protein kinases, competing with the ATP substrate inhibiting interleukin (IL)-8], and cell cycle (Cyclin D1) with clinical outcome in this EGFR/HER2 autophosphorylation through this competition. study population. Treatment with lapatinib in tumor xenografts that Patients received lapatinib 1500 mg orally days 1 through 28. The drug overexpressed both EGFR and HER2 resulted in reduced levels was administered continuously, with one cycle defined as 28 days. Tablets of phosphorylated tyrosine, which correlated with inhibition of were available in a strength of 250 mg, and a total of six were taken daily. tumor growth [17]. Apoptosis and arrest of tumor cell growth Concomitant medications that were considered gastric pH modifiers were have been demonstrated with this agent, even in the presence of not permitted. The use of antacids was permitted, but these were saturating concentrations of EGF [18]. Lapatinib has been administered within 1 hour before or after dosing. Dose adjustments were shown to inhibit Erk1/2 and Akt phosphorylation (pErk and made for grade 3 toxicity or greater. The first dose reduction was from 1500 pAkt) in both EGFR and ErB2-expressing cell lines (BT474 and to 1000 mg/day, the second dose reduction 750 mg/day, and if a third dose HN5). The ability of lapatinib to inhibit pAkt was associated reduction was required, patients were taken off study. Patients continued with a 23-fold increase in the percentage of cells undergoing on protocol treatment until disease progression, symptomatic apoptosis compared with control cells. These results suggest deterioration, unacceptable toxicity, treatment delay for any reason >4 that lapatinib treatment of EGFR/ErB2-expressing tumors weeks, or withdrawal of consent. could lead to inhibition of downstream signaling events [18]. Given evidence of expression of EGFR and potentially, treatment assessments HER2/ErB2 in patients with gastric cancer, and preclinical Baseline assessments included medical history and physical examination, evidence that blockade of these receptors may lead to inhibition performance status, complete blood count with differential and platelet of cell growth and apoptosis, a phase II study using lapatinib as count, bilirubin, SGOT and SGPT, creatinine clearance, diagnostic tumor a single agent for patients with advanced or metastatic imaging, electrocardiogram and submission of paraffin-embedded tumor gastric cancer was conducted through the Southwest specimen, and a blood sample. An echocardiogram or MUGA was also Oncology Group (SWOG) (ClinicalTrials.govIdentifier: NCT carried out and required every 8 weeks. During the study, history, physical 00103324]. exam, performance status, blood counts, SGOT, SGPT, and creatinine clearance were evaluated every 4 weeks. Toxicity assessment, based on the National Cancer Institute Common Toxicity Criteria, version 2, was carried patients and methods out every 4 weeks. Tumor response assessments were done after every two Study eligibility included the following: cytologically or pathologically cycles. Disease assessment was mandated every 9 weeks while patients were verified diagnosis of advanced or metastatic adenocarcinoma gastric cancer on protocol treatment and every 3 months after they were off protocol Volume 22 | No. 12 | December 2011 doi:10.1093/annonc/mdr021 | 2611 Annals of Oncology original article treatment but before progression. Measurable lesions were defined by treatment delivery RECIST. A second sample of blood for molecular correlates was collected 4 The median duration of protocol treatment was 1.9 months weeks after registration. (range 0.3–12.5 months). Reasons for treatment discontinuation include progressive disease (84%), death (7%), molecular correlates toxicity (7%), and patient refusal (2%). Of the 44 eligible genotyping. Peripheral blood or paraffin-embedded tissue samples were patients, 28 (64%) had their lapatinib dose reduced. available from 41 eligible patients. Genomic DNA was extracted from white blood cells or paraffinized tissue using the QiAmp kit (Qiagen, Valencia, treatment efficacy CA). Genomic DNA was obtained in 37 patients from peripheral blood and There were four partial responses (PRs) in 44 assessable in four patients from paraffin-embedded tissue. These 41 genomic DNA patients, with no complete responses observed, for an samples were used to analyze all polymorphisms. overall confirmed response rate of 9% [95% confidence interval Single nucleotide polymorphisms were tested using PCR–RFLP (CI) 3–22%]. There was also one unconfirmed PR for an technique as previously described. Briefly, forward and reverse primers were overall response rate of 11%. There were 10 (23%) patients used for PCR amplification, PCR products were digested by restriction enzymes (New England Biolab, Massachussetts, MA), and alleles were with stable disease. The remainder was not assessable for separated on 4% NuSieve ethidium bromide-stained agarose gel. In case no response (N = 2) or had early progression (N = 27). restriction enzyme could be found, samples were analyzed by Patients who could not be assessed for response were treated as direct sequencing. For the EGFR (CA)n dinucleotide repeat, the 5# end non-responders and included in the denominator. With all [33P-]cATP labeled PCR protocol was used. patients now off protocol treatment, the median TTF was 1.9 months (95% CI 1.6–3.1). Forty-three (98%) patients have gene expression levels. Thirty-seven paraffin-embedded tissue samples were died, with a median OS of 4.8 months (95% CI 3.2–7.4) available for gene expression assay. Laser captured microdissection, (Figure 1). messenger RNA (mRNA) isolation, complementary DNA (cDNA) synthesis, and real-time PCR quantification of mRNA expression were toxicity carried out. There were 15 (34%) grade 3 and 3 (7%) grade 4 adverse events. The most common grade 3 events were fatigue (8), statistical design anorexia (7), and diarrhea (4). There was one treatment-related The primary goal of this study was to evaluate the confirmed response death due to CNS ischemia. One patient each experienced probability (complete and partial) in patients with advanced/metastatic grade 4 fatigue, cardiac ischemia/infarction, and