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Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population., Methods: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete)., Findings: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea., Interpretation: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated., Funding: Merck (CrossRef Funder ID: 10.13039/100009945)., Competing Interests: Declaration of interests Y-LW reports receiving institute grants from AstraZeneca, Bristol Myers Squibb, and Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Merck, and Roche; and speaker fees from AstraZeneca, Eli Lilly, Hengrui, Pfizer, Roche, and Sanofi. VG reports receiving personal fees for advisory board membership from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, and Olema Oncology; speaker fees from Amgen, AstraZeneca, Eli Lilly, Exact Sciences, Gilead, GSK, and Novartis; fees for expert testimony for Eli Lilly; and travel support from Gilead, AstraZeneca, and PharmaMar. PJV reports receiving personal fees for advisory board membership from Amgen, AstraZeneca, BeiGene, Ipsen, MSD, Novartis, Pfizer, and Roche. MWi reports receiving personal advisory board fees, consulting fees, speaker fees, and institute grants from AstraZeneca. CKL reports receiving research grants from AstraZeneca and Boehringer Ingelheim; honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Janssen, MSD, Novartis, Pfizer, Roche, and Zuellig Pharma; travel support from AstraZeneca, Boehringer Ingelheim, Merck, MSD, Novartis, Pfizer, and Roche; and personal fees for advisory board membership from AstraZeneca, Janssen, MSD, Novartis, Pfizer, and Roche. JM reports receiving advisory board fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, Novartis, Merck, Daiichi Sankyo, and MSD, and research funding to his institution from Roche, AstraZeneca, and Pierre Fabre. LMT reports receiving advisory board fees from AstraZeneca, Janssen, Merck, Novartis, Pfizer, and Roche; personal honoraria fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Roche; and travel support from AstraZeneca, Merck, Novartis, Pfizer, and Roche. HH reports receiving honoraria fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, Sysmex Corporation, 3H Medi Solution, Chugai Pharmaceutical, Pfizer, Novartis, Merck Biopharma Co, Tokyo, Japan, an affiliate of Merck, Amgen, Daiichi Sankyo/UCB Japan, Takeda, and MSD; research funding from IQVIA, Syneos Health Clinical, EPS Corporation, Nippon Kayaku, Takeda, MSD, Amgen, Taiho Pharmaceutical, Bristol Myers Squibb, Janssen, CMIC, Pfizer R&D, LabCorp, Kobayashi Pharmaceutical, Pfizer, Eisai, EP-CRSU, Shionogi & Co, Otsuka Pharmaceutical, GSK, Sanofi, Chugai Pharmaceutical, Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, and Bayer; and financial support for the present manuscript from Guardant Health. PLC reports receiving advisory board fees from AstraZeneca, Merck, and Pfizer, and honoraria fees from AstraZeneca. JR reports receiving personal honoraria from Bristol Myers Squibb, speaker fees (to their institution) from Merck, and advisory board fees (to their institution) from Merck. GF reports receiving personal fees for speaker engagements with AstraZeneca, Bristol Myers Squibb, and MSD, and travel support from Roche. TK reports receiving honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; receiving research funding for their institution from AbbVie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis, Pfizer, Regeneron, Takeda, and TurningPoint; receiving advisory board fees from AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck, MSD, Novartis, and Pfizer; and their spouse as an employee of Eli Lilly. EN reports receiving research funding from Roche, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Bristol Myers Squibb; consulting fees from Roche, Bristol Myers Squibb, MSD, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Daiichi Sankyo, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Pierre Fabre, Qiagen, and Bayer; personal honoraria for lectures from Roche, Bristol Myers Squibb, MSD, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Qiagen, Mirati, and Bayer; travel support from Takeda, MSD, AstraZeneca, and Roche; and fees for participation in data safety meetings from Apollomics. HSH reports receiving research grants for their institution from AstraZeneca, Merck, Janssen, Novartis, and Boehringer Ingelheim; honoraria and fees for lectures and advisory board meetings from AstraZeneca, MSD, Novartis, Pfizer, Roche, and Janssen; and travel support from AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Roche. EFS reports receiving advisory or consultancy fees to their institution from Eli Lilly, AstraZeneca, MSD, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, and Daiichi Sankyo; personal speaker fees from Boehringer Ingelheim; and advisory board fees from Merck and Daiichi Sankyo. MWe reports holding a consulting or advisory role for Bristol Myers Squibb, Novartis, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, and ImCheck therapeutics; honoraria fees from Eli Lilly, Boehringer Ingelheim, SYNLAB, Janssen, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, GWT, Amgen, and Novartis; travel support from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics, and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck; and research funding to his institution from Roche. DT reports receiving consulting fees for their institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GSK, Merck, Novartis, Roche, Pfizer, and Takeda; research funding from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer; and speaker fees for their institution from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda. MM reports receiving research funding from Boehringer Ingelheim and Eli Lilly; personal honoraria fees from Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; and other clinical trial support from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Kissei, Taiho, and Novartis. AO’B, SA, BMP, CS, DJ, RS, BE-L, and NK report being employees of Merck. KB reports being an employee of Merck at the time of the study and manuscript preparation. KG reports being an employee of EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck. XL reports receiving consulting fees from EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen Oncology, Daiichi Sankyo, Blueprint Medicines, Sensei Biotherapeutics, AbbVie, Arrivent, and Regeneron; travel support from Spectrum Pharmaceuticals and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and research funding to their institution from Eli Lilly, Boehringer Ingelheim, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Regeneron. TMK reports receiving grants for their institution from AstraZeneca; consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda, and Yuhan; honoraria for lectures from AstraZeneca, IMBDx, Janssen, Takeda, and Yuhan; advisory board fees from AstraZeneca, Janssen, Regeneron, and Takeda; and clinical trial funding to their institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, Dizal, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Roche/Genentech, Hanmi, Genmab, Janssen, Novartis, RAPT Therapeutics, Regeneron, Sanofi, Takeda, and Yuhan. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation., Materials and Methods: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction., Results: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response., Conclusions: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice., Clinical Trial Registration: Eudract No. 2019-001146-17, NCT04028050., (© The Author(s) 2024. Published by Oxford University Press.)

Background: There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma., Methods: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m 2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36., Findings: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths., Interpretation: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting., Funding: Eli Lilly Italy., Translation: For the Italian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CP reports advisory and speaker fees and travel and accommodation expenses from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis Oncology, Eisai, Ipsen, Janssen, Incyte, Merck-Serono, Merck Sharp and Dohme, Novartis, Roche, Sandoz, Sanofi, and Servier. PAZ reports advisory and speaker fees and travel and accommodation expenses from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Myers Squibb, Amgen, AstraZeneca, Roche, and Bayer. FGrosso reports consultancy and speaker fees and travel and accommodation expenses from Merck Sharp and Dohme, Novocure, Bristol Myers Squibb, Boehringer Ingelheim, PharmaMar, and Novartis. GP reports advisory and speaker fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp and Dohme, Roche, and Eli Lilly. MCG reports consultancy and advisory fees from AstraZeneca, Merck Sharp and Dohme, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Incyte, Inivata, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati Threapeutics, Daiichi Sankyo, Bayer, GlaxoSmithKline, Sanofi-Aventis, Spectrum Pharmaceuticals, Blueprint Medicine, Janssen, Regeneron Pharmaceuticals; speaker fees from AstraZeneca, Merck Sharp and Dohme, and Takeda; travel and accommodation expenses from Roche; and a leadership or fiduciary role in European Society for Medical Oncology, American Society of Clinical Oncology, American Association for Cancer Research, Women for Oncology, and Italian collaborative group for thymic malignansies. MT reports advisory fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Takeda, and Eli Lilly; speaker fees from AstraZeneca, Boehringer Ingelheim, and Merck Sharp and Dohme; and research grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche. HSP reports advisory and speaker fees and travel and accommodation expenses from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Roche, Pfizer, and Sanofi. FGrossi reports advisory fees from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Sharp and Dohme, and Roche; speaker fees from Bristol Myers Squibb, AstraZeneca, Eli Lilly, Merck Sharp and Dohme, Roche, Amgen, Boehringer Ingelheim, Pierre Fabre, Pfizer, Takeda, Bayer, and Sotio; and a grant from Bristol Myers Squibb to their institution. FC reports speaker fees from Bristol Myers Squibb and advisory fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Mirati, Merck Sharp and Dohme, PharmaMar, Pfizer, and Roche. FdM reports advisory and speaker fees and travel and accommodation expenses from Merck Sharp and Dohme, Bristol Myers Squibb, Boehringer Ingelheim, Novartis, AstraZeneca, and Roche. AS reports consultancy fees from Arqule and Sanofi; speaker fees from Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Eli Lilly, Sandoz, Eisai, Novartis, Bayer, and Merck Sharp and Dohme; and advisory fees from Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and Merck Sharp and Dohme. GLC reports advisory speaker fees from Merck Sharp and Dohme, Astellas, and Novocure, and travel and accommodation expenses from Merck Sharp and Dohme, Astellas, and Novocure. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017)., Methods: Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant., Results: Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib., Conclusion: Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The goals of this multinational retrospective study were to describe treatment patterns and survival outcomes by receipt of molecular testing and molecular status of patients with advanced non-small cell lung cancer (NSCLC)., Methods: This chart review study, conducted in Italy, Spain, Germany, Australia, Japan, Korea, Taiwan, and Brazil, included 1440 patients with newly diagnosed advanced (stage IIIB/IV) NSCLC initiating systemic therapy from January 2011 through June 2013, with follow-up until July 2016. We evaluated treatment patterns and survival by histology, line of therapy, molecular testing, and test results for epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase (ALK) rearrangement. Country-specific data were analyzed descriptively and presented as ranges (lowest to highest country). Overall survival (OS) was estimated using Kaplan-Meier method., Results: Patients with ≥1 molecular test varied from 43% (Brazil) to 85% (Taiwan). Numerically greater proportions of patients who were female, Asian, or never/former-smokers, and those with nonsquamous histology or stage-IV NSCLC, received a test. Testing was common for nonsquamous NSCLC (54%, Brazil, to 91%, Taiwan), with positive EGFR and ALK tests from 17% (Brazil and Spain) to 67% (Taiwan) and from 0% (Brazil) to 60% (Taiwan), respectively. First-line treatment regimens for nonsquamous NSCLC with positive EGFR/ALK tests included targeted therapy for 30% (Germany) to 89% (Japan); with negative/inconclusive test results, platinum-based combinations for 88% (Japan) to 98% (Brazil); and if not tested, platinum-based combinations for 80% (Australia) to 95% (Japan), except in Taiwan, where 44% received single agents. Median OS from first-line therapy initiation was 10.0 (Japan) to 26.7 (Taiwan) months for those tested and 7.6 (Australia/Brazil) to 19.3 (Taiwan) months for those not tested., Conclusions: We observed substantial variation among countries in testing percentages, treatment patterns, and survival outcomes. Efforts to optimize molecular testing rates should be implemented in the context of each country's health care scenario., Competing Interests: Dae Ho Lee reports honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, Jansen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, and Samyang Biopharm for participating in advisory boards; and receipt of consulting fees from the Ministry of Food and Drug Safety (MFDS), Korea, and Health Insurance Review and Assessment Service (HIRA), Korea. Ming-Sound Tsao reports honoraria for advisory board meetings from AstraZeneca, Bristol-Myers Squibb, Pfizer, Ventana/Roche, and Merck. Hiroshi Isobe has received payment for speaking engagements from AstraZeneca, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai, Boehringer Ingelheim, Ono Pharmaceutical Co. Ltd., and Eli Lilly Japan, K.K. Smita Kothari, Ashwini Arunachalam, Xiting Cao, and Thomas Burke are employees of Merck & Co., Inc., Kenilworth, NJ, USA, which supplied the funding for this study. Amparo Valladares is an employee of Merck Sharp & Dohme de España S.A., Madrid, Spain. All other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function., Methods: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function., Results: Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs., Conclusions: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.

