Tal Zaks

Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy

PURPOSE Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. PATIENTS AND METHODS Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. RESULTS Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. CONCLUSION Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.

Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study

BACKGROUND Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. METHODS From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. FINDINGS Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. INTERPRETATION Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. FUNDING GlaxoSmithKline.

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

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

Distinct patterns of DNA copy number alterations associate with BRAF mutations in melanomas and melanoma derived cell lines

A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation‐associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRASwt/wt, respectively) by array‐based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRASwt/wt, respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1‐36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2‐24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRASwt/wt tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations.

Lapatinib monotherapy in HER2+ relapsed or refractory inflammatory breast cancer (IBC): quality of life (QOL) assessment.

Abstract #4097 Background: IBC is a rare, clinically distinct and aggressive form of breast cancer characterized by severe pain and a poor prognosis. EGF103009 was a phase II, open-label, multicenter study that showed lapatinib monotherapy is clinically active in women with relapsed/refractory HER2+ IBC that progressed on prior therapy with anthracylines, taxanes, and trastuzumab. This analysis focuses on the impact of lapatinib on QOL and pain symptoms (endpoints added during a study amendment) in these patients.
 Methods: QOL was assessed using the EORTC QLQ C-30, a 30-item instrument that assesses 15 domains consisting of 5 functional scales (physical, role, emotional, cognitive, social) and 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global QOL item. A high score for a functional scale/global QOL indicates a high and healthy level of functioning/QOL whereas a high score for a symptom scale indicates a high level of symptoms/problems. Pain was specifically assessed using the Brief Pain Inventory-Short Form (BPI-SF), which includes 4 severity items and 7 items assessing pain interference with general activity, mood, work, walking ability, relations, sleep, and enjoyment of life. Scoring produces 4 scores: pain severity, overall pain interference, activity-related pain interference and mood-related pain interference. Higher scores indicate greater pain severity or pain interference. Both questionnaires were completed at baseline and every 4 weeks thereafter. Mean change in scores from baseline (with 95% CI) were provided by visit.
 Results : Because QOL/pain scales were added late in the study, only 33 of 126 patients in the HER2+ cohort completed at least one question in the health outcome questionnaires at baseline. At week 8, 64% (n=21) of patients completed assessments, and the results showed moderate improvement (10-20 points) in average EORTC QLC scores for global QOL, role functioning and social subscales. The physical function subscale also showed improvement (9 points). All symptom scales (except diarrhea) were lower than baseline at most scheduled visits indicating improvement in symptoms. Scores for all 4 summary pain scores of the BPI-SF at week 8 were also lower than baseline values suggesting improvement in pain severity and pain interference (decrease ranged from 1.3 to 2.7 points). Sixteen of the 33 patients (48%) had partial response to treatment and 9 had stable disease.
 Conclusions: Results suggest that lapatinib monotherapy may improve level of functioning/QOL and provide relief from most symptoms, including pain, in the short term. These QOL benefits add to the clinical improvement associated with lapatinib therapy in these heavily pre-treated patients with an aggressive form of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4097.

Pharmacogenomics in Drug Development: A Pharmaceutical Industry Perspective

The elucidation of the human genome sequence and the advent of genomic technologies have the potential to facilitate drug discovery and development as well as to define individual risks and benefits associated with specific therapeutic interventions. This chapter focuses on the application of this knowledge within the pharmaceutical industry, by providing current examples of the relevance of both germline and somatic genotypic variations to adverse event and efficacy profiles of recently developed anti-cancer drugs. These examples, discussed within the scientific, regulatory, and economic frameworks that shape the industry, highlight both the potential benefits and the emerging challenges to the application of post-genomic science to “real-life” drug development.