vomiting. Of gastric cancer treated with lapatinib. Time to treatment failure (TTF) and note, there were no left ventricular ejection fraction OS were secondary end points. It is assumed that this therapy would be of no further interest if the true response probability was 5% or less and of abnormalities recorded at baseline or during the course of the interest if the true response probability was 20% or more. The study study. employed the two-stage design of Green and Dahlberg [19]. If, after the first 20 patients, at least one confirmed response was observed, an additional 20 patients were to be accrued. Five or more Table 1. Patient and tumor characteristics (N = 44) responses in the total of 40 were considered evidence that this regimen is of interest in the treatment of advanced/metastatic gastric cancer. This design Age (years) had a power of 0.92 when the true response is 20%, at a significance level of Median 68.7 0.05. Forty patients were sufficient to estimate the probability of a particular Range 38.9–90 toxicity to within 616%. Any toxicity occurring with at least a 5% Sex (%) probability was likely (87%) to be seen at least once. Male 29 (66) Additionally, the relationship of protein expression and gene expression Female 15 (34) of EGFR and HER2 and markers of angiogenesis and downstream Race (%) regulatory markers were to be compared in a very preliminary fashion with White 35 (80) clinical outcomes. The associations between gene polymorphisms and Black 4 (9) response were evaluated by Chi-squared test. The associations between gene Asian 4 (9) polymorphisms and OS were examined using Kaplan–Meier plots and the Unknown 1 (2) log-rank test. Zubrod performance status (%) 0 15 (34) 1 29 (66) results Number of metastatic sites (%) 0 1 (2) patient characteristics 1 15 (34) From February 2005 to May 2006, 47 patients were accrued. 2 15 (34) Two patients did not receive any treatment and are not 3+ 13 (30) analyzable for any end point (one of whom was also ineligible Prior therapy (%) due to no measurable disease). One other patient whose disease Surgery 12 (27) recurred too soon after adjuvant therapy was ineligible. Baseline Chemotherapy 3 (7) characteristics for the 44 eligible and assessable patients are Radiation 8 (18) presented in Table 1. 2612 | Iqbal et al. Volume 22 | No. 12 | December 2011 Annals of Oncology original article Table 2. Response and overall survival by polymorphisms Marker N RECIST Overall response (%) survival Yes No Median P (95% CI), months COX-2 G/C 12 0 (0) 12 (100) 5.9 (3.0–9.9) 0.57 G/G 29 4 (14) 25 (86) 4.7 (3.0–8.7) Cyclin D1 A/A 13 1 (8) 12 (92) 3.8 (3.0–9.9) 0.46 A/G 18 1 (6) 17 (94) 4.9 (3.3–7.4) Figure 1. Overall survival Kaplan–Meier curve in patients with advanced G/G 10 2 (20) 8 (80) 4.5 (1.1–13.5) or metastatic gastric cancer treated with lapatinib as first-line therapy. EGF A/A 10 0 (0) 10 (100) 4.9 (3.3–7.4) 0.92 biologic markers A/G 22 3 (14) 19 (86) 3.4 (2.5–9.9) G/G 9 1 (11) 8 (89) 7.6 (3.0–9.9) Genomic DNA from 41 patients was available for evaluation of EGFR eight polymorphisms in the seven genes of interest. Genotyping A/A 21 2 (10) 19 (90) 3.3 (2.5–7.6) 0.38 assays for the polymorphisms were successful as follows: 41 A/G 13 2 (15) 11 (85) 6.1 (4.7–10.4) patients for COX-2, Cyclin D1, EGF, EGFR 497, HER2, and IL-8; G/G 7 0 (0) 7 (100) 7.4 (1.3–13.5) 37 patients for EGFR (CA)n repeats; and 40 patients for VEGF. EGFR (CA)n repeats Table 2 describes patient outcomes within each polymorphism- At least 1 allele ‡20 17 0 (0) 17 (100) 4.7 (2.2–9.9) 0.94 based subgroup. There were four partial responders in the group Both alleles <20 20 3 (15) 17 (85) 4.9 (3.3–7.4) of patients with IL-8 AA genotype compared with none in the HER2 group with AT or TT genotype. Patients with VEGF CC Ile/Ile 28 3 (11) 25 (89) 4.8 (3.0–9.2) 0.86 genotype had 3% (1/30) response rate, while patients with Ile/Val 10 1 (10) 9 (90) 4.7 (2.2–9.9) CT genotype had 22% (2/9) response rate and those with TT Val/Val 3 0 (0) 3 (100) 5.0 (NA) genotype had 100% (1/1) response rate. Patients with the IL-8 IL-8 A/A genotype had median (95% CI) OS of 9.6 (3.0–11.2) months, A/A 14 4 (29) 10 (71) 9.6 (3.0–11.2) 0.20 longer than either the A/T [4.9 (3.2–7.4)] or the T/T [3.0 (2.5– A/T 18 0 (0) 18 (100) 4.9 (3.2–7.4) 4.8)] genotypes, although this result was not statistically T/T 9 0 (0) 9 (100) 3.0 (2.5–4.8) significant (P = 0.20). None of the remaining polymorphisms TF A-603G tested were associated with either response or survival (Table 2). A/A 14 2 (14) 12 (86) 4.2 (3.0–9.9) 0.37 A/G 18 2 (11) 16 (89) 5.3 (3.0–10.5) Tumor cDNA from 36 microdissected tumor tissue G/G 9 0 (0) 9 (100) 6.1 (2.1–9.2) specimens were available for the measurement of gene VEGF expression levels of six genes of interest. The median values C/C 30 1 (3) 29 (97) 4.9 (3.3–7.6) 0.79 used for the gene expression analyses were EGFR, 2.715; HER2, C/T 9 2 (22) 7 (78) 3.0 (3.0–10.4) 0.065; IL-8, 16.59; VEGF, 5.88; COX-2, 1.94; and CYCLIN D1, T/T 1 1 (100) 0 (0) NA 8.77. The gene expression assay was successful as follows: 33 patients for HER2, 34 patients for COX-2 and VEGF, 35 P values from Cox regression test for heterogeneity across subgroups; not patients for EGFR and IL-8, 36 patients for CyclinD1, and 36 adjusted for multiple comparisons. patients for EGFR gene expression levels. Table 3 summarizes CI, confidence interval; COX-2, cyclooxygenase-2; EGFR, epidermal growth tumor response and OS by intratumoral gene expression levels. factor receptor; HER2, human epidermal growth factor receptor 2; IL-8, Higher HER2 and lower IL-8 gene expression levels were interleukin 8; N/A, not applicable; VEGF, vascular endothelial growth significantly (P < 0.05) associated with improved OS, although factor. these P values have not been adjusted for multiple comparisons. For none of the remaining genes were expression levels significantly associated with OS. Clinically, single-agent activity with EGFR inhibitors have been evaluated in a very limited fashion in patients with gastric and gastroesophageal junction adenocarcinoma. Dragovich discussion et al. [20] reported a phase II study using erlotinib in this The current standard treatment of advanced gastric cancer population and did not find any significant activity in gastric includes two or three drug regimens, which can produce cancer but did have a 9% confirmed response rate in significant toxicity with limited efficacy. No targeted single- gastroesophageal junction tumors. Other trials have shown agent biologic therapy to date has demonstrated significant limited efficacy of these agents in esophageal cancer and no activity. In this study, single agent lapatinib demonstrated a significant efficacy in patients with gastric cancer. Combination confirmed response rate of 9% (overall response rate of 11%) therapy with cytotoxics plus EGFR inhibition, i.e. cetuximab and a median overall survival of 4.8 months. has demonstrated promising results in esophageal and Volume 22 | No. 12 | December 2011 doi:10.1093/annonc/mdr021 | 2613 Annals of Oncology original article Table 3. Response and overall survival by intratumoral gene expressions pathway (EGFR, EGF and HER2), angiogenesis pathway (COX- 2, VEGF and IL-8), and cell cycle pathway (CyclinD1). We found that patients with higher HER2 or lower IL-8 gene Marker N RECIST response (%) Overall survival expression levels had increased OS. These data are consistent Yes No Median (95% CI), P with previously reported in vitro data published by Rusnak months et al. [24], wherein lapatinib sensitivity is increased in human COX-2 cell lines with high levels of HER2 expression [15, 16]. This has Above median 17 0 (0) 17 (100) 3.2 (2.1–8.7) 0.24 also been shown in previous reports for HER2 therapy with Below median 17 2 (12) 15 (88) 5.0 (3.0–9.9) treatment with trastuzumab in breast cancer [25, 26]. HER2 Cyclin D1 evaluation by FISH was not carried out due to limitations with Above median 18 1 (6) 17 (94) 4.9 (3.0–9.2) 0.89 Below edian 18 2 (11) 16 (89) 4.0 (2.7–5.7) tissue samples in this study. HER2 gene expression has been EGFR correlated with amplification in prior reports [27]. Above edian 18 2 (11) 16 (89) 3.3 (1.9–5.7) 0.17 Polymorphisms in IL-8 and VEGF, both involved in Below edian 17 0 (0) 17 (100) 5.7 (3.0–8.7) angiogenesis, showed some correlation with response and were Her2 significantly associated with OS. These data suggest that both Above median 16 2 (13) 14 (87) 6.8 (3.3–12.4) 0.0031 EGFR and genes in the angiogenesis pathways may play a role Below median 17 0 (0) 17 (100) 3.0 (1.3–4.7) in determining the efficacy of lapatinib. However, due to the IL-8 small number of the patients involved in our biomarker study, Above median 17 0 (0) 17 (100) 3.0 (2.2–5.7) 0.016 our preliminary results should be interpreted cautiously, with Below median 18 3 (17) 15 (83) 5.6 (3.3–10.5) these findings validated in a larger prospective clinical trial. VEGF Evaluation of EGFR or HER2 status was not required for Above median 17 1 (6) 16 (94) 3.8 (1.1–9.9) 0.63 participation in this study. The patients were thereby not Below median 17 1 (6) 16 (94) 4.8 (3.0–7.4) selected based on the tumor characteristics, which may have affected the potential efficacy of the drug. This may be P values from Cox regression; not adjusted for multiple comparisons. particularly significant given that the lapatinib has CI, confidence interval; COX-2, cyclooxygenase-2; EGFR, epidermal growth demonstrated antitumor activity in HER2-amplified gastric factor receptor; HER2, human epidermal growth factor receptor 2; IL-8, cancer cell lines and HER2 amplification was found to be an interleukin 8; VEGF, vascular endothelial growth factor. important predictive factor for the growth inhibitory activity of lapatinib in gastric cancer [15, 16]. In terms of EGFR gastroesophageal junction cancer [21]. In gastric cancer, expression, there has not been association between EGFR encouraging responses have been reported in phase II studies protein expression and sensitivity to any of the HER-targeted with cetuximab in combination with 5-FU/lecovorin (LV)/ agents [15]. Furthermore, preclinical data have shown lapatinib irinotecan with a time to progression of 8 months and combined with 5-FU, cisplatin, oxaliplatin, or paclitaxel combinations with 5-FU/LV and oxaliplatin with a reported demonstrate an additive or synergistic effect [16, 28]. time to progression of 7.6 months [22, 23]. In this study, single-agent lapatinib demonstrated limited HER2 amplification has been reported as an independent activity, although similar to some reports of treatment with prognostic and potentially, predictive factor in gastric cancer. single-agent chemotherapy in advanced/metastatic gastric The utility of trastuzumab, the monoclonal antibody targeting cancer [2, 29]. Prior evaluation of single-agent ‘targeted HER2, has been limited in its evaluation and efficacy until treatment’ of EGFR or HER2 blockade as single agents has not recently. Van Cutsem et al. [13] presented data from the ToGA demonstrated any significant responses. Dual inhibition of trial, a randomized phase III multicenter study, where more HER2 and EGFR did result in modest activity and provides than 3800 patients with adenocarcinoma of the stomach or support for combination treatment and screening for HER2 gastroesophageal junction were screened and 810 were positive in advanced gastric cancer. for HER2 (22.1%). These patients were randomized to receive fluoropyrimidine with cisplatin and trastuzumab versus acknowledgement chemotherapy alone [13]. Patients were either HER2 positive by IHC3+ and/or FISH+. The OS for patients receiving Clinical and correlative results presented in part at the 43rd chemotherapy with trastuzumab was 13.8 versus 11.1 months Annual Meeting of the American Society of Clinical Oncology, for patients receiving fluoropyrimine and cisplatin alone, 1-5 June 2007, Chicago, IL. hazard ratio 0.74 (0.60–0.91), P = 0.0046. The secondary end point of progression-free survival and response rate were also funding statistically superior in the patients receiving fluropyrimidine, platinum, and trastuzumab. The combination was well This investigation was supported in part by the following PHS tolerated. This is the first time a biological agent resulted in a Cooperative Agreement grant numbers awarded by the survival benefit in advanced gastric cancer. National Cancer Institute, DHHS: CA32102, CA38926, CA46368, CA58882, CA76447, CA45808, CA35261, CA35090, To explore potential molecular markers, we evaluated gene expression levels of six genes of interest in 36 patients and eight CA45560, CA74647, CA12644, CA35119, CA52654, CA22433, germ-line polymorphisms in seven genes of interest in 41 CA45450, CA45461, CA35178, CA67575, CA20319, CA35128, treated patients. These genes included those involved in EGFR CA46441, CA58723, CA27057, CA11083, CA58861, CA35431. 2614 | Iqbal et al. Volume 22 | No. 12 | December 2011 Annals of Oncology original article 15. Wainberg ZA, Anghel A, Desai AJ et al. Lapatinib, a dual EGFR and HER2 kinase disclosure inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is H.-J.L.–stock/ownership interests and honoraria from synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res 2010; 16: 1509–1519. Response Genetics, Inc; research funding from Glaxo Smith 16. 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Int J Oncol breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2003; 23: 1381–1387. 2659–2671. 11. Pinto-de-Sousa J, David L, Almeida R et al. c-erb B-2 expression is associated 26. Vogel C, Cobleigh MA, Tripathy D et al. First-line, single-agent Herceptin(R) with tumor location and venous invasion and influences survival of patients with (trastuzumab) in metastatic breast cancer. A preliminary report. Eur J Cancer gastric carcinoma. Int J Surg Pathol 2002; 10: 247–256. 2001; 37(Suppl 1): 25–29. 12. Oshima CT, Lanzoni VP, Iriya K, Forones NM. C-erbB-2 oncoprotein in gastric 27. Sauter G, Lee J, Bartlett JM et al. Guidelines for human epidermal growth factor carcinoma: correlation with clinical stage and prognosis. Int J Biol Markers 2001; receptor 2 testing: biologic and methodologic considerations. J Clin Oncol 2009; 16: 250–254. 27: 1323–1333. 13. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with 28. Tanizaki J, Okamoto I, Takezawa K et al. Synergistic antitumor effect of S-1 and chemotherapy versus chemotherapy alone for treatment of HER2-positive HER2-targeting agents in gastric cancer with HER2 amplification. Mol Cancer advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, Ther 2010; 9: 1198–1207. open-label, randomised controlled trial. Lancet 2010; 376: 687–697. 29. Berenberg JL, Tangen C, Macdonald JS et al. Phase II study of 5-fluorouracil and 14. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2- folinic acid in the treatment of patients with advanced gastric cancer. A positive advanced breast cancer. N Engl J Med 2006; 355: 2733–2743. Southwest Oncology Group study. Cancer 1995; 76: 715–719. Volume 22 | No. 12 | December 2011 doi:10.1093/annonc/mdr021 | 2615 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Pubmed Central

Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer

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Abstract

Annals of Oncology 22: 2610–2615, 2011 doi:10.1093/annonc/mdr021 original article Published online 17 March 2011 Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer 1 2 3 1 1 4 S. Iqbal *, B. Goldman , C. M. Fenoglio-Preiser , H. J. Lenz , W. Zhang , K. D. Danenberg , 5 6 S. I. Shibata & C. D. Blanke 1 2 3 Division of Medical Oncology, University of Southern California, Los Angeles; Southwest Oncology Group Statistical Center, Seattle; Department of Pathology, 4 5 University of Cincinnati, Cincinnati; Response Genetics, Inc., Los Angeles; Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA; Department of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada Received 2 July 2010; revised 14 January 2011; accepted 17 January 2011 Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%–45% of gastric cancers, making them potential targets. Patients and methods: The primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days. Results: The study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6–3.1) months and OS was 4.8 (3.2–7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS. Conclusions: Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation. Key words: EGFR, gastric cancer, HER2, lapatinib One potential therapeutic target is the epidermal growth introduction factor receptor (EGFR). Both the EGFR and human epidermal In 2010, there were an estimated 21 000 new cases of gastric growth factor receptor 2 (HER2) genes are amplified and cancer in the United States with 10 570 deaths and an overall overexpressed in a variety of solid human cancers and are 5-year survival rate of 22% [1]. Only 20% of cases are associated with a poor prognosis in patients with gastric cancer. diagnosed at an early, potentially curable, stage. Preclinical studies have shown a significant number of gastric Many chemotherapeutic drugs have single-agent activity in cancer cell lines express EGFR, which grow in response to EGF advanced disease, including fluoropyrimidines, platinums, and transforming growth factor-a and show a greater degree of irinotecan, taxanes, and adriamycin. Combination regimens gastric wall invasion and lymph node metastasis, representing have been shown to be more effective, with response rates greater malignant potential [3–5]. Additionally, EGFR ranging from 30% to 50%. However, there can be significant expression is significantly higher in gastric carcinoma than in toxicity associated with these combinations and historically, adjacent normal gastric mucosa, with greater EGFR levels median survival has been 6–9 months. There are more recent found in more advanced tumors [6]. Yasui et al. [7] evaluated phase II and III studies that have reported longer survival, some gastric carcinoma samples for EGFR by 125-labeled EGF >1 year [2]. Nevertheless, there remain limitations of binding, with EGFR expression immunoreactivity detected in traditional therapies and promising preliminary data with novel 33 (34%) of the 96 advanced gastric cancers. Similarly, targeted therapeutics, newer agents are being investigated. evaluation by He et al. [8] of 104 specimens of gastric cancer revealed that 42% demonstrated expression of EGFR. *Correspondence to: Dr S. Iqbal, Division of Medical Oncology, Norris Comprehensive Simultaneous EGF and EGFR expression was noted in 15% of Cancer Center, University of