Johan Vansteenkiste

Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]

International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P <or= .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Ceritinib in ALK-rearranged non-small-cell lung cancer.

BACKGROUND Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial

PURPOSE Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL). RESULTS A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild). CONCLUSION Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING F Hoffmann-La Roche/Genentech Inc.

Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study

BACKGROUND No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. METHODS Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m(2) on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. FINDINGS Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). INTERPRETATION Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. FUNDING AstraZeneca.

Prognostic Importance of the Standardized Uptake Value on 18F-Fluoro-2-Deoxy-Glucose–Positron Emission Tomography Scan in Non–Small-Cell Lung Cancer: An Analysis of 125 Cases

PURPOSE The amount of radio-labeled (18)F-fluoro-2-deoxy-glucose (FDG) uptake, a measurement of the increased glucose metabolism of non-small-cell lung cancer (NSCLC) cells, has recently been correlated with proliferation capacity. The Standardized Uptake Value (SUV), a semi-quantitative measurement of FDG uptake on positron emission tomography (PET) scan, could thus be of prognostic significance. PATIENTS AND METHODS We analyzed the follow-up of 125 potentially operable NSCLC patients, previously included in three of our prospective PET protocols. Performance status, maximal tumor diameter, tumor-cell type, SUV, and final staging were analyzed for their possible association with survival. RESULTS Sixty-five patients had stage I or II NSCLC, 37 had stage IIIA, and 23 had stage IIIB. Treatment was complete resection in 91 cases. In a univariate analysis, performance status (P =.002), stage (P =.001), tumor diameter (P =.06), tumor-cell type (P =.03), and SUV greater than 7 (P =.001) were correlated with survival. For SUV, group dichotomy with a cut-off SUV of 7 had the best discriminative value for prognosis, both in the total and surgical cohort. A multivariate Cox analysis identified performance status (P =.02), stage (P =.01), and SUV (P =.007) as important for the prognosis. In the surgical group, patients with a resected tumor less than 3 cm had an expected 2-year survival of 86%, if the SUV was below 7, and 60%, if above 7. Nearly all resected tumors larger than 3 cm had SUVs greater than 7 and an expected 2-year survival of 43%. CONCLUSION We conclude that the FDG uptake in primary NSCLC on PET has an important prognostic value and could be complementary to other well-known factors in the decision on adjuvant treatment protocols.

Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.

CONTEXT Mediastinal nodal staging is recommended for patients with resectable non-small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging. OBJECTIVE To compare the 2 recommended lung cancer staging strategies. DESIGN, SETTING, AND PATIENTS Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography. INTERVENTION Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread. MAIN OUTCOME MEASURES The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications. RESULTS Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P = .11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P = .02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P = .47) and 94% (62/66; 95% CI, 85%-98%) (P = .02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P = .02). The complication rate was similar in both groups. CONCLUSIONS Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00432640.

Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The Clatterbridge Cancer Centre and Liverpool Heart and Chest Hospital, Liverpool; University of Aberdeen, Aberdeen, UK; Center for Medical Imaging, University of Groningen, Groningen; Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Thoracic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK; University Hospitals KU Leuven, Leuven, Belgium; Oncology Department, Service d’Oncologie Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland