Search

Main conclusion: Drought may be efficiently managed using the following strategies: prevention, mitigation, readiness, recovery, and transformation. Biotechnological interventions may become highly important in reducing plants’ drought stress in order to address key plant challenges such as population growth and climate change. Abstract: Drought is a multidimensional construct with several triggering mechanisms or contributing factors working at various spatiotemporal scales, making it one of the known natural catastrophes. Drought is among the causes of hunger and malnutrition, decreasing agricultural output, and poor nutrition. Many deaths caused in children are due to hunger situations, and one in four children face stunted growth. All this hunger and malnutrition may be responsible for the reduction in agricultural productivity caused due to the drought situations affecting food security. Global Hunger Index has been accelerating due to under-nutrition and under-5 deaths. Drought has been covering more than 20% of the world's agricultural areas, leading to significantly less food production than what is required for consumption. Drought reduces soil fertility and adversely affects soil biological activity reducing the inherent capacity of the soil to support vegetation. Recent droughts have had a much greater effect on people’s lives, even beyond causing poverty and hunger. Drought may have substantial financial consequences across the globe it may cause a severe impact on the world economy. It is a natural feature of the environment that will appear and disappear as it has in history. Due to increasing temperatures and growing vulnerabilities, it will undoubtedly occur more often and seriously in the coming years. To ensure sustainable socio-economic and social development, it is critical to reducing the effects of potential droughts worldwide using different biotechnological interventions. It’s part of a long-term growth plan, and forecasting is essential for early warnings and global hunger management.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC). Objective Our objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs. Methods This was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence. Results Among 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis. Conclusions Rates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-021-00261-8.

Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy.Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment.In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified.The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.

Objectives\ud \ud Small cell lung cancer (SCLC) responds well to chemoradiotherapy but frequently relapses. Here, we evaluate activity and safety of the poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor olaparib as maintenance treatment for patients with chemoresponsive SCLC.\ud \ud \ud \ud Materials and methods\ud \ud Eligible patients had complete or partial response to first line chemotherapy or chemoradiotherapy for SCLC. Patients were randomised 2:2:1:1 to olaparib 300 mg twice a day (BD), olaparib 200 mg three times a day (TDS), placebo BD or placebo TDS. The primary outcome was progression-free survival time (PFS). The trial design had 80% power to detect a 3-month difference in median PFS based on a one-sided 5% significance level. Secondary outcome measures included overall survival time (OS), adverse events and quality of life.\ud \ud \ud \ud ISRCTN 73164486, EudraCT 2010-021165-76.\ud \ud \ud \ud Results\ud \ud 220 patients were randomised: 74 placebo, 73 olaparib BD, 73 olaparib TDS. Median PFS (90% confidence interval (CI)) was 2·5 (1·8, 3·7), 3·7 (3·1, 4·6) and 3·6 (2·8, 4·7) months in the placebo, olaparib BD and TDS arms, respectively. There was no significant difference in PFS between olaparib and placebo for either BD (Hazard Ratio (HR) (90%CI) 0·76 (0·57, 1·02), P = 0·125 or TDS 0·86, (0·64, 1·15), P = 0·402. Common adverse events on olaparib were fatigue, nausea, anaemia, vomiting and anorexia. Of 214 patients who discontinued treatment before 24 months, toxicity was the reason cited for 66 (18 placebo, 24 olaparib BD, 24 olaparib TDS).\ud \ud \ud \ud Conclusion\ud \ud This trial does not provide sufficient evidence that either the BD or TDS regimen for maintenance olaparib monotherapy improves PFS or OS in an unselected SCLC population to warrant further research. Toxicity for olaparib was similar to other studies.

Objectives To describe rates of confirmed and suspected neutropenic sepsis (NS) and associated hospital resource utilisation in patients with non-small cell lung cancer (NSCLC) treated with docetaxel monotherapy following relapse after ≥1 line of chemotherapy in routine UK clinical practice. Materials and methods A multi-centre, retrospective, observational research study was conducted in seven centres across England and Wales. Adult patients with stage III/IV NSCLC initiated on docetaxel monotherapy between 2010 and 2016 in routine clinical practice (aged ≥18 years at initiation) following failure of first-line chemotherapy were eligible. Data were collected from hospital medical records between May 2016 and July 2016, on all episodes of confirmed or suspected NS related to docetaxel monotherapy, including patient characteristics. Episodes of confirmed NS were defined as documented absolute neutrophil count 9 /L, plus temperature >38 °C or other signs/symptoms of sepsis, otherwise episodes were classified as suspected NS. Results 121 patients were included (median age 65.5 years; 57.9% male; median 4.0 cycles of docetaxel; 19.8% treated with prophylactic granulocyte-colony stimulating factor). Episodes of confirmed or suspected NS were recorded in 21/121 (17.4%) patients (11 confirmed episodes in 11 [9.1%] patients and 11 suspected episodes in 10 [8.3%] patients). Resource utilisation data were available for 21/22 episodes; the mean length of stay for confirmed NS admissions (n = 11) was 9.2 (SD: 9.2) days and for suspected NS admissions (n = 10) was 4.7 (SD: 4.6) days. The most commonly prescribed treatment for NS was piperacillin/tazobactam therapy (46.5% of all documented treatments). The mean total costs of managing patients with confirmed NS (n = 11) and suspected NS (n = 9) were £3163 (SD: £2921) and £1790 (SD: £1585) per patient, respectively. Conclusion Rates of confirmed NS in UK clinical practice were broadly similar to those reported in clinical trials; however, the burden of suspected NS, not routinely reported elsewhere, is also substantial.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing andIn this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with anThe median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group.Among patients with previously untreated advanced NSCLC with an

