First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.

BACKGROUND Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). METHODS Treatment: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.

First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.

BACKGROUND: Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). METHODS: TREATMENT: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS: Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.

Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC

Résumé : Objectif: Analyse d'un traitement de chimiothérapie à base de cisplatine de type néoadjuvant en comparaison à un traitement de radio-chimiothérapie suivi de la résection chirurgicale chez des patients présentant un carcinome pulmonaire non à petites cellules de stade Ill (N2) prouvé histologiquement par médiastinoscopie. Evaluation de la morbidité postopératoire, du down-staging ganglionnaire, des taux de survie globale et sans récidive ainsi que du site de récidive. Matériel et méthodes : 82 patients ont été inclus dans l'étude entre Janvier 1994 et Juin 2003, parmi eux 36 ont été traités avec une chimiothérapie néoadjuvante à base de cisplatine et doxétacel (groupe l). Les autres 46 patients ont été soumis à une radio-chimiothérapie néoadjuvante avec administration de 44 Gy (groupe II), soit de façon séquentielle (25 cas) soit concomitante (21 cas). Dans tous les cas des métastases à distance ont été exclues par une évaluation préopératoire comprenant une scintigraphie osseuse, un Ct scan thoraco-abdominal, ou un examen PET scan ainsi qu'une IRM cérébrale. La médiastinoscopie effectuée avant le traitement d'induction chez la totalité des patients, de même que la résection chirurgicale de la tumeur pulmonaire et la lymphadenectomie médiastinale ont été effectuées par le même chirurgien. Résultats : La tumeur pulmonaire était de stade Ti à T2 dans respectivement 47% et 28% des patients des groupes (e II, T3 dans 45% et 41% et T4 dans 8% et 31% des cas. Le type de résection effectué (lobectomie, lobectomie en manchon, pneumonectomie) était comparable dans les deux collectifs (p=0.03) Le taux de mortalité postopératoire à 90 jours était de respectivement 3% et 4 "Vo (p=0.6). Une résection complète (RO) a pu être obtenue dans 92% et 94% des cas (p=0.6) avec un downstaging ganglionnaire médiastinal dans 61% et 78% des patients respectivement (p<0.001). Les taux de survie globale à 5 ans et de survie sans récidive à 5 ans s'élevaient à 40% et à 36% respectivement, sans différence significative entre des tumeurs de stade Ti à T3 et T4. Le taux de survie globale n'était pas significativement différent entre les deux modalités de traitement d'induction, toutefois après radio-chimiothérapie on observait une plus longue survie sans récidive (p.0.04). Il n'y avait par ailleurs pas de différence significative, en termes de morbidité post-opératoire, résecabilité, downstaging ganglionnaire, survie globale et sans récidive, entre les patients traités par radio-chimiothérapie séquentielle ou concomitante. Conclusions : En cas de carcinome pulmonaire non à petites cellules de stade III (N2) un traitement d'induction par radio chimiothérapie suivi de la résection chirurgicale est associé avec un meilleur downstaqing médiastinal ainsi qu'une plus longue survie sans récidive en comparaison au traitement d'induction par chimiothérapie seule. Abstract : Objective: Comparison of prospectively treated patients with neoadjuvant cisplatin-based chemotherapy vs radiochemotherapy followed by resection for mediastinoscopically proven stage III NZ non-small cell lung cancer with respect to postoperative morbidity, pathological nodal downstaging, overall and disease-free survival, and site of recurrence. Methods: Eighty-two patients were enrolled between January 1994 to June 2003, 36 had cisplatin and doxetacel-based chemotherapy (group I) and 46 cisplatin-based radiochemotherapy up to 44 Gy (group II), either as sequential (25 patients) or concomitant (21 patients) treatment. All patients had evaluation of absence of distant metastases by bone scintigraphy, thoracoabdominal CT scan or PET scan, and brain MRI, and all underwent pre-induction mediastinoscopy, resection and mediastinal lymph node dissection by the same surgeon. Results: Group I and II comprised T1/2 tumors in 47 and 28%, 13 tumors in 45 and 41%, and 14 tumors in 8 and 31% of the patients, respectively (P=0.03). There was a similar distribution of the extent of resection (lobectomy, sleeve lobectomy, left and right pneumonectomy) in both groups (P=0.9). Group I and II revealed a postoperative 90-d mortality of 3 and 4% (P=0.6), a RO-resection rate of 92 and 94% (P=0.9), and a pathological mediastinal downstaging in 61 and 78% of the patients (P<0.01), respectively. 5y-overall survival and disease-free survival of all patients were 40 and 36%, respectively, without significant difference between T1-3 and T4 tumors. There was no significant difference in overall survival rate in either induction regimens, however, radiochemotherapy was associated with a longer disease-free survival than chemotherapy (P=0.04). There was no significant difference between concurrent vs sequential radiochemotherapy with respect to postoperative morbidity, resectability, pathological nodal downstaging, survival and disease-free survival. Conclusions: Neoadjuvant cisplatin-based radiochemotherapy was associated with a similar postoperative mortality, an increased pathological nodal downstaging and a better disease-free survival as compared to cisplatin doxetacel-based chemotherapy in patients with stage III (N2) NSCLC although a higher number of 14 tumors were admitted to radiochemotherapy.

Value of PET/CT versus contrast-enhanced CT in identifying chest wall invasion (T3) by NSCLC [B-671]

Purpose: To determine the diagnostic value of 18F-FDG PET/CT versus contrastenhanced CT in identifying chest wall invasion by NSCLC. Methods and Materials: The primary selection criterion was a peripheral tumor of any size with contact to the chest wall. A total of 25 patients with pathologically proven NSCLC satisfied these criteria. Chest wall invasion was interpreted upon PET/CT when a frank costal or intercostal 18F-FDG uptake was identified with or without concomitant morphologic alterations. On the other hand, the existence of periosteal rib reaction/erosion, chest wall thickening or obliteration of the pleural fat layer either separately or combined were considered essential diagnostic criteria for disease extension into the chest wall upon contrast-enhanced CT. The results were correlated with the final histological analysis. Results: Among the studied cohort, 13/25 (52%) patients had chest wall invasion consistent with T3 disease. Both PET/CT and contrast-enhanced CT successfully identified 12/13 (92%) of these patients. The single false-negative result was due to parietal pleural invasion. On the other hand, one false-positive result was encountered by PET/CT in a dyspneic patient; whereas, CT analysis revealed false-positive results in six patients. In these patients, periosteal rib reaction (n = 2) or asymmetric enlargement of adjacent chest wall muscles (n = 1) were identified along with an obliterated pleural fat layer (n = 6). The sensitivity, specificity, and accuracy of PET/CT and contrast-enhanced CT were 92, 91 and 92% versus 92, 50 and 72%. Conclusion: 18F-FDG PET/CT is an accurate diagnostic modality in identifying.

Treatment and detection of ALK-rearranged NSCLC.

The recent approval of crizotinib for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC) in the US and other countries has provoked intense interest in ALK rearrangements as oncogenic drivers, and promises to revolutionise the way in which NSCLC is diagnosed and treated. Here, we review clinical data to date for the use of crizotinib to treat patients with advanced, ALK-positive NSCLC and consider issues surrounding the detection of ALK-positivity including the use of fluorescence in situ hybridisation and the other potential techniques available, and their suitability for ALK screening. We also discuss the emergence of resistance to crizotinib therapy and the range of other ALK inhibitors currently in development.

Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC.

OBJECTIVE: Comparison of prospectively treated patients with neoadjuvant cisplatin-based chemotherapy vs radiochemotherapy followed by resection for mediastinoscopically proven stage III N2 non-small cell lung cancer with respect to postoperative morbidity, pathological nodal downstaging, overall and disease-free survival, and site of recurrence. METHODS: Eighty-two patients were enrolled between January 1994 to June 2003, 36 had cisplatin and doxetacel-based chemotherapy (group I) and 46 cisplatin-based radiochemotherapy up to 44 Gy (group II), either as sequential (25 patients) or concomitant (21 patients) treatment. All patients had evaluation of absence of distant metastases by bone scintigraphy, thoracoabdominal CT scan or PET scan, and brain MRI, and all underwent pre-induction mediastinoscopy, resection and mediastinal lymph node dissection by the same surgeon. RESULTS: Group I and II comprised T1/2 tumors in 47 and 28%, T3 tumors in 45 and 41%, and T4 tumors in 8 and 31% of the patients, respectively (P=0.03). There was a similar distribution of the extent of resection (lobectomy, sleeve lobectomy, left and right pneumonectomy) in both groups (P=0.9). Group I and II revealed a postoperative 90-d mortality of 3 and 4% (P=0.6), a R0-resection rate of 92 and 94% (P=0.9), and a pathological mediastinal downstaging in 61 and 78% of the patients (P<0.01), respectively. 5y-overall survival and disease-free survival of all patients were 40 and 36%, respectively, without significant difference between T1-3 and T4 tumors. There was no significant difference in overall survival rate in either induction regimens, however, radiochemotherapy was associated with a longer disease-free survival than chemotherapy (P=0.04). There was no significant difference between concurrent vs sequential radiochemotherapy with respect to postoperative morbidity, resectability, pathological nodal downstaging, survival and disease-free survival. CONCLUSIONS: Neoadjuvant cisplatin-based radiochemotherapy was associated with a similar postoperative mortality, an increased pathological nodal downstaging and a better disease-free survival as compared to cisplatin doxetacel-based chemotherapy in patients with stage III (N2) NSCLC although a higher number of T4 tumors were admitted to radiochemotherapy.

Strategies for improving outcomes in NSCLC: a look to the future.

Advances in the management of non-small cell lung cancer (NSCLC) over the past 30 years have led to small increases in 5-year survival rates across Europe, though further improvements may require new treatment strategies. In order to improve efficiency and reduce the cost of development, future trials for new targeted agents in NSCLC should aim to recruit patients on the basis of tumour biology rather than clinical characteristics. However, identification of predictive biomarkers is required to maximise the benefits of new approaches and expedite the drug development process. Nevertheless, the NSCLC landscape is changing rapidly, and recent improvements in our understanding of the molecular biology of the disease will help in the identification of novel targeted agents as well as assisting in the development of personalised strategies for the numerous small subsets of defined NSCLC. Progress in imaging and treatment delivery is also likely to improve outcomes for patients with the disease. This article outlines recent progress in the treatment of NSCLC, identifies current challenges and describes proposals for improving the future management of the disease. It is hoped that implementation of some of these strategies will go some way to improving the outlook for patients with NSCLC.

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.

ALK inhibitors in the treatment of advanced NSCLC.

Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule-associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50 years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in-class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC.