Incurable Non-small Cell Lung Cancer Research Articles

EP08.01-074 'Long Responders' Compared to 'Non-Responders' to a First Line Immune Checkpoint Inhibitor in Incurable Non-Small Cell Lung Cancer

KEYNOTE-024 compared single agent pembrolizumab to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) with PDL1 >50%, illustrating improved progression free survival (PFS) and overall survival (OS) for pembrolizumab. The objective of this study is to identify the proportion of real-world NSCLC patients who have a long-term benefit with first line pembrolizumab and examine their characteristics compared to patients who show limited benefit to the drug.

Metronomic oral vinorelbine doublet chemotherapy with carboplatin in treatment of advanced lung cancer: a feasibility and safety study

Background: Non-small cell lung cancer (NSCLC) is globally one of the most common forms of cancer. Palliative treatment is a delicate balance against toxicity and survival. Using small frequent doses of chemotherapy, metronomic regimens have been hypothesized to maintain or even improve efficacy while achieving a lower treatment-related toxicity. The mechanism is thought to result from a more continuous exposure of the tumour cells to the drugs. Treating NSCLC, this study addresses the feasibility and tolerability of carboplatin in combination with 12 weeks of daily metronomic vinorelbine. Method: Patients were included over a period of ten months. All patients had biopsy-verified incurable NSCLC and were candidates for first line chemotherapy (PD-L1<50% and no targetable mutations). This open label, non-randomized prospective safety and feasibility study was investigator initiated. Patients received up-to four cycles of standard dose carboplatin AUC 5 every third week in combination with 12 weeks of metronomic oral daily Navelbine® (20/30 mg). Patients were evaluated by CT scans after end of treatment and then every 8 weeks (+/- 1 week) until progression. Results: A total of 20 patients were included. Male/female-ratio was 4/16. Age ranged from 49-83 with a median of 70.5 years. Majority had adenocarcinoma (95%). Two patients withdrew their consent within a week. 18 patients were included in safety analysis. 13 received all four cycles. Grade 1/2 toxicity was frequently seen and included fatigue 13 (72%), diarrhoea 13 (72%), constipation/congestion 13 (72%). Grade 3 toxicities were dyspnoea 2 (11%), nausea 3 (17%) and fatigue 3 (17%). Two (11%) had grade 4 toxicity with neutropenic fever, both recovered. No grade 5 toxicity was detected. Conclusion: In treatment of NSCLC this study is the first addressing the regimen of carboplatin in combination with daily metronomic vinorelbine. We conclude that doublet chemotherapy with daily vinorelbine is safe and feasible.

The effect of prior cancer on non-small cell lung cancer trial eligibility.

ObjectivesApproximately 20% of patients diagnosed with non‐small cell lung cancer (NSCLC) have a history of prior (non‐lung) cancer. Patients with prior cancer are frequently excluded from clinical trials. We aimed to assess the potential impact of prior cancer on commonly used clinical trial endpoints.Materials and MethodsClinical trials of systemic therapy for incurable NSCLC from clinicaltrials.gov were reviewed to determine the frequency of exclusion on the basis of prior cancer. A cohort of patients with incurable NSCLC and prior cancer, treated with first‐line systemic treatment at our institution were reviewed as a surrogate clinical trial population. A list of priori events was developed to capture the potential for prior cancer to negatively affect clinical trial conduct or endpoints. The proportions of patients that developed an outcome were assessed.ResultsAmong trials registered on clinicaltrials.gov, 66% listed prior cancer in the eligibility criteria, and of these 35% excluded patients with prior cancer in the last 5 years. Of NSCLC patients treated with systemic therapy at Princess Margaret Cancer Center, 20% had prior cancer, of these, breast (20%) and prostate (19%) were the most common malignancies. Median time between prior cancer and NSCLC was 82 months. Median survival was 20 months. For patients without evidence of active prior cancer at baseline, and not on active therapy for prior cancer, no patients had evidence of a recurrence of prior cancer during the treatment and follow‐up for the NSCLC, nor died from prior cancer. However, two patients developed new primaries.ConclusionsA history of prior cancer has a low likelihood of impacting clinical trial endpoints in patients with incurable NSCLC, if not active or requiring treatment. These findings should be validated in larger data sets.