Background: Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC beyond old chemotherapy agents (docetaxel and pemetrexed) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI, erlotinib). In particular, the new antiangiogenetics (nindetanib and ramucirumab) in combination with docetaxel and immunotherapy (nivolumab, pembrolizumab and atezolizumab) have been recently approved and represent new treatment options., Methods: The Italian Association of Thoracic Oncology (AIOT) organized five meetings in different Italian regions representing North, Middle and South of the country in order to discuss the issue., Results: In light of these new approvals, it is valuable to understand the uptake of these new therapies in routine clinical practice and their impact on patient care. With these treatment options to define an appropriate algorythm is object of debate., Conclusion: The present paper discusses the old and new treatment opportunities, proposing a shared algorithm for second-line setting in advanced NSCLC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Immune checkpoint inhibitors (ICIs) have emerged as one of the main new therapeutic options for advanced non-small cell lung cancer (NSCLC) patients. Even though they demonstrated superiority towards standard chemotherapy in different disease settings, the response rates do not exceed 45% in highly molecularly selected patients. This is related to known limitations of the available biomarkers, as well to the complex and dynamic nature of tumor microenvironment. The study of the different strategies adopted by tumor cells to escape the immune system lays the basis of the new combination strategies. This review focuses on analyzing the biological rationale and early clinical data available concerning therapeutic strategies combining ICIs together, ICIs with different regimens and schedules of standard chemotherapy, ICIs with tyrosine kinase inhibitors, ICIs with antiangiogenic agents and ICs with radiotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In a phase III study, maintenance pemetrexed showed superior survival over placebo (PARAMOUNT) for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who completed 4 cycles of pemetrexed plus cisplatin (PC) induction therapy, with low incidence of treatment-emergent adverse events (TEAEs) generally associated with pemetrexed. Prior analyses did not account for toxicities carried over from induction; thus, the current analysis was developed to understand toxicities that may be attributed to pemetrexed maintenance versus PC induction, and how treatment duration affects toxicity., Patients and Methods: Selected clinically relevant TEAEs were explored in 2 analyses: assessing induction versus maintenance treatment in PARAMOUNT, and comparing PC from PARAMOUNT with toxicity data from a previous phase III study that established the role of PC in front-line therapy of non-squamous NSCLC (JMDB trial)., Results: In PARAMOUNT, the incidence of most drug-related TEAEs was higher during induction than maintenance, for both the pemetrexed and placebo randomized populations. The majority of TEAEs during maintenance, except renal events, were carried over from induction with no change in severity from the end of induction; the incidence of TEAEs associated with pemetrexed maintenance was low. The cross-trial analysis showed that 6 cycles of PC in JMDB compared with 4 cycles in PARAMOUNT increased grade 1/2 fatigue (34.1% vs. 25.0%), anemia (24.0% vs. 13.5%), and renal events (11.8% vs. 3.6%)., Conclusions: Safety data presented here support the favorable risk benefit of 4 cycles of PC followed by maintenance pemetrexed in patients with advanced non-squamous NSCLC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aim: The management of elderly patients with advanced non-squamous NSCLC includes several strategies., Patients and Methods: Patients (≥70 years) were randomly assigned to bevacizumab (7.5 mg/kg i.v. on day 1) plus gemcitabine (1,200 mg/m 2 i.v. on days 1-8) (arm A) or bevacizumab (7.5 mg/kg i.v.) and cisplatin (60 mg/m 2 i.v.) plus gemcitabine (1,000 mg/m 2 i.v. on days 1-8) (arm B), to independently evaluate treatments. The primary endpoint was progression-free rate at 6 months; secondary endpoints included progression-free survival (PFS) and safety profiles., Results: At 6 months, 5 (11.6%) patients in arm A and 5 patients (12.5%) in arm B were found to be progression-free. Median PFS was 4.8 months in arm A and 6.5 months in arm B, respectively., Conclusion: In our experience, combination of bevacizumab and chemotherapy had encouraging anti-tumor efficacy as first-line therapy in elderly patients with non-squamous NSCLC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The TArceva and docetaxeL In former-Smokers MAle patients with recurrent non-small cell lung cancer (TALISMAN) phase II, open-label randomized trial evaluates the combination of erlotinib with docetaxel in the second-line therapy of ex-smoker males with advanced squamous non-small cell lung cancer (NSCLC)., Patients and Methods: Patients received erlotinib 150 mg/day (arm A; n=36) or docetaxel 75 mg/m 2 on day 1 of each 3-week cycle and erlotinib 150 mg/day on days 2-16 of each cycle (arm B; n=38). The primary end-point was progression-free rate (PFR) at 6 months., Results: The study was prematurely interrupted due to slow enrolment. Three (8.3%) patients in arm A and 3 (8.1%) in arm B remained progression-free at 6 months. Median progression-free survival (PFS) was 2.3 months in arm A and 2.8 months in arm B. Median overall survival (OS) was 5.6 and 8.9 months, respectively. Overall, 77.8% of patients in arm A and 89.2% in arm B experienced treatment-related adverse events (AEs)., Conclusion: Results do not support further investigation of the combination of erlotinib and docetaxel in this setting., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: About 20% of advanced non-small-cell lung cancer (NSCLC) cases harbor somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene. In these patients, the standard first-line treatments are the EGFR-tyrosine kinase inhibitors, such as gefitinib, erlotinib, or afatinib. Most of these patients develop resistance and relapse within about 1 year of initiation of an EGFR-tyrosine kinase inhibitor. Consequently, it is important to develop new combination strategies to delay this resistance. Preclinical data have showed that EGFR and vascular endothelial growth factor (VEGF) share a common downstream pathway, suggesting the important role of VEGF in the resistance to EGFR blockade. The combination of erlotinib and bevacizumab, an anti-VEGF agent, showed very interesting clinical results., Patients and Methods: The bevacizumab plus erlotinib study (BEVERLY) is a randomized, open-label, phase III trial investigating first-line erlotinib plus bevacizumab versus erlotinib in patients with advanced NSCLC harboring activating EGFR mutations. The co-primary endpoints are investigator-assessed progression-free survival (PFS) and blinded, independent centrally reviewed PFS. The secondary endpoints include overall survival, quality of life, objective response rate, and safety. A total of 200 patients will be randomized 1:1 to receive oral erlotinib (150 mg daily) plus bevacizumab (15 mg/kg, intravenously, on day 1 of every 21-day cycle) or erlotinib alone, until objective disease progression or unacceptable toxicity or the patient's or physician's motivated decision to stop the treatment., Conclusion: If the primary endpoint of PFS is met, the erlotinib plus bevacizumab combination will be confirmed as the best first-line treatment for patients with advanced NSCLC harboring activating EGFR mutations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy., Patients and Methods: Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires)., Results: All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment., Conclusion: Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases., (© 2016 by American Society of Clinical Oncology.)