Southern California, 1441 Eastlake Avenue, Room 3457, gastric cancers, suggesting that these tumors may grow in an Los Angeles, CA 90033, USA. Tel: +1-323-865-3907; Fax: +1-323-865-0061; E-mail: iqbal@usc.edu Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. original article Annals of Oncology original article not surgically curable; measurable disease by RECIST criteria; 2-week autocrine fashion. Twelve percent of specimens in this study period between any surgery and study entry; completion of prior were found to be positive for c-ErB2 [9]. chemotherapy, hormonal therapy, immunotherapy, radiation therapy (to HER2 has also been associated with poor prognosis, and <25% of bone marrow), or chemoradiotherapy as neoadjuvant or adjuvant expression of HER2 assessed in many trials and tissue series in treatment at least 6 months before documented recurrence or advanced/ gastric cancer specimens have shown conflicting results. This metastatic disease; Zubrod’s performance status from 0 to 1; ability to may be due to the differing methodology used in measuring swallow and/or receive enteral medications via gastrostomy feeding tube HER2 status [6]. In fact, evaluations of both EGFR and HER2 (including ability to absorb medication); adequate bone marrow reserve as have revealed varying expression, which may relate to the evidenced by absolute granulocyte count ‡1500/ll and platelets ‡100 000/ methods used to evaluate these markers [10–12]. Most recently, ll; adequate hepatic function as evidenced by serum bilirubin £ HER2 expression was noted to be 22% in the ToGA institutional upper limit of normal (IULN), serum transaminases [serum trial, carried out by both FISH and immunohistochemistry glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic (IHC) [13]. transaminase (SGPT)] £2.5 · (IULN) [if liver metastasis were present, In the laboratory, the combination of anti-EGFR and anti- SGOT or SGPT had to be £5 · (IULN)]; measured or calculated creatinine ErB2 mAbs results in additive antiproliferative effects, clearance of >60 ml/min (utilizing G–K equation); cardiac ejection fraction suggesting a potential benefit of this combined therapy in the within the institutional range as measured by echocardiogram or Multi treatment of cancers stimulated by EGFR and HER2 signals. Gated Acquisition (MUGA) scan. Patients must not have received previous Lapatinib was approved by the Food and Drug treatment of metastatic disease or received any prior therapy with EGFR Administration in March 2007 for use in patients only in targeting therapies. Human immunodeficiency virus-positive patients were combination with capecitabine for HER2-positive breast cancer excluded because of possible pharmacokinetic interactions with patients, who have completely responded to previous antiretroviral therapy. HER2 amplification was not an entry criterion for chemotherapy with anthracycline, taxanes, and trastuzumab this study. All patients must have signed the informed consent in accordance with institutional and federal guidelines. [14]. Preclinical data have shown that lapatinib, an ErbB1 (EGFR) and ErB2 (HER2) inhibitor, may down-regulate thymidylate synthase in vitro. study design The antitumor effect of lapatinib in gastric cancer cell lines This was a phase II, open-label, multicenter trial administered and has been reported to have the greatest effects in HER2- monitored by SWOG. The primary objective of this study was to assess the amplified cells [15]. Lapatinib inhibited phosphorylation of response rate of lapatinib in patients with advanced/metastatic gastric cancer. Secondary objectives included (i) assessment of overall survival HER2, EGFR, and downstream signaling proteins resulting in (OS) in these patients; (ii) quantitative and qualitative toxic effects of this G1 arrest and induction of apoptosis [16]. regimen; (iii) preliminary assessment of the relationship of protein Lapatinib, a dual tyrosine kinase inhibitor of both EGFR and expression and gene expression of EGFR, HER2, markers of angiogenesis HER2/erbB2, is thought to react with the ATP binding site of [cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), protein kinases, competing with the ATP substrate inhibiting interleukin (IL)-8], and cell cycle (Cyclin D1) with clinical outcome in this EGFR/HER2 autophosphorylation through this competition. study population. Treatment with lapatinib in tumor xenografts that Patients received lapatinib 1500 mg orally days 1 through 28. The drug overexpressed both EGFR and HER2 resulted in reduced levels was administered continuously, with one cycle defined as 28 days. Tablets of phosphorylated tyrosine, which correlated with inhibition of were available in a strength of 250 mg, and a total of six were taken daily. tumor growth [17]. Apoptosis and arrest of tumor cell growth Concomitant medications that were considered gastric pH modifiers were have been demonstrated with this agent, even in the presence of not permitted. The use of antacids was permitted, but these were saturating concentrations of EGF [18]. Lapatinib has been administered within 1 hour before or after dosing. Dose adjustments were shown to inhibit Erk1/2 and Akt phosphorylation (pErk and made for grade 3 toxicity or greater. The first dose reduction was from 1500 pAkt) in both EGFR and ErB2-expressing cell lines (BT474 and to 1000 mg/day, the second dose reduction 750 mg/day, and if a third dose HN5). The ability of lapatinib to inhibit pAkt was associated reduction was required, patients were taken off study. Patients continued with a 23-fold increase in the percentage of cells undergoing on protocol treatment until disease progression, symptomatic apoptosis compared with control cells. These results suggest deterioration, unacceptable toxicity, treatment delay for any reason >4 that lapatinib treatment of EGFR/ErB2-expressing tumors weeks, or withdrawal of consent. could lead to inhibition of downstream signaling events [18]. Given evidence of expression of EGFR and potentially, treatment assessments HER2/ErB2 in patients with gastric cancer, and preclinical Baseline assessments included medical history and physical examination, evidence that blockade of these receptors may lead to inhibition performance status, complete blood count with differential and platelet of cell growth and apoptosis, a phase II study using lapatinib as count, bilirubin, SGOT and SGPT, creatinine clearance, diagnostic tumor a single agent for patients with advanced or metastatic imaging, electrocardiogram and submission of paraffin-embedded tumor gastric cancer was conducted through the Southwest specimen, and a blood sample. An echocardiogram or MUGA was also Oncology Group (SWOG) (ClinicalTrials.govIdentifier: NCT carried out and required every 8 weeks. During the study, history, physical 00103324]. exam, performance status, blood counts, SGOT, SGPT, and creatinine clearance were evaluated every 4 weeks. Toxicity assessment, based on the National Cancer Institute Common Toxicity Criteria, version 2, was carried patients and methods out every 4 weeks. Tumor response assessments were done after every two Study eligibility included the following: cytologically or pathologically cycles. Disease assessment was mandated every 9 weeks while patients were verified diagnosis of advanced or metastatic adenocarcinoma gastric cancer on protocol treatment and every 3 months after they were off protocol Volume 22 | No. 12 | December 2011 doi:10.1093/annonc/mdr021 | 2611 Annals of Oncology original article treatment but before progression. Measurable lesions were defined by treatment delivery RECIST. A second sample of blood for molecular correlates was collected 4 The median duration of protocol treatment was 1.9 months weeks after registration. (range 0.3–12.5 months). Reasons for treatment discontinuation include progressive disease (84%), death (7%), molecular correlates toxicity (7%), and patient refusal (2%). Of the 44 eligible genotyping. Peripheral blood or paraffin-embedded tissue samples were patients, 28 (64%) had their lapatinib dose reduced. available from 41 eligible patients. Genomic DNA was extracted from white blood cells or paraffinized tissue using the QiAmp kit (Qiagen, Valencia, treatment efficacy CA). Genomic DNA was obtained in 37 patients from peripheral blood and There were four partial responses (PRs) in 44 assessable in four patients from paraffin-embedded tissue. These 41 genomic DNA patients, with no complete responses observed, for an samples were used to analyze all polymorphisms. overall confirmed response rate of 9% [95% confidence interval Single nucleotide polymorphisms were tested using PCR–RFLP (CI) 3–22%]. There was also one unconfirmed PR for an technique as previously described. Briefly, forward and reverse primers were overall response rate of 11%. There were 10 (23%) patients used for PCR amplification, PCR products were digested by restriction enzymes (New England Biolab, Massachussetts, MA), and alleles were with stable disease. The remainder was not assessable for separated on 4% NuSieve ethidium bromide-stained agarose gel. In case no response (N = 2) or had early progression (N = 27). restriction enzyme could be found, samples were analyzed by Patients who could not be assessed for response were treated as direct sequencing. For the EGFR (CA)n dinucleotide repeat, the 5# end non-responders and included in the denominator. With all [33P-]cATP labeled PCR protocol was used. patients now off protocol treatment, the median TTF was 1.9 months (95% CI 1.6–3.1). Forty-three (98%) patients have gene expression levels. Thirty-seven paraffin-embedded tissue samples were died, with a median OS of 4.8 months (95% CI 3.2–7.4) available for gene expression assay. Laser captured microdissection, (Figure 1). messenger RNA (mRNA) isolation, complementary DNA (cDNA) synthesis, and real-time PCR quantification of mRNA expression were toxicity carried out. There were 15 (34%) grade 3 and 3 (7%) grade 4 adverse events. The most common grade 3 events were fatigue (8), statistical design anorexia (7), and diarrhea (4). There was one treatment-related The primary goal of this study was to evaluate the confirmed response death due to CNS ischemia. One patient each experienced probability (complete and partial) in patients with advanced/metastatic grade 4 fatigue, cardiac ischemia/infarction, and vomiting. Of gastric cancer treated with lapatinib. Time to treatment failure (TTF) and note, there were no left ventricular ejection fraction OS were secondary end points. It is assumed that this therapy would be of no further interest if the true response probability was 5% or less and of abnormalities recorded at baseline or during the course of the interest if the true response probability was 20% or more. The study study. employed the two-stage design of Green and Dahlberg [19]. If, after the first 20 patients, at least one confirmed response was observed, an additional 20 patients were to be accrued. Five or more Table 1. Patient and tumor characteristics (N = 44) responses in the total of 40 were considered evidence that this regimen is of interest in the treatment of advanced/metastatic gastric cancer. This design Age (years) had a power of 0.92 when the true response is 20%, at a significance level of Median 68.7 0.05. Forty patients were sufficient to estimate the probability of a particular Range 38.9–90 toxicity to within 616%. Any toxicity occurring with at least a 5% Sex (%) probability was likely (87%) to be seen at least once. Male 29 (66) Additionally, the relationship of protein expression and gene expression Female 15 (34) of EGFR and HER2 and markers of angiogenesis and downstream Race (%) regulatory markers were to be compared in a very preliminary fashion with White 35 (80) clinical outcomes. The associations between gene polymorphisms and Black 4 (9) response were evaluated by Chi-squared test. The associations between gene Asian 4 (9) polymorphisms and OS were examined using Kaplan–Meier plots and the Unknown 1 (2) log-rank test. Zubrod performance status (%) 0 15 (34) 1 29 (66) results Number of metastatic sites (%) 0 1 (2) patient characteristics 1 15 (34) From February 2005 to May 2006, 47 patients were accrued. 