Steven M. Grunberg

First-Line Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer Harboring Somatic EGFR Mutations

PURPOSE Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms. PATIENTS AND METHODS Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. RESULTS Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification. CONCLUSION First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines

THE GOAL OF ANTIEMETIC therapy is to prevent nausea and vomiting completely. This goal is achieved for many patients receiving chemotherapy or radiation therapy, and is based on clinical and basic research that has steadily improved the control of emesis over the last 20 years. As therapy has become more effective, it has also become safer, with few side effects associated with the most commonly used regimens. These regimens are convenient for patients to receive and for health care professionals to administer. However, despite improvements, a significant number of patients still experience emesis, and efforts to reduce this side effect of treatment must continue. As antiemetic usage has grown, the classes of agents available for antiemetic treatment, the number of agents, and the indications for antiemetics have all increased as well. The prevention of delayed emesis and anticipatory emesis is equal in importance to the need to prevent acute chemotherapyand radiation-induced emesis. Additionally, managing special and difficult emetic problems and selecting the proper antiemetic approach necessitate identification of the patient’s emetic risk. Although the neuropharmacologic basis of emesis is still incompletely understood, the selection of an appropriate antiemetic regimen is possible and can have an impact on several aspects of clinical care. Goals related to the complete control of emesis, ie, no vomiting, include providing care that is convenient for the patient, treatment that reduces hospitalization and time in the ambulatory setting, and therapy that enhances the patient’s quality of life. Additionally, practitioners need to be mindful of reducing costs of treatment while achieving these goals. 1-3

The Oral Neurokinin-1 Antagonist Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients Receiving High-Dose Cisplatin—The Aprepitant Protocol 052 Study Group

PURPOSE In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.

Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference

Despite the relevant progress achieved in the last 20 years,vomiting and, especially, nausea, continue to be two of themost distressing side-effects of cancer chemotherapy. In the late1990s several professional organizations publishedrecommendations on the optimal antiemetic prophylaxis inpatients submitted to chemotherapy and radiotherapy.Subsequently, due to the emergence of new findings and newantiemetic agents since the first recommendations from 1997,representatives from several oncology societies met in Perugia,Italy, in 2004 and updated the antiemetic guidelines. On 20–21June 2009 the European Society of Medical Oncology (ESMO)and the Multinational Association of Supportive Care inCancer (MASCC) organized the third Consensus Conferenceon antiemetics in Perugia. The results of this Conference arereported in this paper.The methodology for the guideline process was based ona literature review through 1 June 2009 using MEDLINE(National Library of Medicine, Bethesda, MD, USA) and otherdatabases, with evaluation of the evidence by an expert panelcomposed of 23 oncology professionals in clinical medicine,medical oncology, radiation oncology, surgical oncology,oncology nursing, statistics, pharmacy, pharmacology, medicalpolicy and decision making. With the participating expertscoming from 10 different countries, on five continents, webelieve that this is the most representative and evidence-basedguideline process that has yet been performed.The panel comprised 10 committees dealing with majortopics in this field (e.g. acute or delayed nausea and vomitinginduced by highly emetogenic chemotherapy). Althoughprevention of acute and delayed nausea and vomiting inducedby highly and moderately emetogenic chemotherapy (HEC andMEC) had specific committees, these worked finally together, as

Proposal for classifying the acute emetogenicity of cancer chemotherapy.

PURPOSE To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens. METHODS A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials. RESULTS Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. CONCLUSION The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients With Breast Cancer After Moderately Emetogenic Chemotherapy

PURPOSE This is the first study in which the NK(1)-receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy. PATIENTS AND METHODS Eligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide +/- doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) [DOSAGE ERROR CORRECTED] or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index-Emesis questionnaire. RESULTS Of 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated. CONCLUSION The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.

Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: Results of a phase III, single-dose trial versus dolasetron

Palonosetron, a highly selective and potent 5‐HT3 receptor antagonist with a strong binding affinity and a long plasma elimination half‐life (approximately 40 hours), has shown efficacy in Phase II trials in preventing chemotherapy‐induced nausea and vomiting (CINV) resulting from highly emetogenic chemotherapy. The current Phase III trial evaluated the efficacy and safety of palonosetron in preventing acute and delayed CINV after moderately emetogenic chemotherapy.

REDUCTION OF CISPLATIN-INDUCED EMESIS BY A SELECTIVE NEUROKININ-1-RECEPTOR ANTAGONIST

BACKGROUND The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1-receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy. METHODS In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 microg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea. RESULTS In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030. CONCLUSIONS The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.

Control of Chemotherapy-Induced Emesis

The development of antiemetic drugs has been one of the most rewarding areas of oncologic research, since therapeutic advances in this area can result in immediate improvement in the quality of life for patients undergoing chemotherapy. Antiemetic therapy has progressed dramatically during the past decade and a half. Fifteen years ago, patients receiving cisplatin for the first time had a median of 12 vomiting episodes within the first 24 hours, whereas now more than 50 percent of such patients have no vomiting episodes at all. Theoretical and clinical challenges remain, however, in the effort to control chemotherapy-induced emesis. The mechanisms of anticipatory vomiting and delayed vomiting are still not understood, and consistently effective therapeutic approaches to these problems have yet to be developed.

Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting

The neurokinin‐1 antagonist aprepitant (EMEND™; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy‐induced nausea and vomiting when it is given with a 5‐hydroxytryptamine‐3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant.