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After weeks under lockdown, metropolitan areas fighting the spread of COVID-19 aim to balance public health goals with social and economic standards for well-being. Mathematical models of disease transmission seeking to evaluate mitigation strategies must assess the possible impacts of social distancing, economic lockdowns and other measures. However, obscure relations between model parameters and real-world phenomena complicate such analyses. Here, we use a high-resolution metapopulation model of Guadalajara (GDL, Western Mexico) to represent daily mobility patterns driven by economic activities and their relation to epidemic growth. Given the prominence of essential activities in the city’s economy, we find that strategies aiming to mitigate the risk of out-of-home interactions are insufficient to stop the catastrophic spread of COVID-19. Using baseline reproduction numbers R0 = [2.5, 3.0] in the absence of interventions, our simulations suggest that household transmission alone can make Rt ∼ 1, and is estimated to drive 70 ±15% of current epidemic growth. This sets an upper bound for the impact of mobility-based interventions, which are unlikely to lower Rt below 1.3 and must be complemented with aggressive campaigns for early case detection and isolation. As laboratory testing and health services become insufficient to meet demand in GDL and most other cities, we propose that cities facilitate guidelines and equipment to help people curb spreading within their own homes. Postponing these actions will increase their economic cost and decrease their potential returns.Author summaryPublic health strategies to mitigate the spread of COVID-19 in metropolitan areas have focused on preventing transmission in schools, work sites and other public spaces. Here, we use a demographically- and spatially-explicit model of Guadalajara (GDL, Western Mexico) to represent economic lockdowns and their impact on disease spread. Our findings suggest that viral exposure within households accounts for 70±15% of the epidemic’s current growth rate. This highlights the importance of early case detection and isolation as necessary measures to prevent the spread of COVID-19 between strangers and close contacts alike.

Background Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stag...

In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC.Patients received up to six 21-day cycles of P 200mg/m131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive.The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway.

We proposed a novel algorithm to generate multifractal traffic finite-length traces.The algorithm is based on the MultiFractal Hurst model and Multifractal Wavelet Model.To validate the algorithm, a trace with specific parameters values is synthetized.The main contribution is to allow adjusting the Hurst parameter and spectrum width. The available multifractal traffic finite-length time series to implement performance test of the management, control and admission algorithms, and level of service about M/M/1 models for WAN/LAN communication systems are very few and their recollection through current mechanisms is very slow due to the amount of data that must be obtained. Hence, it is necessary to develop a tool which synthesizes traces with multifractal features and allows the stochastic parameters configuration as its average, Hurst parameter and, multifractal spectrum width. This article describes the development of a proposed algorithm to generate multifractal traffic finite-length time series with a Hurst parameter and the multifractal spectrum width, sampling and adjustable, called MultiFractal Hurst Spectrum Width (MFHSW). The MFHSW algorithm is based on the MultiFractal Hurst model (MFH) and on the Multifractal Wavelet Model (MWM), to construct the time series through a binomial multiplicative cascade. The main contribution of the MFHSW algorithm is to allow adjusting both the Hurst parameter and the multifractal spectrum width, the aforementioned is achieved by appropriately modifying the beta distributions that conform the binomial cascade. Consequently, the impact developed by the algorithm to the trace generation with multifractal features will be the improvement in the simulation and data network modeling.The MFHW algorithm behaves as an expert system when inferring to distribution of the beta coefficients present in the scales that make part of the binomial cascade starting from the stochastic parameters configured by the user, and obtaining the corresponding time series through an inference engine. To validate the algorithm effectiveness, a trace with the Hurst parameter sampling and the multifractal spectrum width similar to the presented in a network traffic time series are synthetized. The MFHSW happens to be a promising tool for the modeling of time series applicable to diverse fields as the traffic engineering, finances, biomedical signals, among other real traces with multifractal features.

Purpose Epidermal growth factor receptor (EGFR) mutations confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced non–small-cell lung cancer (NSCLC). There are limited and conflicting reports on the frequency of EGFR mutations in Latinos. Patients and Methods Samples from 642 patients with NSCLC from seven institutions in the United States and Latin America were assessed for EGFR mutations (exons 18 to 21) at Clinical Laboratory Improvement Amendments-certified central laboratories. Results EGFR mutation analysis was successfully performed in 480 (75%) of 642 patients; 90 (19%) were Latinos, 318 (66%) were non-Latino whites, 35 (7%) were non-Latino Asians, 30 (6%) were non-Latino blacks, and seven (2%) were of other races or ethnicities. EGFR mutations were found in 21 (23%) of 90 Latinos with varying frequencies according to the country of origin; Latinos from Peru (37%), followed by the United States (23%), Mexico (18%), Venezuela (10%), and Bolivia (8%). In never-smoker Latinos and Latinos with adenocarcinoma histology, EGFR mutation frequencies were 38% and 30%, respectively. There was a significant difference in the frequency of EGFR mutations among the different racial and ethnic subgroups analyzed (P < .001), with non-Latino Asians having the highest frequency (57%) followed by Latinos (23%), non-Latino whites (19%), and non-Latino blacks (10%). There was no difference between Latinos (23%) and non-Latinos (22%; P = .78) and Latinos and non-Latino whites (P = .37). Patients from Peru had an overall higher frequency of mutations (37%) than all other Latinos (17%), but this difference only exhibited a trend toward significance (P = .058). Conclusion There was no significant difference between the frequency of EGFR mutations in NSCLC in Latinos and non-Latinos.