Background Osimertinib is a 3rd-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-mutated (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in NSCLC CNS metastases. In the phase III FLAURA study (NCT02296125), osimertinib resulted in significant progression-free survival (PFS) benefit (primary endpoint; datacut off [DCO] 12 June 2017) over comparator EGFR-TKI (HR 0.46, p Methods Eligible patients (pts): ≥18 years (Japan: ≥20), treatment-naive with Ex19del/L858R EGFRm advanced NSCLC; WHO performance status 0–1. Pts with stable CNS metastases not requiring steroids for ≥2 weeks were allowed. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or comparator EGFR-TKI (gefitinib 250 mg qd/erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover was allowed for pts in the comparator EGFR-TKI arm upon central confirmation of progression and T790M positivity. Primary endpoint: PFS by RECIST v1.1, per investigator. OS was a secondary endpoint. DCO 25 June 2019. Results Globally, 556 pts were randomised to osimertinib (n = 279) or comparator EGFR-TKI (n = 277). Per study protocol, 70 (25%) pts crossed over from comparator EGFR-TKI to osimertinib. Osimertinib significantly improved OS vs comparator EGFR-TKI. All causality AEs, per investigator: osimertinib, 98% (grade ≥3, 42%); comparator EGFR-TKI, 98% (grade ≥3, 47%). AEs leading to discontinuation: osimertinib, 15%; comparator EGFR-TKI, 18%. The safety profile appears consistent with previously reported data. Table . LBA5_PR Efficacy output Osimertinib n = 279 Comparator EGFR-TKI n = 277 OS hazard ratio 0.799 (0.641, 0.997); p = 0.0462 (95.05% confidence interval) Median OS, months 38.6 31.8 (95% confidence interval) (34.5, 41.8) (26.6, 36.0) Deaths, total pts (%) 155 (56) 166 (60) Median follow-up for OS in all pts, months 35.8 27.0 Median follow-up for OS in censored* pts, months 43.1 43.1 12-month survival rate, % 89 83 (95% confidence interval) (85, 92) (77, 87) 24-month survival rate, % 74 59 (95% confidence interval) (69, 79) (53, 65) 36-month survival rate, % 54 44 (95% confidence interval) (48, 60) (38, 50) OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O’Brien-Fleming approach was required due the previous interim analysis.*Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Conclusions Osimertinib provided a statistically significant and clinically meaningful improvement in OS vs comparator EGFR-TKI in first-line pts with EGFRm advanced NSCLC. Clinical trial identification NCT02296125. Editorial acknowledgement Natalie Griffiths, PhD, from iMed Comms, an Ashfield Company; funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Celgene, Takeda; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion, Kissei, Amgen, Janssen, ROXO. B.C. Cho: Honoraria (institution), Advisory / Consultancy: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc.. J. Vansteenkiste: Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Roche; Speaker Bureau / Expert testimony: AstraZeneca, BMS, MSD, Roche. C. Zhou: Honoraria (self): Roche, Eli Lilly, Boehringer Ingelheim, Merck, Hengrui and Qiru. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca. P. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Merck, Takeda, Novartis, Genomic Health, Pfizer. M. Tiseo: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. F. Imamura: Honoraria (self), Research grant / Funding (institution): AstraZeneca. R. Hodge: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Shareholder / Stockholder / Stock options: AstraZeneca, Gritstone; Full / Part-time employment: AstraZeneca. D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck,Novartis, prIME Oncology, Pfizer. All other authors have declared no conflicts of interest.

