Randomized Phase II Multicenter Trial of Two Schedules of Lapatinib ...

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Mar 15, 2010 - Helen J. Ross1, George R. Blumenschein, Jr.2, Joseph Aisner3, Nevena Damjanov4, Afshin Dowlati5, ...... Thatcher N, Chang A, Parikh P, et al.

Clinical Cancer Research

Cancer Therapy: Clinical

Randomized Phase II Multicenter Trial of Two Schedules of Lapatinib as First- or Second-Line Monotherapy in Patients with Advanced or Metastatic Non–Small Cell Lung Cancer Helen J. Ross1, George R. Blumenschein, Jr.2, Joseph Aisner3, Nevena Damjanov4, Afshin Dowlati5, Jennifer Garst6, James R. Rigas7, Michael Smylie8, Habib Hassani9, Kimberly E. Allen9, Lance Leopold9, Tal Z. Zaks9, and Frances A. Shepherd10

Abstract Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49. ©2010 AACR.

Authors' Affiliations: 1Mayo Clinic, Scottsdale, Arizona; 2University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3 Cancer Institute of New Jersey, New Brunswick, New Jersey; 4University of Pennsylvania, Penn Presbyterian Medical Center, Philadelphia, Pennsylvania; 5 University Hospitals of Cleveland, Cleveland, Ohio; 6Duke University Medical Center, Durham, North Carolina; 7Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; 8Cross Cancer Institute, Edmonton, Alberta, Canada; 9GlaxoSmithKline, Collegeville, Pennsylvania; and 10 Princess Margaret Hospital, Toronto, Ontario, Canada Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Current address for T.Z. Zaks: Cephalon, Inc., Frazer, Pennsylvania. Current address for L. Leopold: Ascenta Therapeutics, Malvern, Pennsylvania. Corresponding Author: Helen J. Ross, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259. Phone: 480-301-8000; Fax: 480-3017006; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-08-3328 ©2010 American Association for Cancer Research.

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Clin Cancer Res; 16(6) March 15, 2010

Lung cancer is the leading cause of cancer-related deaths worldwide, with an estimated incidence of 1.35 million cases resulting in 1.2 million deaths annually (1). With advances in the treatment of newly diagnosed advanced non–small cell lung cancer (NSCLC), survival in patients able to receive chemotherapy has improved modestly over the past 2 decades (2). Platinum-based chemotherapy offers an initial response rate of 15% to 30%, with a median survival of 8 to 14 months. Approximately 35% to 50% of patients with good performance status will survive 1 year, although only 15% to 20% of patients survive 2 years from initial diagnosis (3–5). Targeted agents such as bevacizumab may add efficacy in selected patients at the cost of additional toxicity (6). Current strategies for drug design are focused on molecular mechanisms of tumorigenesis, such as the activation of protein kinases by somatic mutation or amplification.

Lapatinib in Advanced NSCLC

Translational Relevance The primary objective of this study was to evaluate the overall response rate to lapatinib in patients with advanced non–small cell lung cancer. During the trial, studies of tyrosine kinase inhibitors in non–small cell lung cancer reported that epidermal growth factor receptor mutations were highly predictive of response. Therefore, this study was amended to target patients with bronchioloalveolar carcinoma or never smokers because these individuals were most likely to have epidermal growth factor receptor mutations and might be more likely to respond to lapatinib therapy. Although well tolerated, oral lapatinib (1,500 mg once daily and 500 mg twice daily) failed to achieve a predetermined response rate in the target population, although there were several patients with long-duration stabilization of disease. Lapatinib as a single agent at the doses studied seems to have minimal single-agent activity, at least as measured by response rates. Although there may be a subgroup of patients who benefit, such as patients with HER2 amplification, this could not be determined by the current study.

The finding that members of the ErbB gene family are often amplified or mutated in NSCLC has led to this family as a target of investigation (7). The human ErbB receptor family consists of four transmembrane glycoproteins involved in transmission of signals controlling cell growth and differentiation. Two members of this family, epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2), are transmembrane tyrosine kinase receptors expressed on normal epithelial cells but overexpressed on some cancer cells (8, 9). In NSCLC, overexpression of EGFR ranges from 43% to 89% and that of HER2 from 16% to 32% (10). Some studies have shown no correlation between expression of these receptors and disease severity or clinical outcome (11), whereas others have shown an association between EGFR overexpression and poor prognosis in NSCLC, or between elevated levels of EGFR phosphorylation and time to disease progression (12, 13). EGFR and HER2 have been the targets of considerable research to develop therapies that will interfere with their oncogenic potential. Activation of the ErbB family of receptors requires homodimerization or heterodimerization. HER2 is the preferred dimerization partner for all other members of the family; thus, EGFR preferentially forms heterodimers with HER2 (14). Available small-molecule EGFR tyrosine kinase inhibitors inhibit EGFR homodimers but may be less effective at inhibiting heterodimers of EGFR and HER2. Lapatinib is a novel, small-molecule, tyrosine kinase inhibitor of both EGFR and HER2. As EGFR can signal via both homodimers and heterodimers with HER2, dual inhibition of both receptors should be advantageous. Clinical studies are required to determine whether the

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theoretical benefit of dual ErbB tyrosine kinase inhibition will improve patient outcomes compared with inhibitors of either EGFR or HER2 alone. The current study was initially developed to evaluate lapatinib for first-line treatment of unselected patients with advanced NSCLC. The three main histologic subtypes of NSCLC (squamous, large cell, and adenocarcinoma) have until recently been grouped together due to their similar natural history and response to cytotoxic chemotherapy. While the current trial was being conducted, preclinical and clinical evidence began to suggest greater efficacy of EGFR tyrosine kinase inhibitors in patients with advanced NSCLC who had never smoked or who had bronchioloalveolar carcinoma (BAC; ref. 15), perhaps because of an alternate mechanism of carcinogenesis in these patients involving EGFR mutations and/or amplification. BAC is a subset of adenocarcinoma that has been increasing in incidence over recent years. “Pure” BAC, defined as having a purely lepidic spreading pattern with no evidence of stromal, vascular, or pleural invasion, represents

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