BACKGROUND. Seribantumab (MM‐121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)‐mediated ErbB3 signaling and induce receptor downregulation. This open‐label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non‐small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild‐type tumors and describe the potential predictive power of HRG. MATERIALS AND METHODS. Patients with EGFR wild‐type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. RESULTS. One hundred twenty‐nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression‐free survival (PFS) in the unselected intent‐to‐treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p = .059, HRG‐by‐treatment interaction, p value = .0016). CONCLUSION. The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). IMPLICATIONS FOR PRACTICE. The poor prognosis of patients with non‐small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open‐label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin‐positive advanced adenocarcinoma.

Purpose We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. Patients and Methods We enrolled patients with advanced non–small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. Results Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). Conclusion This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.

Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%–50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049). Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. ©2014 AACR.

Lung cancer patients suffer considerable morbidity and mortality along with substantial psychological distress [1]. Lung cancer patients with diagnoses of depression experience greater mortality than their non-depressed peers [2], but the causes of this increased mortality are not well understood. For patients with advanced stage non-small cell lung cancer (NSCLC), platinum-based chemotherapy prolongs survival, improves symptom control, and yields superior quality of life compared to best supportive care [3]. The utilization of chemotherapy and patient factors impacting its receipt have not been characterized in depressed patients. The National Comprehensive Cancer Network (NCCN) has established Clinical Practice Guidelines for the treatment of lung cancer [3]. Previous studies have revealed that patients’ age and comorbidities affect receipt of recommended therapies [4], which is in accordance with guidelines. Other patient characteristics, such as black race, reduce the likelihood of chemotherapy receipt and represent an important treatment disparity [5–7]. It is unclear to what extent patients’ psychological comorbidities, such as a diagnosis of depression, influence utilization of guideline recommended chemotherapy. In addition, interactions between patient characteristics, such as race and depression, and their impact on chemotherapy receipt have not been explored. We examined chemotherapy receipt among lung cancer patients with a diagnosis of depression, including an analysis of patient risk factors associated with reduced receipt, in order to determine if differences in receipt may contribute to increased mortality.

This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) and paclitaxel (P).Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m(2)) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m(2) in combination with standard doses of C (AUC6) and P (200 mg/m(2)) for six cycles. S was administered as a continuous intravenous infusion (CIVI) over 72 h in 21-day treatment cycles. Study end points included safety and toxic effect, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates.Treatment with S was well tolerated, and toxic effects were mostly hematological in the phase II study. Two (11%) partial responses were observed with a median PFS of 5.7 months and median OS 16.1 months. Pharmacodynamic analysis did not demonstrate an association with response.The combination of S (10 mg/m(2)/day 72-h CIVI) administered with C and P every 3 weeks exhibited a favorable safety profile but failed to demonstrate an improvement in response rate in advanced NSCLC.NCT01100931.