Background EGFR-TKIs are the preferred 1L therapy for pts with EGFRm metastatic NSCLC. However, treatment and survival in this population with 2L therapy and beyond are not well defined in the RW setting. To address this, we analysed RW cohort data in the USA, UK, Germany and France. Methods A retrospective chart review was conducted for 472 pts with EGFRm NSCLC receiving a 1L 1G / 2G EGFR-TKI (1 Jan 2015–31 Dec 2017). Data on 1L and 2L treatment and progression after 1L initiation (defined by clinical progression, start of 2L treatment or death before 2L treatment initiation) were extracted. 1L progression-free (PFS) and overall survival (OS) were estimated via Kaplan–Meier methods. Results Baseline characteristics at 1L: median age 62 yrs; 43% female; 61% current/former smokers; 60% Caucasian; 76% Exon 19 deletion. 1L EGFR-TKI treatments: 44% afatinib; 36% erlotinib; 21% gefitinib. Median duration of overall follow-up from start of 1L was 19.9 months (mo; range 0.3–50.3). Of 472 pts, 344 (73%) progressed on 1L treatment, including 158 who died during follow-up. 128 (27%) pts did not progress: 86 (18%) remained on 1L treatment and 42 (9%) pts discontinued 1L treatment before follow-up end. Median 1L PFS (95% CI) was 14.5 (13.3, 15.6) mo and median OS (95% CI) from start of 1L was 34.6 (29.5, 45.5) mo. Of 344 pts with 1L progression, 255 (74%) were tested for T790M; 129 (38%) were positive, of whom 97 received osimertinib (75%). Of 126 pts testing negative, 17 (13%) received osimertinib. Of 344 pts with 1L progression, 258 (75%) received 2L treatment, osimertinib-containing regimens being most common (n = 109/258, 42%). For 86 (25%) pts with 1L progression but no 2L treatment, 73 (85%) died and 13 (15%) were alive at follow-up end. Conclusions 25% of pts progressing on 1L EGFR-TKIs did not receive 2L treatment (due to death in most cases). Furthermore, 25% of pts who progressed on 1L treatment and tested T790M positive did not receive osimertinib. Findings indicate that rates of resistance mutation testing and utilisation of effective EGFRm NSCLC therapies may be suboptimal. Editorial acknowledgement Robert Harrison, PhD, of iMed Comms, Macclesfield, UK, an Ashfield Company; funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca. N. Girard: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca, Boehringer Ingelheim. S.P. Nagar: Advisory / Consultancy, Employee of RTI-HS who provides consulting services to AstraZeneca: AstraZeneca. F. Griesinger: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Celgene, Lilly, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Takeda, Siemens; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AbbVie. J. Roeper: Honoraria (institution): Boehringer Ingelheim, Roche, AstraZeneca. K. Davis: Research grant / Funding (institution): AstraZeneca, Novartis, Celgene, Sanofi, Pfizer, Amgen. N. Bakker: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. B. Thakrar: Full / Part-time employment: AstraZeneca. A. Taylor: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest. J. Feliciano: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Eli Lilly.

OBJECTIVES To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). MATERIALS AND METHODS Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. RESULTS 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. CONCLUSION HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management.

Summary Background Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment. Methods NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m2 intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000–1250 mg/m2 intravenously), vinorelbine (25 mg/m2 intravenously or 60 mg/m2 orally), doxorubicin (60–75 mg/m2 intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266). Findings Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1–24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2–9·9] in the NGR-hTNF group vs 8·0 months [6·6–8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75–1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related. Interpretation The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis. Funding MolMed.

Summary Background The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor ( EGFR ) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR -mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation. Methods BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028. Findings Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3–15·5), with a 12 month progression-free survival of 55% (95% CI 45–64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50–81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4–14·2), with a 12 month progression-free survival of 48% (36–59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis. Interpretation The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations. Funding European Thoracic Oncology Platform, Roche.

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/m2/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).

Introduction The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data. Methods Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively. Results Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome. Conclusions Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.

LBA7500 Background: Afatinib (A) is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. This global study investigated the efficacy and safety of A compared with pemetrexed/cisplatin (PC) in pts with EGFR mutation positive advanced lung adenocarcinoma. Methods: Following central testing for EGFR mutations (companion diagnostic TheraScreen EGFR RGQ PCR kit), 345 pts (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1 (A: 230; PC: 115) to daily A 40 mg or iv PC (500 mg/m2 + 75 mg/m2 q21 days up to 6 cycles). Primary endpoint was progression-free survival (PFS) by central independent review. Results: Baseline characteristics were balanced in both arms: median age, 61 y; female, 65%; Asian, 72%; never-smoker, 68%; Del19, 49%; L858R, 40%; other mutations, 11%. Treatment with A led to a significantly prolonged PFS vs PC (median 11.1 vs 6.9 mos; HR 0.58 [0.43–0.78]; p=0.0004). In 308 pts with common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 mos, respectively (HR=0.47 [0.34–0.65]; p