2 15 (34) Two patients did not receive any treatment and are not 3+ 13 (30) analyzable for any end point (one of whom was also ineligible Prior therapy (%) due to no measurable disease). One other patient whose disease Surgery 12 (27) recurred too soon after adjuvant therapy was ineligible. Baseline Chemotherapy 3 (7) characteristics for the 44 eligible and assessable patients are Radiation 8 (18) presented in Table 1. 2612 | Iqbal et al. Volume 22 | No. 12 | December 2011 Annals of Oncology original article Table 2. Response and overall survival by polymorphisms Marker N RECIST Overall response (%) survival Yes No Median P (95% CI), months COX-2 G/C 12 0 (0) 12 (100) 5.9 (3.0–9.9) 0.57 G/G 29 4 (14) 25 (86) 4.7 (3.0–8.7) Cyclin D1 A/A 13 1 (8) 12 (92) 3.8 (3.0–9.9) 0.46 A/G 18 1 (6) 17 (94) 4.9 (3.3–7.4) Figure 1. Overall survival Kaplan–Meier curve in patients with advanced G/G 10 2 (20) 8 (80) 4.5 (1.1–13.5) or metastatic gastric cancer treated with lapatinib as first-line therapy. EGF A/A 10 0 (0) 10 (100) 4.9 (3.3–7.4) 0.92 biologic markers A/G 22 3 (14) 19 (86) 3.4 (2.5–9.9) G/G 9 1 (11) 8 (89) 7.6 (3.0–9.9) Genomic DNA from 41 patients was available for evaluation of EGFR eight polymorphisms in the seven genes of interest. Genotyping A/A 21 2 (10) 19 (90) 3.3 (2.5–7.6) 0.38 assays for the polymorphisms were successful as follows: 41 A/G 13 2 (15) 11 (85) 6.1 (4.7–10.4) patients for COX-2, Cyclin D1, EGF, EGFR 497, HER2, and IL-8; G/G 7 0 (0) 7 (100) 7.4 (1.3–13.5) 37 patients for EGFR (CA)n repeats; and 40 patients for VEGF. EGFR (CA)n repeats Table 2 describes patient outcomes within each polymorphism- At least 1 allele ‡20 17 0 (0) 17 (100) 4.7 (2.2–9.9) 0.94 based subgroup. There were four partial responders in the group Both alleles <20 20 3 (15) 17 (85) 4.9 (3.3–7.4) of patients with IL-8 AA genotype compared with none in the HER2 group with AT or TT genotype. Patients with VEGF CC Ile/Ile 28 3 (11) 25 (89) 4.8 (3.0–9.2) 0.86 genotype had 3% (1/30) response rate, while patients with Ile/Val 10 1 (10) 9 (90) 4.7 (2.2–9.9) CT genotype had 22% (2/9) response rate and those with TT Val/Val 3 0 (0) 3 (100) 5.0 (NA) genotype had 100% (1/1) response rate. Patients with the IL-8 IL-8 A/A genotype had median (95% CI) OS of 9.6 (3.0–11.2) months, A/A 14 4 (29) 10 (71) 9.6 (3.0–11.2) 0.20 longer than either the A/T [4.9 (3.2–7.4)] or the T/T [3.0 (2.5– A/T 18 0 (0) 18 (100) 4.9 (3.2–7.4) 4.8)] genotypes, although this result was not statistically T/T 9 0 (0) 9 (100) 3.0 (2.5–4.8) significant (P = 0.20). None of the remaining polymorphisms TF A-603G tested were associated with either response or survival (Table 2). A/A 14 2 (14) 12 (86) 4.2 (3.0–9.9) 0.37 A/G 18 2 (11) 16 (89) 5.3 (3.0–10.5) Tumor cDNA from 36 microdissected tumor tissue G/G 9 0 (0) 9 (100) 6.1 (2.1–9.2) specimens were available for the measurement of gene VEGF expression levels of six genes of interest. The median values C/C 30 1 (3) 29 (97) 4.9 (3.3–7.6) 0.79 used for the gene expression analyses were EGFR, 2.715; HER2, C/T 9 2 (22) 7 (78) 3.0 (3.0–10.4) 0.065; IL-8, 16.59; VEGF, 5.88; COX-2, 1.94; and CYCLIN D1, T/T 1 1 (100) 0 (0) NA 8.77. The gene expression assay was successful as follows: 33 patients for HER2, 34 patients for COX-2 and VEGF, 35 P values from Cox regression test for heterogeneity across subgroups; not patients for EGFR and IL-8, 36 patients for CyclinD1, and 36 adjusted for multiple comparisons. patients for EGFR gene expression levels. Table 3 summarizes CI, confidence interval; COX-2, cyclooxygenase-2; EGFR, epidermal growth tumor response and OS by intratumoral gene expression levels. factor receptor; HER2, human epidermal growth factor receptor 2; IL-8, Higher HER2 and lower IL-8 gene expression levels were interleukin 8; N/A, not applicable; VEGF, vascular endothelial growth significantly (P < 0.05) associated with improved OS, although factor. these P values have not been adjusted for multiple comparisons. For none of the remaining genes were expression levels significantly associated with OS. Clinically, single-agent activity with EGFR inhibitors have been evaluated in a very limited fashion in patients with gastric and gastroesophageal junction adenocarcinoma. Dragovich discussion et al. [20] reported a phase II study using erlotinib in this The current standard treatment of advanced gastric cancer population and did not find any significant activity in gastric includes two or three drug regimens, which can produce cancer but did have a 9% confirmed response rate in significant toxicity with limited efficacy. No targeted single- gastroesophageal junction tumors. Other trials have shown agent biologic therapy to date has demonstrated significant limited efficacy of these agents in esophageal cancer and no activity. In this study, single agent lapatinib demonstrated a significant efficacy in patients with gastric cancer. Combination confirmed response rate of 9% (overall response rate of 11%) therapy with cytotoxics plus EGFR inhibition, i.e. cetuximab and a median overall survival of 4.8 months. has demonstrated promising results in esophageal and Volume 22 | No. 12 | December 2011 doi:10.1093/annonc/mdr021 | 2613 Annals of Oncology original article Table 3. Response and overall survival by intratumoral gene expressions pathway (EGFR, EGF and HER2), angiogenesis pathway (COX- 2, VEGF and IL-8), and cell cycle pathway (CyclinD1). We found that patients with higher HER2 or lower IL-8 gene Marker N RECIST response (%) Overall survival expression levels had increased OS. These data are consistent Yes No Median (95% CI), P with previously reported in vitro data published by Rusnak months et al. [24], wherein lapatinib sensitivity is increased in human COX-2 cell lines with high levels of HER2 expression [15, 16]. This has Above median 17 0 (0) 17 (100) 3.2 (2.1–8.7) 0.24 also been shown in previous reports for HER2 therapy with Below median 17 2 (12) 15 (88) 5.0 (3.0–9.9) treatment with trastuzumab in breast cancer [25, 26]. HER2 Cyclin D1 evaluation by FISH was not carried out due to limitations with Above median 18 1 (6) 17 (94) 4.9 (3.0–9.2) 0.89 Below edian 18 2 (11) 16 (89) 4.0 (2.7–5.7) tissue samples in this study. HER2 gene expression has been EGFR correlated with amplification in prior reports [27]. Above edian 18 2 (11) 16 (89) 3.3 (1.9–5.7) 0.17 Polymorphisms in IL-8 and VEGF, both involved in Below edian 17 0 (0) 