IntroductionThe Eastern Cooperative Oncology Group (ECOG) 4599 study showed a significant survival benefit with the use of bevacizumab (BV) in combination with carboplatin and paclitaxel (CP) in comparison with CP chemotherapy alone in patients with previously untreated advanced, metastatic or recurrent non–small-cell lung cancer (NSCLC). Such results were achieved using BV as maintenance therapy until progressive disease. Because current data on single-agent BV maintenance in non–small-cell lung cancer are limited, we present a retrospective analysis of safety and efficacy outcomes for patients who received maintenance BV after induction treatment and the maintenance-eligible population of the control arm in ECOG 4599.MethodsLandmark analyses were conducted in patients in both the CP and CP+BV groups who were alive and progression free through the completion of six cycles + 21 days. The BV maintenance population consisted of patients in the CP+BV arm, who were alive without progressive disease before the start of maintenance (maintenance-nonprogressor population). CP nonprogressors were those patients in the CP-alone arm without progressive disease after six cycles of CP + 21 days.ResultsTwo hundred and seventeen patients (51%) were alive, progression free, and eligible for maintenance therapy six cycles + 21 days after induction CP+ BV compared with 134 patients (30%) in the CP-alone arm. Postinduction progression-free survival was significantly longer in the BV maintenance group relative to CP nonprogressors (4.4 versus 2.8 months; hazards ratio [HR] 0.64; p < 0.001). One-year overall survival rates were 75% for the BV maintenance group versus 69% in the CP nonprogressor group. Two-year overall survival rates were 34% for the BV maintenance group versus 25% in the CP nonprogressor group. Median postinduction overall survival (OS) was also significantly longer for the BV-maintenance group compared with CP nonprogressors (12.8 versus 11.4 months; HR 0.75; p = 0.030). Within the subgroup having complete response or partial response after induction, the progression-free survival and OS hazard ratio estimates were 0.59 (95% [confidence interval] CI: 0.41–0.84) and 0.78 (95% CI: 0.53–1.14), respectively. In the maintenance setting, BV was associated with a less-than 1% rate of grade 3 or 4 hematological toxicities, no grade 3 or 4 nausea, vomiting or diarrhea, and no grade 5 toxicities.ConclusionsIn this retrospective analysis of patients in the ECOG 4599 study, who were alive, progression free, and on-study 21 days after six cycles of induction therapy, significant reductions in HRs for progression (0.64, p < 0.001) and survival (0.75, p = 0.03) were associated with BV treatment during induction and maintenance compared with CP induction therapy alone and suggestive of possible benefit because of bevacizumab maintenance.

ACTH-producing neuroendocrine tumor (NET) of the thymus is a rare cause of Cushing's syndrome (CS). The literature consists mainly of isolated case reports.We studied 12 cases (eight males and four females) diagnosed between 1986 and 2010 with CS and thymic NET who underwent surgical resection.We measured time from onset of CS to diagnosis of thymic NET, tumor size, histological grade, time to recurrence, and survival and performed a meta-analysis of other published cases of CS associated with thymic NET.Eleven of 12 patients presented with classic features of CS at a median age of 21 yr (range, 7-51). Four were children. The 24-h urine free cortisol was greater than 16-fold of normal, and biochemical testing was consistent with ectopic ACTH production in all 11. Another patient presenting with pulmonary embolus had a thymic mass and was later diagnosed with CS. All patients underwent thymectomy, and nine of 10 tumors exhibited positive ACTH immunochemistry. Median tumor diameter was 5 cm (range, 1-11.5). Six patients recurred 20-28 months after surgery with metastases to mediastinal lymph nodes (n = 5), bone (n = 5), liver (n = 1), parotid gland (n = 1), and breast (n = 1). Four of five patients treated with radiation therapy also received chemotherapy. All recurrent patients received ketoconazole; four later underwent bilateral adrenalectomy. Six recurrent patients died 22-90 months (median, 57) after thymectomy. At last review, six patients were alive 14-90 months (median, 49) after thymectomy. These data are similar to those from the meta-analysis.Thymic ACTH-producing NET is an aggressive disease that should be considered in CS with ectopic ACTH secretion, particularly in younger patients.

Preclinical models and data from clinical trials suggest that cancer is a preventable disease. However, demonstration of a preventive effect requires large phase III clinical trials of long duration and involves many thousands of participants. The decision to proceed with phase III studies therefore must be informed by robust efficacy and safety data. This requires a systematic review of all available preclinical, epidemiological, and clinical data, along with a mechanistic understanding of the biology of the disease under study. In this review we identify the issues that are critical to decision-making prior to embarking on late phase prevention clinical trials and provide a framework for making such decisions.

Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non–small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (6; P = 0.028). Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition. Clin Cancer Res; 17(5); 1190–9. ©2011 AACR.