Aim: Some patients with adv nsqNSCLC may not need hospital-based chemotherapy. This study evaluated the feasibility and adherence to HD of maintenance PEM therapy in these patients. PEM is suitable for HD due to its favorable safety profile and ease of use (10-minute i.v. infusion). Methods: Exploratory, prospective, single-arm, Phase 2 study in adv nsqNSCLC patients, ECOG performance status 0 or 1 without progression after 4 induction cycles of platinum doublet. The first cycle of PEM (500mg/m2) was hospital administered, further cycles as HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or discontinuation due to HD) as primary endpoint, and by health related quality of life (HRQoL) (EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, Overall Survival (OS), and safety. Results: 52 patients (UK/Sweden) had a median of 4 (range 1-19) maintenance PEM cycles. Adherence rate up to Cycle 6 was 98% (95% CI: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (before first HD, [safety concerns]) and 1 patient after Cycle 6 (investigator decision [non-compliance with oral dexamethasone]). 82% (31/38) patients preferred home treatment and in 90% (28/31) of cases, physicians were satisfied with distant patient management. During HD Cycles 2-4 mean change from baseline ranged from 3-8 for EQ-5D VAS and from –5 to –8 for LCSS average symptom burden index. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD related AE (device related infection Grade [G] 2) and 1 patient died (possibly drug related atypical pneumonia). National Cancer Institute Common Terminology Criteria for AEs (V4) G 3/4 toxicities AEs n (%) Fatigue 6 (12) Anemia 4 (8) Dyspnea 3 (6) Thrombocytopenia 2 (4) Lower respiratory infection 2 (4) Neutropenia 1 (2) Nausea 1 (2) Pulmonary fibrosis 1 (2) Sepsis 1 (2) Conclusions: HD of maintenance PEM therapy in adv nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management. Community-based clinical research requires specific consideration and resource allocation. Disclosure: M.C. Nicolson: The author has a personal specific interest in terms of advisory board work and also paid lectures for Lilly; also non-personal specific in terms of research support and meeting attendance support; C.M. Visseren-Grul: Lilly Employee The author declares no conflict of interest; M. Lorenzo: Lilly Employee The author declares no conflict of interest; Y. D'Yachkova: Lilly Employee The author declares no conflict of interest; N. Bourayou: Lilly Employee The author declares no conflict of interest. All other authors have declared no conflicts of interest.

7583 Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to be associated with TS expression. Our primary objective was to assess the correlation between TS and PFS, prospectively. Methods: Context: A Phase II, single-arm, exploratory, multicenter, UK study with appropriate approvals and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC histology, stage IIIB/IV. Patients (n=70) received pem/cisplatin induction x 4. Non-progressive patients continued on maintenance pem until tumor progression or discontinuation. All patients were followed until death or study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for median PFS (mPFS) and Cox regression to determine the statistical correlation between PFS and TS IHC nuclear score, (continuous variable) were performed. Maximal Chi-square analysis identified the optimal association cutpoints between PFS and low vs. high TS scores. Results: Patient demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) had adenocarcinoma; 15 were not otherwise specified. Maintenance pem was started in 43/70 (61.4%) patients. Evaluable patients had at least one dose of study treatment and a valid TS score (n=60). For the evaluable population, the mPFS from start of induction was 5.5 months (95% CI 3.9-6.9). A statistically significant correlation between PFS and TS IHC nuclear scores was observed [p

Background: Single arm phase 1 and 2 studies on Crizotinib in ALK-positive patients so far have shown rapid and durable responses. Spontaneous pneumothoraces as a result of response to anti-cancer therapy are rare in oncology but have been documented in a number of tumour types including lung cancer. This includes cytotoxic chemotherapy as well as molecular targeted agents such as gefitinib and Bevacizumab. These often require chest drain insertion or surgical intervention with associated morbidity and mortality. They have also been associated with response to treatment. This is the first report we are aware of documenting pneumothorax as response to crizotinib therapy.Case presentation: A 48-year-old Caucasian male presented with a Stage IV, TTF1 positive, EGFR wild-type adenocarcinoma of the lung. He received first line chemotherapy with three cycles of cisplatin-pemetrexed chemotherapy with a differential response, and then second-line erlotinib for two months before further radiological evidence of disease progression. Further analysis of his diagnostic specimen identified an ALK rearrangement by fluorescence in situ hybridization (FISH). He was commenced on crizotinib therapy 250 mg orally twice daily. At his 4-week assessment he had a chest radiograph that identified a large left-sided pneumothorax with disease response evident on the right. Chest CT confirmed a 50% left-sided pneumothorax on a background of overall disease response. A chest tube was inserted with complete resolution of the pneumothorax that did not recur following its removal.Conclusion: Our case demonstrates this potential complication of crizotinib therapy and we therefore recommend that pneumothorax be considered in patients on crizotinib presenting with high lung metastatic burden and with worsening dyspnoea. © 2013 Gennatas et al.; licensee BioMed Central Ltd.