Patients with stage IIIA-ipsilateral mediastinal lymph node involvement (N2) non-small cell lung cancer (NSCLC) represent a heterogeneous group with different clinical presentation. The aim of this study was to analyze a series of patients with "potentially resectable" stage IIIA-pathologically proven N2 (pN2) NSCLC undergoing induction chemotherapy followed by surgery to evaluate their long-term outcomes and to identify prognostic factors. Out of 287 patients who underwent induction chemotherapy for NSCLC with ipsilateral mediastinal lymph node involvement pathologically proven, we retrospectively evaluated 141 (49%) patients with no clinical evidence of progression after induction chemotherapy and candidates for surgery. Most of them (73%) underwent at least 3 cycles of cisplatin-based chemotherapy. We used the Kaplan-Meier method to plot survival and the log-rank test to assess the survival difference between groups. Multivariable analysis was performed using Cox proportional hazards regression. A total of 15 (10.6%) patients underwent explorative thoracotomy; 126 patients underwent surgical anatomical resection after a median 27 days (range: 21-30) from the last cycle of chemotherapy. A total of 113 (89.7%) patients had a radical resection. A total of 22 (17.5%) patients had a complete pathologic lymph node downstaging (pN0), and 8 (6.3%) patients had a complete pathological response (pT0N0). The median overall survival was 24 months, with a 5-year overall survival of 30%. At multivariable analysis, downstaging and number of cycles of chemotherapy were independent prognostic factors (P = 0.006); downstaging benefit was mostly because of complete pathological response (hazards ratio = 0.23, 95% CI: 0.07-0.76). In conclusion, more than 3 cycles of chemotherapy and pathological downstaging could significantly improve 5-year survival in selected patients with "potentially resectable" pathologically proven N2 disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy., Patients and Methods: Patients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m(2)/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes., Results: Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent., Conclusion: Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy., Trial Registration Number: NCT01085136 (clinicaltrials.gov)., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

The assessment of special categories of non-small-cell lung cancer (NSCLC) patients requires a comprehensive analysis of all factors potentially influencing the daily quality of life and the relative contribution of tumor-related symptoms on the overall patient health status. While for elderly patients prospective evidence and recommendations allow clinicians to better address their patients to a shared treatment, a paucity of reliable data refers to treatment opportunities for these patients, termed frail or unfit, who are not considered eligible for chemotherapy usually administered to adult patients. This consensus was inspired by the absence of clear criteria to define the category of unfit patients in the context of advanced NSCLC in order to share all the available tools for their classification and evaluation and to support decisions for clinical practice on a daily basis. After review of the literature and panelist consensus, a series of items was identified as relevant: age, performance status, renal function, heart failure, previous cerebrovascular events, uncontrolled hypertension, neuropathy, hearing loss, symptomatic brain metastases, severe psychiatric disorders, and absence of caregiver support. On the basis of these factors, a treatment algorithm for clinical practice to categorize unfit NSCLC patient into 3 major clinical scenarios was defined: (1) unfit for cisplatin-based chemotherapy, (2) unfit for carboplatin-based chemotherapy, and (3) unfit for single-agent chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: In recent years, the treatment landscape in advanced non-squamous non-small-cell lung cancer (nsNSCLC) has changed. New therapies (e.g., bevacizumab indicated in first line) have become available and other therapies (e.g., pemetrexed in first line and second line) moved into earlier lines in the treatment paradigm. While there has been an expansion of the available treatment options, it is still a key research question which therapy sequence results in the best survival outcomes for patients with nsNSCLC., Methods: A therapy-sequencing disease model that approximates treatment outcomes in up to five lines of treatment was developed for patients with nsNSCLC. The primary source of data for progression-free survival (PFS) and time to death was published pivotal trial data. All patients were treatment-naïve and in the PFS state, received first-line treatment with either bevacizumab-based therapy or doublet chemotherapy (including the option of pemetrexed + cisplatin). Patients would then progress to a subsequent line of therapy, remain in PFS or die. In case of progression, it was assumed that each survivor would receive a subsequent line of therapy, based on EMA licensed therapies. Weibull distribution curves were fitted to the data., Results: All bevacizumab-based first-line therapy sequences analyzed achieved total PFS of around 15 months. Bevacizumab + carboplatin + paclitaxel (first line) → pemetrexed (second line) → erlotinib (third line) → docetaxel (fourth line) resulted in total mean PFS time of 15.7 months, for instance. Sequences with pemetrexed in combination with cisplatin in first line achieved total PFS times between 12.6 and 12.8 months with a slightly higher total PFS time achieved when assuming pemetrexed continuation therapy in maintenance after pemetrexed + cisplatin in first-line induction. Overall survival results followed the same trend as PFS., Conclusion: The model suggests that treatment-sequencing strategies starting with a bevacizumab-based combination in first line yield better survival outcomes than those starting with pemetrexed-based combinations, a result that is attributable to the possibility of one further line of treatment with first-line bevacizumab-based treatment sequences.

Introduction: In the PARAMOUNT ("A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer") trial, patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL., Materials and Methods: Patients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m(2), day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed., Results: A median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms., Conclusion: PARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: LIFE (non-small cell Lung cancer management In patients progressing after First-linE of treatment in the metastatic setting) is a multicentre Italian observational study, including a cross-sectional and a longitudinal phase, with the aim of describing the therapeutic approach in clinical practice for advanced non-small cell lung cancer (NSCLC) patients, progressing after first-line treatment., Methods: In this paper, the cross-sectional phase is outlined, with the primary endpoint of describing the proportion of patients receiving second-line treatment among those progressed during or after first-line treatment according to clinical practice., Results: From July 2011 to January 2012, 603 patients were enrolled and 541 (90 %) were evaluable. A total of 464 (86 %) patients received a second-line therapy outside clinical trials. Chemotherapy and targeted therapies were administered to 65 and 34 % of patients, respectively (1 % both). No tissue collection was required within the observational trial, and biomarkers analysis was performed at diagnosis or later in 314 patients (58 %). In details, activating epidermal growth factor receptor mutations were detected in 21 % of 311 evaluable patients, Kirsten rat sarcoma 2 viral oncogene homolog mutation in 22 % of the 77 evaluable patients and anaplastic lymphoma kinase translocations analysis was performed in 74 patients and resulted positive in 23 % of cases. These high proportions were probably due to enriched patient population tested., Conclusions: These results showed a pattern of care for NSCLC second-line therapy which reflects international guidelines recommendations and current expected clinical practice. Interestingly, biomarkers analyses were performed in a higher percentage than expected.

Objectives: Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin (pemetrexed 500mg/m(2) plus cisplatin 75mg/m(2) every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression., Methods: Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population., Results: Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p=0.117, HR=1.16; median OS: 14.0 versus 14.2 months, p=0.979, HR=1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p<0.00001, HR=0.66; median OS: 16.9 versus 14.2 months, p=0.003, HR=0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1-44) following 4 cycles of pemetrexed-cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed-cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT., Conclusions: The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Introduction: The aim of the present study was to evaluate the efficacy and tolerability of vandetanib plus gemcitabine (V/G) compared with gemcitabine alone in elderly patients with untreated advanced non-small-cell lung cancer., Methods: This was a phase II, randomized, double-blind study. A total of 124 elderly patients (mean age, 75 yr; age range, 70-84 yr; 73% men) received V/G (n = 61) or placebo plus gemcitabine (n = 63). Progression-free survival (PFS) was the primary endpoint. Secondary endpoints were overall survival, objective response rate, duration of response, disease control rate, time to deterioration of performance status, and safety outcomes., Results: PFS was significantly prolonged with V/G (median, 183 days; 95% confidence interval, 116-214) compared with placebo plus gemcitabine (median, 169 days; 95% confidence interval, 95-194; p = 0.047). No statistically significant differences between arms were observed in all secondary endpoints, including overall survival. The addition of vandetanib to gemcitabine was well tolerated. The rate of patients with ≥1 treatment-related adverse event was comparable in the two arms, pyrexia, dyspnea, and neutropenia being the most common adverse events., Conclusions: V/G combination was associated with a statistically significant prolongation of PFS compared with gemcitabine alone in untreated elderly patients with advanced non-small-cell lung cancer, with an acceptable safety profile.

Introduction: The PARAMOUNT phase III trial demonstrated that pemetrexed continuation maintenance significantly reduced the risk of disease progression (hazard ratio = 0.62) and death (hazard ratio = 0.78) versus placebo in patients with advanced nonsquamous non-small-cell lung cancer. To further understand the survival data, descriptive subgroup analyses were undertaken., Methods: Nine hundred thirty-nine patients received induction therapy (four 21-day cycles pemetrexed 500 mg/m and cisplatin 75 mg/m), after which 539 nonprogressing patients with an Eastern Cooperative Oncology Group performance status (PS) of 0/1 were randomized (2:1) to maintenance pemetrexed (500 mg/m) cycles or placebo until disease progression., Results: Baseline characteristics of patients surviving for longer periods were comparable to patients surviving shorter periods, suggesting overall survival (OS) benefit for all subgroups of patients on maintenance therapy. An examination of type and severity of induction adverse events also found no association with survival duration. Response to induction (tumor response versus stable disease) was not determinate of pemetrexed maintenance OS outcome as assessed by waterfall plot and scattergrams and by the distribution of patients among various OS intervals. The length of the interval before beginning maintenance therapy (<7 days versus ≥7/≤30 days) also did not impact the survival results. PS, a known prognostic factor, was the only baseline characteristic associated with improved OS; however, both PS 0 and PS 1 patients exhibited a survival benefit from pemetrexed maintenance., Conclusions: In PARAMOUNT, the OS benefit was seen across all subgroups. Other than PS, no baseline or clinical parameter clearly identified a subgroup more likely to benefit. Maintenance treatment decisions should be made on an individual basis.

Purpose: In the phase III PARAMOUNT trial, pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo (hazard ratio [HR], 0.62; 95% CI, 0.49 to 0.79; P < .001). Here we report final overall survival (OS) and updated safety data., Patients and Methods: In all, 939 patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) received four cycles of pemetrexed-cisplatin induction therapy; then, 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were randomly assigned (2:1) to maintenance pemetrexed (500 mg/m(2) on day 1 of 21-day cycles; n = 359) or placebo (n = 180). Log-rank test compared OS between arms as measured from random assignment (α = .0498)., Results: The mean number of maintenance cycles was 7.9 (range, one to 44) for pemetrexed and 5.0 (range, one to 38) for placebo. After 397 deaths (pemetrexed, 71%; placebo, 78%) and a median follow-up of 24.3 months for alive patients (95% CI, 23.2 to 25.1 months), pemetrexed therapy resulted in a statistically significant 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64 to 0.96; P = .0195; median OS: pemetrexed, 13.9 months; placebo, 11.0 months). Survival on pemetrexed was consistently improved for all patient subgroups, including induction response: complete/partial responders (n = 234) OS HR, 0.81; 95% CI, 0.59 to 1.11 and stable disease (n = 285) OS HR, 0.76; 95% CI, 0.57 to 1.01). Postdiscontinuation therapy use was similar: pemetrexed, 64%; placebo, 72%. No new safety findings emerged. Drug-related grade 3 to 4 anemia, fatigue, and neutropenia were significantly higher in pemetrexed-treated patients., Conclusion: Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo, further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.

Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS)., Results: From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039)., Conclusion: Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.

Introduction: In a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non-small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results., Methods: After four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D)., Results: Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p <0.001), anti-infectives (25.3% versus 16.7%; p = 0.028), and hospitalizations because of study drug (8.4% versus 3.3%, p = 0.028) than placebo-treated patients did. No significant treatment-by-time interactions, overall treatment differences, or clinically relevant changes from baseline were observed in EQ-5D scores during treatment., Conclusions: Long-term use of continuation maintenance pemetrexed was well tolerated; resource use was low, corresponding with known pemetrexed toxicities. The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening QoL.

The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin., Methods: In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage (IIIB or IV), ECOG performance status (0 or 1), and induction response (complete or partial response, or stable disease), and randomly assigned (2:1 ratio) to receive maintenance therapy with either pemetrexed (500 mg/m(2) every 21 days) plus best supportive care or placebo plus best supportive care until disease progression. Randomisation was done with the Pocock and Simon minimisation method. Patients and investigators were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00789373., Findings: Of the 1022 patients enrolled, 939 participated in the induction phase. Of these, 539 patients were randomly assigned to receive continuation maintenance with pemetrexed plus best supportive care (n=359) or with placebo plus best supportive care (n=180). Among the 359 patients randomised to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR 0·62, 95% CI 0·49-0·79; p<0·0001). The median progression-free survival, measured from randomisation, was 4·1 months (95% CI 3·2-4·6) for pemetrexed and 2·8 months (2·6-3·1) for placebo. Possibly treatment-related laboratory grade 3-4 adverse events were more common in the pemetrexed group (33 [9%] of 359 patients) than in the placebo group (one [<1%] of 180 patients; p<0·0001), as were non-laboratory grade 3-5 adverse events (32 [9%] of 359 patients in the pemetrexed group; eight [4%] of 180 patients in the placebo group; p=0·080); one possibly treatment-related death was reported in each group. The most common adverse events of grade 3-4 in the pemetrexed group were anaemia (16 [4%] of 359 patients), neutropenia (13 [4%]), and fatigue (15 [4%]). In the placebo group, these adverse events were less common: anaemia (one [<1%] of 180 patients), neutropenia (none), and fatigue (one <1%]). The most frequent serious adverse events were anaemia (eight [2%] of 359 patients in the pemetrexed group vs none in the placebo group) and febrile neutropenia (five [1%] vs none). Discontinuations due to drug-related adverse events occurred in 19 (5%) patients in the pemetrexed group and six (3%) patients in the placebo group., Interpretation: Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin., Funding: Eli Lilly and Company., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC., Methods: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225., Findings: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes., Interpretation: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors., Funding: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC)., Methods: Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75 mg/m(2) cisplatin plus 75 mg/m(2) docetaxel, both administered on day 1 every 21 days, followed by three cycles of 1,200 mg/m(2) gemcitabine on days 1 and 8 every 3 weeks (arm A), or three cycles of 25 mg/m(2) cisplatin plus 25 mg/m(2) docetaxel on days 1, 8 and 15 every 28 days, followed by three cycles of 1,200 mg/m(2) gemcitabine on days 1 and 8 every 3 weeks (arm B)., Results: Of the evaluable patients, 61% in arm A (n = 41) and 36% (n = 44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3 months in arm A, respectively, 3.1 and 7.7 months in arm B. Grade 3-4 adverse events were more common in arm A. Grade 3-4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B)., Conclusions: Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients., Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798., Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044)., Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting., Funding: Merck KGaA., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: AIOT (Italian Association of Thoracic Oncology) produces up-to-date, clinical practice guidelines for the management of lung cancer in Italy. Guidelines were developed by answering clinical relevant questions. Here we report only major clinical issues concerning the management of advanced non-small-cell lung cancer (NSCLC)., Methods: A PubMed search was performed to identify published data until December 2009. Abstracts presented at the main International meetings between 2004 and 2009 were also searched. The writing committee developed and graded recommendations, which were subsequently revised by experts. The search has been subsequently updated for this manuscript in December 2010., Results: In patients with epidermal growth factor receptor (EGFR) mutation positive tumour, gefitinib is recommended as first-line treatment. In presence of EGFR mutation negative or unknown status, patients with advanced squamous NSCLC, with good performance status (PS) and without major co-morbidities, chemotherapy with third-generation regimens containing cisplatin is the recommended treatment. In non-squamous NSCLC patients, also cisplatin plus pemetrexed and platinum-based chemotherapy plus bevacizumab should be considered. Carboplatin is a valid option for patients unsuitable for cisplatin. Maintenance therapy with pemetrexed or erlotinib is a reasonable choice if allowed by reimbursement procedures and discussed with patients. Elderly patients, defined as ≥ 70 years old, should receive third-generation single-agent chemotherapy, but in elderly patients with good PS, without major co-morbidities and with adequate organ function, platinum-based doublets with attenuated doses can be a valid option. In PS 2 patients, single-agent third-generation drug is a reasonable choice. Combination chemotherapy with carboplatin or low doses of cisplatin is a suitable alternative. For second-line treatment, two cytotoxic drugs (docetaxel and pemetrexed, the latter only in non-squamous tumours), and erlotinib, an EGFR inhibitor, are available. There are no strong data to help the choice between chemotherapy and erlotinib., Conclusions: Many developments have been made in advanced NSCLC treatment, and the appropriate use of available therapeutic approaches and the improved understanding of lung cancer molecular abnormalities continue to enhance the outcomes on the basis of well-designed clinical trials which address critical issues in this population., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Sorafenib is a small-molecule multitargeted kinase inhibitor that blocks the activation of C-RAF, B-RAF, c-KIT, FLT-3, RET, vascular endothelial growth factor receptor 2 (VEGFR-2), VEGFR-3 and platelet-derived growth factor receptor β. The aim of this multicenter, randomized phase II study was to evaluate clinical activity and safety of sorafenib in combination with erlotinib or gemcitabine in unselected untreated elderly patients with non-small-cell lung cancer (NSCLC)., Methods: The trial was designed to select the most promising sorafenib-containing combination in previously untreated elderly (≥70 years) stage IIIB or IV NSCLC patients, with performance status of zero to two. Patients were randomly assigned to one of the following combinations: gemcitabine, 1200 mg/m(2) days 1 and 8, every 21 days, for a maximum of six cycles, plus sorafenib, 800 mg/day, until disease progression or unacceptable toxicity (arm 1); or erlotinib, 150 mg/day, plus sorafenib, 800 mg/day, until disease progression or unacceptable toxicity (arm 2). A selection design was applied with 1-year survival rate as the primary end point of the study, requiring 58 patients., Results: Sixty patients were randomly allocated to the study (31 patients in arm 1 and 29 patients in arm 2). After a median follow-up of 15 months, 10 patients [32%, 95% confidence interval (CI) 16% to 49%] in arm 1 and 13 patients (45%, 95% CI 27% to 63%) in arm 2 were alive at 1 year. Median overall survival was 6.6 and 12.6 months in arm 1 and arm 2, respectively. Observed toxic effects were consistent with the expected drug profiles., Conclusions: The combination of erlotinib and sorafenib was feasible in elderly patients with advanced NSCLC and was associated with a higher 1-year survival rate than the other arm. According to the selection design, this combination warrants further investigation in phase III trials.

Purpose: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer., Patients and Methods: Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m(2) every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments., Results: There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed., Conclusion: This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.

Background: The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit., Methods: We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798., Findings: 518 patients in the chemotherapy plus cetuximab group-290 of whom had first-cycle rash-and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8-16·4] vs 8·8 months [7·6-11·1]; hazard ratio [HR] 0·631 [0·515-0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2-5·7] vs 4·3 months [4·1-5·3]; HR 0·741 [0·607-0·905]; p=0·0031) and response (rate 44·8% [39·0-50·8] vs 32·0% [26·0-38·5]; odds ratio 1·703 [1·186-2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6-11·1] vs 10·3 months [9·6-11·3]; HR 1·085 [0·910-1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, [14·1-20·6] vs 9·3 months [7·7-13·2]; HR 0·614 [0·453-0·832]; p=0·0015), squamous-cell carcinoma (median 13·2 months [10·6-16·0] vs 8·1 months [6·7-12·6]; HR 0·659 [0·472-0·921]; p=0·014), and carcinomas of other histology (median 12·6 months [9·2-16·4] vs 6·9 months [5·2-11·0]; HR 0·616 [0·392-0·966]; p=0·033)., Interpretation: First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We present the treatment rationale and study design of the TALISMAN (TArceva and docetaxeL In former-Smokers MAle patients with recurrent Non-small-cell lung cancer) study, an open-label, randomized phase II trial of erlotinib (arm A) or intermittent erlotinib and docetaxel (arm B) in male former smokers affected by recurrent squamous non-small-cell lung cancer (NSCLC). In arm A, treatment consists of erlotinib 150 mg daily orally until progression or inacceptable toxicity; in arm B, treatment consists of docetaxel 75 mg/m² on day 1 and erlotinib 150 mg orally on days 2-16, recycled every 3 weeks up to 4 cycles followed, in patients not progressed, by erlotinib 150 mg daily orally until disease progression or inacceptable toxicity. The primary endpoint of this study is the rate of patients without progression at 6 months, and secondary objectives include median progression-free survival, median overall survival, activity, and toxicity. In addition, translational research evaluating EGFR and KRAS mutational status will be investigated for both arms.

Introduction: The new targeted agent bevacizumab in combination with cisplatin and gemcitabine (BCG), and a third-generation chemotherapy pemetrexed in combination with cisplatin (PC), are approved as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC)., Methods: An indirect comparison between BCG and PC showed that the bevacizumab triplet achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the detailed costs and benefits of these treatments for advanced non-squamous NSCLC in Italy., Results: The monthly cost of single-agent bevacizumab, including administration and supportive care costs, and costs for adverse events as a single agent was 4,007 euro/patient less than pemetrexed over the patient's lifetime. BCG also achieved a mean gain of 0.12 life-years compared with PC over this period. The incremental cost-effectiveness ratio of BCG relative to PC was calculated to be 34,919 euro per additional life-year gained suggesting that BCG is cost-effective compared with PC as first-line treatment for advanced NSCLC in Italy., Conclusions: In conclusion, bevacizumab-based therapy can be considered as a cost-effective option when compared to chemotherapy treatments such as pemetrexed for the treatment for advanced non-squamous NSCLC., (Copyright 2010 Elsevier Ltd. All rights reserved.)

PURPOSE This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2) (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. RESULTS Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century--that is, two-drug combinations consisting of either cisplatin or carboplatin plus a third-generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)--remain the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin-pemetrexed over cisplatin-gemcitabine as first-line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single-agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta-analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy-naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.