Efficacy and safety of immune checkpoint inhibitors in a Danish real life non-small cell lung cancer population: a retrospective cohort study

Background: To investigate effect and toxicity of immune checkpoint inhibition (ICI) in a Danish real-life non-small cell lung cancer (NSCLC) population. By including patients underrepresented in clinical trials, such as those with brain metastasis (BM), higher age, more comorbidity and poorer performance status (ECOG), comparison of unselected patients to clinical trial populations is possible.Material and methods: Real life data were gathered from 118 consecutive NSCLC patients with incurable NSCLC treated with ICI at the Department of Oncology at the University Hospital of Odense, Denmark from September 2015 to April 2018. Immune-related adverse events (irAEs) grades 3–5 were registered prospectively during the same period. Additional patient related data were obtained retrospectively from patients' files. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan–Meier estimates, the log-rank test and cox regression analysis performed for factors affecting survival.Results: Median age for patients was 66 years (IQR 59–71) and 62 years (range: 55–64) for those with BM. Females 63%; adenocarcinoma (AC)/squamous/others 69%/23%/8%; ECOG ≥ 2 10%; bone/brain/liver metastases 36%/18%/15%; PD-L1 (TPS) <1%/ ≥ 1%/ ≤ 49%/ ≥ 50%/NR: 3%/14%/68%/15%; baseline autoimmunity 10%, Charlson's Comorbidity Index Score (CCIS) ≥ 2 39%, treatment line: 1st/2nd/ ≥ 3rd 39%/30%/31%. Median OS for patients receiving ICI in ≥2 line was 11.5 months versus not reached in first line (HR 2.6, [95% CI: 1.3–5.0], p = .005). For patients with BM, the median OS was 8.2 months (HR 1.38, [95% CI: 0.7–2.5], p = .37). Twenty-four percent of patients terminated ICI due to irAE grades 3–5 alone (grade 5, n = 1), which were not associated with higher age or BM.Conclusions: OS and PFS were comparable to clinical trial reports. Long-lasting remission is also possible in patients with BM. Real-life populations have higher rates of irAE grades 3 and 4 than reported in clinical trials, but it does not seem to impact median OS.

Needs with Regard to Decision Support Systems for Treating Patients with Incurable Non-small Cell Lung Cancer

Treatment decision-making for patients with incurable non-small cell lung cancer (NSCLC) is complex due to the rapidly increasing number of treatments and discovery of new biomarkers. Decision support systems (DSS) could assist thoracic oncologists (TO) weighing of the pros and cons of treatments in order to arrive at an evidence-based and personalized treatment advice. Our aim is to inventory (1) TO’s needs with regard to DSS in the treatment of incurable (stage IIIB/IV) NSCLC patients, and (2) preferences regarding the development of future tools in this field. We disseminated an online inventory questionnaire among all members of the Section of Oncology within the Society of Physicians in Chest Medicine and Tuberculosis. Telephone interviews were conducted to better contextualize the findings from the questionnaire. In total, 58 TO completed the questionnaire and expressed a need for new DSS. They reported that it is important for tools to include genetic and immune markers, to be sufficiently validated, regularly updated, and time-efficient. Also, future DSS should incorporate multiple treatment options, integrate estimates of toxicity, quality of life and cost-effectiveness of treatments, enhance communication between caregivers and patients, and use IT solutions for a clear interface and continuous updating of tools. With this inventory among Dutch TO, we summarized the need for new DSS to aid treatment decision-making for patients with incurable NSCLC. To meet the expressed needs, substantial additional efforts will be required by DSS developers, above already existing tools.