17 (100) 5.7 (3.0–8.7) angiogenesis, showed some correlation with response and were Her2 significantly associated with OS. These data suggest that both Above median 16 2 (13) 14 (87) 6.8 (3.3–12.4) 0.0031 EGFR and genes in the angiogenesis pathways may play a role Below median 17 0 (0) 17 (100) 3.0 (1.3–4.7) in determining the efficacy of lapatinib. However, due to the IL-8 small number of the patients involved in our biomarker study, Above median 17 0 (0) 17 (100) 3.0 (2.2–5.7) 0.016 our preliminary results should be interpreted cautiously, with Below median 18 3 (17) 15 (83) 5.6 (3.3–10.5) these findings validated in a larger prospective clinical trial. VEGF Evaluation of EGFR or HER2 status was not required for Above median 17 1 (6) 16 (94) 3.8 (1.1–9.9) 0.63 participation in this study. The patients were thereby not Below median 17 1 (6) 16 (94) 4.8 (3.0–7.4) selected based on the tumor characteristics, which may have affected the potential efficacy of the drug. This may be P values from Cox regression; not adjusted for multiple comparisons. particularly significant given that the lapatinib has CI, confidence interval; COX-2, cyclooxygenase-2; EGFR, epidermal growth demonstrated antitumor activity in HER2-amplified gastric factor receptor; HER2, human epidermal growth factor receptor 2; IL-8, cancer cell lines and HER2 amplification was found to be an interleukin 8; VEGF, vascular endothelial growth factor. important predictive factor for the growth inhibitory activity of lapatinib in gastric cancer [15, 16]. In terms of EGFR gastroesophageal junction cancer [21]. In gastric cancer, expression, there has not been association between EGFR encouraging responses have been reported in phase II studies protein expression and sensitivity to any of the HER-targeted with cetuximab in combination with 5-FU/lecovorin (LV)/ agents [15]. Furthermore, preclinical data have shown lapatinib irinotecan with a time to progression of 8 months and combined with 5-FU, cisplatin, oxaliplatin, or paclitaxel combinations with 5-FU/LV and oxaliplatin with a reported demonstrate an additive or synergistic effect [16, 28]. time to progression of 7.6 months [22, 23]. In this study, single-agent lapatinib demonstrated limited HER2 amplification has been reported as an independent activity, although similar to some reports of treatment with prognostic and potentially, predictive factor in gastric cancer. single-agent chemotherapy in advanced/metastatic gastric The utility of trastuzumab, the monoclonal antibody targeting cancer [2, 29]. Prior evaluation of single-agent ‘targeted HER2, has been limited in its evaluation and efficacy until treatment’ of EGFR or HER2 blockade as single agents has not recently. Van Cutsem et al. [13] presented data from the ToGA demonstrated any significant responses. Dual inhibition of trial, a randomized phase III multicenter study, where more HER2 and EGFR did result in modest activity and provides than 3800 patients with adenocarcinoma of the stomach or support for combination treatment and screening for HER2 gastroesophageal junction were screened and 810 were positive in advanced gastric cancer. for HER2 (22.1%). These patients were randomized to receive fluoropyrimidine with cisplatin and trastuzumab versus acknowledgement chemotherapy alone [13]. Patients were either HER2 positive by IHC3+ and/or FISH+. The OS for patients receiving Clinical and correlative results presented in part at the 43rd chemotherapy with trastuzumab was 13.8 versus 11.1 months Annual Meeting of the American Society of Clinical Oncology, for patients receiving fluoropyrimine and cisplatin alone, 1-5 June 2007, Chicago, IL. hazard ratio 0.74 (0.60–0.91), P = 0.0046. The secondary end point of progression-free survival and response rate were also funding statistically superior in the patients receiving fluropyrimidine, platinum, and trastuzumab. The combination was well This investigation was supported in part by the following PHS tolerated. This is the first time a biological agent resulted in a Cooperative Agreement grant numbers awarded by the survival benefit in advanced gastric cancer. National Cancer Institute, DHHS: CA32102, CA38926, CA46368, CA58882, CA76447, CA45808, CA35261, CA35090, To explore potential molecular markers, we evaluated gene expression levels of six genes of interest in 36 patients and eight CA45560, CA74647, CA12644, CA35119, CA52654, CA22433, germ-line polymorphisms in seven genes of interest in 41 CA45450, CA45461, CA35178, CA67575, CA20319, CA35128, treated patients. These genes included those involved in EGFR CA46441, CA58723, CA27057, CA11083, CA58861, CA35431. 2614 | Iqbal et al. Volume 22 | No. 12 | December 2011 Annals of Oncology original article 15. Wainberg ZA, Anghel A, Desai AJ et al. Lapatinib, a dual EGFR and HER2 kinase disclosure inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is H.-J.L.–stock/ownership interests and honoraria from synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res 2010; 16: 1509–1519. Response Genetics, Inc; research funding from Glaxo Smith 16. 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Int J Oncol breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2003; 23: 1381–1387. 2659–2671. 11. Pinto-de-Sousa J, David L, Almeida R et al. c-erb B-2 expression is associated 26. Vogel C, Cobleigh MA, Tripathy D et al. First-line, single-agent Herceptin(R) with tumor location and venous invasion and influences survival of patients with (trastuzumab) in metastatic breast cancer. A preliminary report. Eur J Cancer gastric carcinoma. Int J Surg Pathol 2002; 10: 247–256. 2001; 37(Suppl 1): 25–29. 12. Oshima CT, Lanzoni VP, Iriya K, Forones NM. C-erbB-2 oncoprotein in gastric 27. Sauter G, Lee J, Bartlett JM et al. Guidelines for human epidermal growth factor carcinoma: correlation with clinical stage and prognosis. Int J Biol Markers 2001; receptor 2 testing: biologic and methodologic considerations. J Clin Oncol 2009; 16: 250–254. 27: 1323–1333. 13. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with 28. 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Annals of OncologyPubmed Central

Published: Mar 17, 2011

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