Introduction: Although histology has not consistently been associated with treatment outcome in advanced non-small cell lung cancer, a recent phase III trial comparing pemetrexed plus cisplatin and gemcitabine plus cisplatin (GC) demonstrated better efficacy for pemetrexed plus cisplatin in nonsquamous (adenocarcinoma and large cell carcinoma) carcinoma than in squamous cell carcinoma. Herein, retrospective analysis is used to explore the potential predictive and prognostic role of non-small cell lung cancer histology in patients treated with three first-line, platinum-based regimens., Methods: Survival and time to progression (TTP) data from a phase III trial comparing paclitaxel plus carboplatin (PCb), GC, and vinorelbine plus cisplatin (VC) were analyzed. Using Cox multiple regression, factors for one model included treatment (PCb, GC, and VC), histology (squamous, adenocarcinoma, large cell, and other), gender, Eastern Cooperative Oncology Group performance status (0/1 and 2), stage (IIIB and IV), number of metastatic sites (< or = 1 and >1), and smoking history (yes or no). In another model, histology was simply considered as squamous versus nonsquamous. An interaction value of p < 0.10 was considered significant., Results: Baseline patient and disease characteristics for the 607 treated patients were balanced among the arms. No significant treatment-by-histology interaction was seen in either model for either end point. Nevertheless, histology was a significant prognostic factor for survival in the first model (p = 0.0183) and marginally significant for TTP (p = 0.0783). Subsequent pairwise comparisons of histology groups demonstrated a survival advantage for squamous cell carcinoma over adenocarcinoma (p = 0.0021)., Conclusions: Histology was not predictive of PCb, GC, or VC treatment effect for either survival or TTP. Histology was prognostic for survival, with better outcomes associated with squamous cell carcinoma.

Background: In the attempt to optimize the efficacy of chemotherapy in advanced non-small cell lung cancer (NSCLC) several strategies need to be investigated including the use of non-platinum combinations and the sequential use of different agents., Patients and Methods: In a phase II randomised study 165 patients with stage IIIB or IV NSCLC were assigned to receive docetaxel 40 mg/m(2) days 1 and 8 plus gemcitabine 1200 mg/m(2) days 1 and 8 every 21 days (arm A, N=54) or docetaxel 50 mg/m(2) days 1 and 15 plus gemcitabine 1600 mg/m(2) days 1 and 15 every 28 days (arm B, N=57) or gemcitabine 1200 mg/m(2) days 1 and 8 plus cisplatin 100mg/m(2) day 2 every 21 days for 3 cycles followed by docetaxel 75 mg/m(2) day 1 every 21 days for 3 cycles (arm C, N=54). The primary endpoint of the trial was overall response rate. Secondary end points included safety, progression-free and overall survival., Results: Response rate was 22.2%, 23.2% and 33.3% after 3 cycles, whereas at the end of treatment was 24.1%, 12.5% and 27.8% in arm A-C, respectively. Median time to progression was similar in all the 3 arms: 6.7 months in arm A (95% CI: 4.8-9.7), 5.6 in arm B (5.0-7.9) and 6.6 in arm C (5.7-9.1). The median survival time was 10.7 months in arm A (95% CI: 6.8-15.6), 8.9 in arm B (7.4-12.5) and 14.6 in arm C (8.0-22.4) and 1-year survival rate was 46.3%, 37.9% and 53.9%, respectively. Grade 3-4 haematological toxicities were more frequent in arm C while non-haematological were more common in the gemcitabine and docetaxel arms., Conclusions: The results of this phase II randomised clinical trial do not indicate a clear superior efficacy of one of the tested combinations according to the planned statistical design and none of these regimens is sufficiently active or less toxic to warrant further investigation in a phase III study.

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer., Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (>or=18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m(2) intravenous infusion on day 1, and vinorelbine 25 mg/m(2) intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m(2) intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m(2) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798., Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762-0.996]; p=0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3)., Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer., Funding: Merck KGaA.

Lung cancer is the leading cause of cancer deaths worldwide. Novel targeted therapies based on specific molecular and biological characteristics of lung cancer have emerged as a new treatment paradigm. The current globally accepted standard of treatment for advanced non-small-cell lung cancer (NSCLC) is platinum-based combination therapy. Recently, several ongoing phase I and II trials with new drugs in NSCLC have been registered, such as sorafenib, sunitinib, mTOR inhibitors and ASA404. The optimal use of new agents is more likely in combination with standard cytotoxic or other targeted agents. Further investigations into adverse events with targeted therapy are urgently needed as these impact an increasing number of patients., (Copyright 2010 S. Karger AG, Basel.)

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

After failure of first-line chemotherapy for advanced non-small cell lung cancer, many patients remain candidates to receive further antitumor treatment. To guide clinical management of these patients and to suggest priorities for clinical research, an International Panel of Experts met in Naples (Italy) in April 2007. Results and evidence-based conclusions are presented in this article. Single-agent chemotherapy with docetaxel or pemetrexed is the recommended option for unselected patients with performance status 0 to 2 who are candidates for second-line chemotherapy for advanced non-small cell lung cancer. Docetaxel has demonstrated superiority compared with best supportive care. Pemetrexed has been shown to be noninferior to docetaxel, with a more favorable toxicity profile. Erlotinib is effective in pretreated patients, and can be given second-line in patients not suitable or intolerant to chemotherapy, and in all patients as third-line treatment after failure of second-line chemotherapy. Gefitinib failed to show superiority to placebo as second- or third-line treatment, but it has been shown to be noninferior to docetaxel. In selected patients such as lifetime nonsmokers or those of East-Asian ethnicity, erlotinib, or gefitinib (where licensed) may be considered as second-line treatment even if they are fit for chemotherapy. Best supportive care in addition to active treatment remains important for all patients, but may be the exclusive option for patients unsuitable for more aggressive therapy. Further research is mandatory, to find better treatments, and to identify clinical and molecular predictive markers of efficacy, both for chemotherapy and for novel biologic agents.

In the U.S. and Europe, the current options for the second- and third-line treatment of advanced non-small cell lung cancer (NSCLC) are cytotoxic drugs and targeted agents. Docetaxel was the first drug approved for second-line treatment after two phase III trials demonstrated its superiority over best supportive care (BSC) alone and single-agent chemotherapy. Pemetrexed was also registered for use as second-line therapy after it was demonstrated to have activity comparable with, and a more favorable toxicity profile than, docetaxel. Erlotinib, an epidermal growth factor receptor inhibitor, is the only biological agent to have been approved in the U.S. and Europe for lung cancer treatment after a study showed its superiority over BSC in recurrent (second-/third-line) NSCLC patients. This review focuses on these drugs, dealing with the results supporting the choice among docetaxel, pemetrexed, and erlotinib in second- and/or third-line treatment.