Opioid Dose and Survival of Patients with Incurable Nonsmall Cell Lung Cancer: A Prospective Cohort Study.

Preclinical studies show that opioids promote angiogenesis, tumor progression, and metastasis, resulting in shorter survival. To explore whether opioids are associated with the overall survival (OS) of patients with incurable nonsmall cell lung cancer (NSCLC). Prospective cohort study of patients with NSCLC. We investigated patients newly diagnosed with advanced or post-operative recurrent NSCLC between April 2013 and December 2015 at a single institute. We evaluated OS, opioid requirements, opioid doses, pain levels, and prognostic factors of advanced NSCLC. The effects of variables on survival were analyzed using univariable and multivariable models. Patients were stratified according to oral morphine equivalents (OMEs)/day (<60 or ≥60 mg) to assess the association between opioid dose and OS. We analyzed 150 patients, including 64 who received opioid treatment during follow-up. The median OS was 242 days in the opioid group and 627 days in the no-opioid group (log-rank p < 0.001). Multivariable models revealed that the opioid requirement was an independent predictor of shorter OS, after adjustment for prognostic variables, including sex, histology, stage, history of systemic chemotherapy, and performance status (hazard ratio 1.73, 95% confidence interval 1.137-2.631). There was no significant difference in OS between patients who received ≥60 mg OME/day for 250 days versus <60 OME/day for 242 days. The opioid dose does not shorten the survival of patients with advanced NSCLC. The opioid requirement is associated with shorter survival when opioids are administered any time during the clinical course, independent of the influence of other key factors.

Palliative radiation and fractionation in medicare patients with incurable non-small cell lung cancer

PurposePalliative radiation therapy (RT) can improve quality of life but also incurs time and financial costs. The aim of this study was to evaluate factors associated with use and intensity of palliative RT for incurable non-small cell lung cancer (NSCLC). Methods and materialsThis was a retrospective analysis of Medicare's Surveillance, Epidemiology and End Results data. We identified patients who were diagnosed with incurable (American Joint Committee on Cancer 6th edition stage IIIB with malignant effusion or stage IV) NSCLC between 2004 and 2011. Univariable and multivariable logistic regressions were used to identify factors associated with the receipt of palliative RT and the use of >10 fractions during the first course of radiation. Among patients who were treated with radiation, freestanding versus hospital-based center information was collected on the basis of the location of the RT delivery claim. ResultsAmong 55,258 patients with incurable NSCLC, 38% (21,053 patients) received palliative RT during the first year after diagnosis. Among patients who received RT, 56% (11,717 patients) received >10 fractions. On multivariable analysis, factors associated with greater RT use included younger age group (overall P < .01), lower modified Charlson comorbidity score (overall P < .01), female sex (odds ratio [OR]: 1.1; P < .01), marital status (OR: 1.1; P < .01), and chemotherapy use (OR: 3.6; P < .01). Predictors for >10 fractions were chemotherapy use (OR: 1.7; P < .01) and treatment at a freestanding versus hospital-based facility (58% vs 43%; OR: 1.7; P < .01). ConclusionsMore than a third of patients diagnosed with incurable lung cancer receive palliative RT and 56% received >10 fractions. The use of RT varied by region and patient characteristics, and patients treated at freestanding RT centers were more likely to receive >10 fractions. Further research into factors that influence treatment decisions including potential financial incentives may contribute to the high value and strategic utilization of palliative RT.

Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline

PurposeTo revise the recommendation on the use of concurrent chemotherapy (CC) with palliative thoracic external beam radiation therapy (EBRT) made in the original 2011 American Society for Radiation Oncology guideline on palliative thoracic radiation for lung cancer. Methods and materialsBased on a systematic PubMed search showing new evidence for this key question, the task force felt an update was merited. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology–approved tools for grading evidence quality and recommendation strength. ResultsAlthough few randomized clinical trials address the question of CC combined with palliative thoracic EBRT for non-small cell lung cancer (NSCLC), a strong consensus was reached among the task force on recommendations for incurable stage III and IV NSCLC. For patients with stage III NSCLC deemed unsuitable for curative therapy but who are (1) candidates for chemotherapy, (2) have an Eastern Cooperative Oncology Group PS of 0 to 2, and (3) have a life expectancy of at least 3 months, administration of a platinum-containing chemotherapy doublet concurrently with moderately hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone. For patients with stage IV NSCLC, routine use of concurrent thoracic chemoradiation is not recommended. ConclusionsOptimal palliation of patients with incurable NSCLC requires coordinated interdisciplinary care. Recent data establish a rationale for CC with palliative thoracic EBRT for a well-defined subset of patients with incurable stage III NSCLC. For all other patients with incurable NSCLC, data remain insufficient to support this treatment approach.

The best platinum regimens for chemo-naive incurable non-small cell lung cancer: network meta-analysis

Platinum regimens still play a key role in chemotherapy for incurable non-small cell lung cancer (NSCLC). Although guidelines list many platina regimens, the best regimens have not yet clarified. Electronic searches were carried out during November 26th-28th, 2016. We included individually randomized trials comparing two or more platinum regimes for incurable chemo-naive NSCLC published in English full papers. The platinum doublets should be either Cisplatin (CDDP), Carboplatin (CBDCA), or Nedaplatin (CDGP) plus one of the third-generation agents. The platinum triplet should be the doublet plus bevacizumab (BEV). The data were independently extracted and cross-checked by two investigators. We did not observed heterogeneity (whole network level Q = 28.9, df = 34, P = 0.717) among 59 pairwise comparisons from 45 studies with 16141 cases for the primary outcome, hazard ratio for overall survival (HRos). Using CBDCA + Paclitaxel (PTX) + BEV as a common comparator, CDGP + Docetaxel (DTX) (HRos = 0.98, 95%CI: 0.75–1.29, P = 0.884), CDDP + Tegafur gimeracil oteracil (S1) (HRos = 1.23, 95%CI: 0.96–1.57, P = 0.099), CBDCA + S1 (HRos = 1.23, 95%CI: 0.99–1.53, P = 0.062), and CDGP + Gemcitabine (GEM) (HRos = 1.24, 95%CI: 0.71–2.17, P = 0.45) did not have significantly poorer HRos. We suggest that these regimens as acceptable first-choice regimens.

Decision support systems for incurable non-small cell lung cancer: a systematic review

BackgroundIndividually tailored cancer treatment is essential to ensure optimal treatment and resource use. Treatments for incurable metastatic non-small cell lung cancer (NSCLC) are evolving rapidly, and decision support systems (DSS) for this patient population have been developed to balance benefits and harms for decision-making. The aim of this systematic review was to inventory DSS for stage IIIB/IV NSCLC patients.MethodsA systematic literature search was performed in Pubmed, Embase and the Cochrane Library. DSS were described extensively, including their predictors, model performances (i.e., discriminative ability and calibration), levels of validation and user friendliness.ResultsThe systematic search yielded 3531 articles. In total, 67 articles were included after additional reference tracking. The 39 identified DSS aim to predict overall survival and/or progression-free survival, but give no information about toxicity or cost-effectiveness. Various predictors were incorporated, such as performance status, serum and inflammatory markers, and patient and tumor characteristics. Some DSS were developed for the entire incurable NSCLC population, whereas others were specifically for patients with brain or spinal metastases. Few DSS had been validated externally using recent clinical data, and the discrimination and calibration were often poor.ConclusionsMany DSS have been developed for incurable NSCLC patients, but DSS are still lacking that are up-to-date with a good model performance, while covering the entire treatment spectrum. Future DSS should incorporate genetic and biological markers based on state-of-the-art evidence, and compare multiple treatment options to estimate survival, toxicity and cost-effectiveness.

PROGNOSIS IN ADVANCED NON-SMALL CELL LUNG CANCER - A RETROSPECTIVE STUDY EXAMINING ECOG PERFORMANCE STATUS SCORES OF PATIENTS

Objective: Increasing prevalence and poor survival of advanced incurable non-small cell lung cancer (NSCLC) make it a major health problem globally, especially in developing countries. This awakens need for identification of the strongest prognostic factor that helps in the selection of appropriate treatment and hence palliates symptoms and improves survival. Lung cancer treatment guidelines advise performance status (PS) as the most established prognostic factor in advanced NSCLC patients. This study investigated the prognostic significance of PS.Methods: An observational study was done for 163 advanced NSCLC adult Malaysian patients in Radiotherapy and Oncology Clinic, Hospital Kuala Lumpur, Malaysia. Demographic and clinical data were recorded. Kaplan-Meier test was used to measure median overall survival (OS) and Cox proportional hazard model to calculate the hazard ratio for different categories of Eastern Cooperative Oncology Group (ECOG) PS.Results: The mean age and body weight were 56.7±10.1 years old and 57.42±13.5 kg, respectively. Majority patients were male (68.7%), Stage IV NSCLC (65.0%), and ECOG PS score of 2 (41.1%). ECOG PS had a significant association with age and body weight. Median OS was least for ECOG PS score of 4 (253 days) and was statistically significant (p=0.003). ECOG PS was a significant independent prognostic factor for survival in advanced NSCLC patients (p&lt;0.001).Conclusion: PS is a strong prognostic factor in advanced NSCLC.

Palliative systemic therapy for advanced non-small cell lung cancer: Investigating disparities between patients who are treated versus those who are not

BackgroundPalliative systemic therapy (ST) in advanced non-small cell lung cancer (NSCLC) is associated with improved overall survival (OS) and quality of life, yet many patients remain untreated. We explored differences between patients who did and did not receive palliative ST in order to gain evidence to support and advocate for the untreated. MethodsWe performed a retrospective analysis of newly diagnosed patients with advanced, incurable NSCLC seen as outpatients at our institution between 2009 and 2012. Demographics, treatment, and survival data were collected. Results528 patients were seen: 291 (55%) received palliative ST, while 237 (45%) received none. Demographics were as follows: Median age 67, 55% male, 50% ECOG performance status (PS) 0–1, 48% with weight loss. Untreated patients were older (median 71 vs. 64, p<0.01), less fit (PS 0–1 in 27% vs. 69%, p<0.01), and more likely to have lost weight (57% vs. 41%, p<0.01). Reasons for no treatment included poor PS (67%) and patient choice (23%). Median OS was shorter amongst untreated patients (3.9 vs. 10.7 months, HR 1.80 [95% CI 1.4–2.3], p<0.01). In multivariate analysis, not receiving ST was associated with shorter OS. ConclusionUnsurprisingly, untreated patients had poorer prognostic features and worse OS. However, it is concerning that, despite being seen in an active academic center, nearly half of all referred patients with advanced NSCLC received no anti-cancer treatment. Current research primarily seeks to improve outcomes in treated patients with good PS. This review suggests that this is an inappropriate allocation of research effort. Our research should be more equitably split between good and poor performance patient groups if we are to improve the survival of all patients with advanced NSCLC. Potential strategies include more rapid diagnosis prior to functional decline, and the development of therapies effective and tolerated in a sicker population.

Efficacy and Tolerability of Palliative Split-Course Thoracic Chemoradiotherapy for Symptomatic Non–Small Cell Lung Cancer

To assess the efficacy and tolerability of palliative split-course concurrent thoracic chemoradiotherapy (CRT) in patients with incurable locally advanced and metastatic non-small cell lung cancer. All patients with incurable non-small cell lung cancer and symptomatic thoracic disease treated with palliative split-course CRT between March 2006 and February 2013 at a single institution were included in this retrospective study. The primary endpoint was improvement in presenting thoracic symptoms. Secondary endpoints included toxicity, overall survival, and the cumulative incidence of locoregional failure. Fifty-five patients were identified, of whom 89% had distant metastatic disease at the initiation of treatment. The median radiotherapy dose delivered was 40 Gy over 20 fractions. Over 90% of patients were able to complete at least 2 cycles of chemotherapy, and 89% of patients completed the prescribed course of radiotherapy. Forty percent of patients had improvement in all presenting symptoms and 78% experienced improvement in at least 1 symptom. Nine and 2 patients, respectively, experienced grade 1 and 2 esophagitis and 1 patient experienced grade 2 pneumonitis. There were no cases of grade 3 toxicity. With a median follow-up for surviving patients of 4.5 months, the estimated actuarial 6-, 12-, and 24-month overall survival was 56%, 25%, and 13%, respectively. The actuarial 6-, 12-, and 24-month cumulative incidence of locoregional failure was 6%, 14%, and 22%, respectively. Split-course CRT allows for early introduction of systemic therapy while providing durable locoregional control with tolerable morbidity and significant improvement in chest symptomatology. This paradigm is a viable model for chest palliation in selected patients with intact performance status.

Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer.

Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. This is an update of a Cochrane review first published in 2001 and previously updated in 2006. The two objectives of this review were:1. To assess the effects of different palliative radiotherapy regimens on improving thoracic symptoms in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent.2. To assess the effects of radiotherapy dose on overall survival in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent. The electronic databases MEDLINE (1966 - Jan 2014), EMBASE and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished.Two authors (FM and RS) independently identified all studies that may be suitable for inclusion in the review.We updated the search up to January 2014. Randomised controlled clinical trials comparing different regimens of palliative thoracic radiotherapy in patients with non-small cell lung cancer. The reviewers assessed search results independently and possible studies were highlighted and the full text obtained. Data were extracted and attempts were made to contact the original authors for missing information.The primary outcome measure was improvement in major thoracic symptoms (degree and duration). Secondary outcome measures were short and long term toxicities, effect on quality of life and overall survival.Patient reported outcomes were reported descriptively. Quantitative data such as survival and toxicity were analysed as dichotomous variables and reported using relative risks (RR).For this update of the review a meta-analysis of the survival data was carried out. Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update.There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens.Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop-outs were accounted for in all but one study.All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta-analysis should be treated with caution.Meta-analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence.The meta-analysis showed no significant difference in 1-year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta-analysis of 1-year overall survival for patients with good performance status (WHO performance status 0-1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1-year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence). Radiotherapy for patients with incurable non-small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

Montreal prognostic score: estimating survival of patients with non-small cell lung cancer using clinical biomarkers

Background:For evidence-based medical practice, well-defined risk scoring systems are essential to identify patients with a poor prognosis. The objective of this study was to develop a prognostic score, the Montreal prognostic score (MPS), to improve prognostication of patients with incurable non-small cell lung cancer (NSCLC) in everyday practice.Methods:A training cohort (TC) and a confirmatory cohort (CC) of newly diagnosed patients with NSCLC planning to receive chemotherapy were used to develop the MPS. Stage and clinically available biomarkers were entered into a Cox model and risk weights were estimated. C-statistics were used to test the accuracy.Results:The TC consisted of 258 patients and the CC consisted of 433 patients. Montreal prognostic score classified patients into three distinct groups with median survivals of 2.5 months (95% confidence interval (CI): 1.8, 4.2), 8.2 months (95% CI: 7.0, 9.4) and 18.2 months (95% CI: 14.0, 27.5), respectively (log-rank, P<0.001). Overall, the C-statistics were 0.691 (95% CI: 0.685, 0.697) for the TC and 0.665 (95% CI: 0.661, 0.670) for the CC.Conclusion:The MPS, by classifying patients into three well-defined prognostic groups, provides valuable information, which physicians could use to better inform their patients about treatment options, especially the best timing to involve palliative care teams.

A phase I/II trial combining erlotinib with gamma secretase inhibitor RO4929097 in advanced non-small cell lung cancer (NSCLC).

8104 Background: All NSCLC patients treated with erlotinib (E) eventually develop resistance. Both the epithelial-mesenchymal transition (EMT) and cancer stem cells may contribute to resistance to E. The Notch pathway plays a key role in maintaining stem cell viability and in EMT. Gamma secretase inhibitors such as RO4929097 (R) inhibit Notch activity by preventing cleavage of Notch to its active form. In this CTEP-sponsored study, primary endpoint of phase I was to determine maximum tolerated dose (MTD) of the combination of E and R; primary endpoint of phase II was response rate. Methods: Eligible pts had incurable NSCLC, measurable disease, ECOG PS 0-1, and adequate laboratory parameters. There were no limits on prior therapy. All pts were required to have a tumor biopsy. Patients received E PO daily on a continuous schedule and R PO daily on days 1-3, 8-10, and 14-17 of a 21 day cycle. Dose cohorts (E/R both in mg) were as follows: 100 /20, 150/20, 150/30, 150/45. Imaging was performed every 6 weeks. Patients could remain on therapy until progression. Results: 21 pts were enrolled between 9/2010 and 3/2012. 5 were not eligible and did not receive treatment. For the 16 treated pts: median age was 61 yrs (40-75), 7 (44%) were male, 14 (88%) had adenocarcinoma. All pts had received prior chemotherapy (1-8 regimens); 7 (44%) had prior E. 3 pts had known EGFR mutations; 2 pts had KRAS mutations. Time on therapy ranged from 20 to 248 days. Median PFS was 42 days. Pts with prior progression on E had a median PFS of 64 days. 1 pt (6%) had a partial response, 4 (19%) had stable disease at 6 weeks. Median overall survival is 6.5 months (1.3 to 24.5+ months). Observed dose-limiting toxicity was hypophosphatemia in 1 pt in 150/45 cohort. Other toxicities included rash, neuropathic pain and nausea. MTD was determined to be 150/45. The study was halted early, after completion of the phase I cohort, as production of R was discontinued by the manufacturer. 12 pts (75%) have adequate tumor tissue for analyses. Biomarker studies are pending. Conclusions: Combination of R and E is safe and feasible in pts with NSCLC. Though development of R has been discontinued, other drugs targeting the Notch pathway are in development (NCI R21CA153017). Clinical trial information: NCT01193881.

PC-FACS

PC-FACS

1200P - Concomitant Chemoradiation gives Significant Survival and Hrqol Benefits in Patients with Locally Advanced Stage III Non Small Cell Lung Cancer (NSCLC) Not Eligible for Radical Treatment: A Randomized Trial by the Norwegian Lung Cancer Study Group

ABSTRACT Background In patients with locally advanced, inoperable NSCLC and negative prognostic factors, treatment will be of palliative intent. Platinum-based chemotherapy and thoracic radiation are both well documented, but the role of chemoradiation has not been established. Objective: Will concomitant radio- and chemotherapy (chemoradiation), when compared to chemotherapy alone, be superior with respect to survival and health-related quality of life (HRQOL) in patients with incurable NSCLC stage III (negative prognostic factors)? Methods Stage III NSCLC patients, not eligible for curative radiotherapy due to tumor size ≥ 8 cm or performance status 2 or weight loss ≥ 10 % during the last 6 months, were randomized to receive either chemoradiation or chemotherapy alone. Chemotherapy consisted of 4 cycles of carboplatin iv day 1 and vinorelbine po day 1 and 8, with 3-week intervals. Patients in the chemoradiation arm also received radiotherapy with fractionation 42 Gy/2.8 Gy, starting at the 2nd chemo course. The primary endpoint was overall survival. Secondary endpoints were HRQOL and toxicity. Results 191 patients from 25 Norwegian hospitals were randomized from Nov 2006 until Nov 2011, when enrollment was terminated due to slow accrual. Median age was 67 years and 20% had PS 2. In the chemotherapy versus the concomitant arm, the median overall survival was 9.7 and 13.3 months, respectively (p Conclusions Of the 2 investigated treatment regimens; chemoradiation was superior to chemotherapy alone with respect to both survival and global HRQOL, at the expense of more hospital admissions due to toxicity. Disclosure All authors have declared no conflicts of interest.

A randomized double-blind trial of carboplatin plus paclitaxel (CP) with daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo (PLA) in patients (pts) with previously untreated advanced non-small cell lung cancer (NSCLC): NCIC Clinical Trials Group study BR29.

7511 Background: In NCIC CTG study BR24, CED 30 mg/d + CP increased objective response rate (RR) and progression-free survival (PFS), but there were concerns regarding toxicity in some pts. BR29 tested a lower dose of CED 20 mg/d limiting accrual to pts without significant weight loss/hypoalbuminemia. Methods: Consenting, eligible adult pts with advanced incurable NSCLC of any histology were randomized to receive CED 20 mg/d or PLA with up to 6 cycles of C (AUC = 6) P (200 mg/m2); non-progressing pts continued CED/PLA after CP until progression, unacceptable toxicity or pt request. The primary endpoint was overall survival (OS). An interim analysis (IA) for PFS was planned after 170 events in the first 260 pts; the study would continue if the hazard ratio (HR) for PFS was &lt; 0.7. Accrual continued until the required number of events was reached then held pending IA. Results: The trial was halted when the IA (n=260) revealed a HR for PFS of 0.89 (95% CI 0.66-1.20). A final analysis including all 306 randomized pts (median age 62, male 55%, PS 0 26%, PS 1 74%, adenocarcinoma 64%, squamous 13%, other histology 23%. RR was significantly higher with CED (52% vs 34 %, p = 0.001). For CED/PLA, respectively, median OS and PFS were 12.2/12.1 [HR: 0.95 (0.69-1.30, p=0.74)] and 5.5/5.5 months [HR: 0.91 (0.71-1.18, p=0.5)]. Grade &gt;3 hypertension (15% vs 3%, p=0.0002), anorexia (7% vs 1%, p=0.02) and diarrhea (16% vs 1%, p&lt;0.0001) were all significantly increased with CED; there were 2 deaths possibly-related to CED [1 each hemorrhage, leukoencephalopathy (prior radiation)]. Conclusions: Adding a lower dose of CED to CP increased RR and toxicity, but not PFS or OS.

Radiation therapy at the end of life in patients with incurable nonsmall cell lung cancer

Receipt of chemotherapy at the end of life (EOL) is considered an indicator of poor quality of care for medical oncology. The objective of this study was to characterize the use of radiotherapy (RT) in patients with nonsmall cell lung cancer (NSCLC) during the same period. Treatment characteristics of patients with incurable NSCLC who received RT at the EOL, defined as within 14 days of death, were analyzed from the National Comprehensive Cancer Network NSCLC Outcomes Database. Among 1098 patients who died, 10% had received EOL RT. Patients who did and did not receive EOL RT were similar in terms of sex, race, comorbid disease, and Eastern Cooperative Oncology Group performance status. On multivariable logistic regression analysis, independent predictors of receiving EOL RT included stage IV disease (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.09-3.83) or multiorgan involvement (OR, 1.75; 95% CI, 1.08-2.84) at diagnosis, age <65 years at diagnosis (OR, 1.85; 95% CI, 1.21-2.83), and treating institution (OR, 1.24-5.94; P = .02). Nearly 50% of EOL RT recipients did not complete it, most commonly because of death or patient preference. In general, EOL RT was received infrequently, was delivered more commonly to younger patients with more advanced disease, and often was not completed as planned. There also was considerable variation in its use among National Comprehensive Cancer Network institutions. Next steps include expanding this research to other cancers and settings and investigating the clinical benefit of such treatment.