Introduction: Atezo (anti-PD-L1) + bev + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L non-squamous mNSCLC in the randomized Ph 3 IMpower150 study regardless of PD-L1 expression. This analysis aims to further understand the efficacy of atezo + bev + chemo in key subgroups: PD-L1 expression subgroups defined by the SP142 and SP263 IHC assays, patients with EGFR/ALK genetic alterations and patients with liver metastases at baseline. Methods: Pts received atezo 1200 mg + bev 15 mg/kg + carboplatin (C) AUC 6 + paclitaxel (P) 200 mg/m2 (Arm B) or bev + C + P (Arm C) IV q3w. A co-primary endpoint (EP) was PFS in the ITT-WT (EGFR or ALK wild-type pts); a secondary EP was PFS in subgroups defined by PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) with SP142. Retrospective analysis with SP263 was a prespecified exploratory EP. Results: In Arms B and C of the ITT-WT (n = 692), 503 pts had available tumor sections for SP263 testing (BEP). Pt characteristics in the ITT-WT and BEP were similar. A similar PFS benefit was observed for Arm B vs C across all PD-L1 expression subgroups defined by either assay, including pts with PD-L1-negative and PD-L1-low tumors (Table). PFS benefit with Arm B vs C was also observed in patients with EGFR or ALK genomic alterations, including patients with actionable EGFR mutations, and in patients with liver metastases at baseline (Table). Conclusion: PFS benefit with atezo + bev + chemo was observed across all PD-L1 subgroups, regardless of the IHC assay used. Additionally, clinically meaningful PFS benefit was observed in patients with EGFR/ALK genomic alterations, and in patients with liver metastases with this combination. Table. PFS in Biomarker Subgroups and Other Subgroups of Interest in IMpower150Median PFS, moPFSan (%)HRb (95% CI)P ValueArm BArm CITT-WT692 (100%)0.62 (0.52, 0.74) Citation Format: Marcin Kowanetz, Mark A. Socinski, Wei Zou, Mark McCleland, Nancy Yang, Ariel Lopez Chavez, Alexander Spira, Julien Mazières, Fadi Braiteh, David Shames, Alan Sandler, Martin Reck. IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT076.

9047Background: Atezo (anti–PD-L1) + bev (anti-VEGF) + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L nonsquamous mNSCLC in the randomized, Phase III IMpower150 study. PRO data, inclu...

9002Background: Atezo (anti–PD-L1) inhibits PD-L1 to restore anticancer immunity; bev may enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumor infiltration. IMpower150 is the first randomized Ph 3 trial evaluating atezo + chemo (carboplatin [C] + paclitaxel [P]) ± bev vs CP + bev in 1L NSQ NSCLC. PFS benefit was observed with atezo + CP + bev vs CP + bev regardless of PD-L1 expression. Here we present the IMpower150 interim OS results. Methods: 1202 patients (pts) received atezo 1200 mg + C AUC 6 + P 200 mg/m2 (Arm A) or atezo + CP + bev 15 mg/kg (Arm B) vs CP + bev (Arm C) IV q3w for 4 or 6 cycles per investigator (INV); then maintenance atezo, atezo + bev, or bev, respectively. Co-primary endpoints were INV-assessed PFS in the ITT-WT (EGFR/ALK WT) and in WT pts with expression of a tumor T-effector gene signature (Teff-high WT) and OS in the ITT-WT. Data cutoff: 1/22/2018. Results: 349, 359, and 337 ITT-WT pts were enrolled in Arms A, B, and C, respectively, with median...

Basket trials investigate the effects of targeted therapies against specific molecular alterations across multiple histologic subtypes, including tumors arising in parallel from different primary organs. The rationale is that the presence of a specific molecular aberration would predict the response to a targeted therapy regardless of the histologic subtype. Patient enrollment in basket trials is based on the molecular profiles of their tumors. The CUSTOM (Molecular Profiling and Targeted Therapies in Advanced Thoracic Malignancies) trial used a basket trial design to simultaneously evaluate targeted therapies in patients with advanced non–small-cell lung cancer, small-cell lung cancer, and thymic malignancies; patients were grouped by molecular alterations along with tumor histology. Stenzinger et al raise concerns about the viability of basket trial designs in their current form: directing targeted treatments of patients with disparate histologies on the basis of single genetic alterations to address the mutational complexity of cancer. We fully agree. As Stenzinger et al point out, the biologic relevance of molecular drivers has been reported to vary between tumors arising from different primary sites; for example, the effect of BRAF V600E is different in nevi, malignant melanoma, and colorectal cancer. Further extending these observations are reports that show the effect of coexisting mutations in determining response to the same targeted therapy, even among primary cancers that harbor identical genetic mutations. In KRAS-mutant non–small-cell lung cancer, for example, therapeutic response to a combination of the MEK inhibitor selumetinib and docetaxel has been reported to vary, depending on concurrent alterations in tumor suppressor genes, including P53 and LKB1; in KRAS-/P53-mutant mice, selumetinib plus docetaxel led to responses in 61% of mice whereas only 33% of mice with KRAS-/ LKB1-mutant cancers achieved a partial response with the combination. Indeed, most basket trial designs ignore the biologic context not only with respect to coexisting mutations but also with respect to other interactions that may have an impact on the clinical response, including the proteome, epigenome, and the immune milieu. Basket trials are a relatively new and evolving area in oncology trial design. Treatment arms of basket trials will show clinical efficacy only when the tumor depends on the target pathway and the targeted therapy reliably inhibits the target. Basket trial designs are therefore best used to identify early signals of clinical activity of targeted therapies with a small number of patients and to validate a clinical target. This is particularly useful when the cancer type or the mutation is rare. So where do we go from here with basket trials? Future basket trials, as indicated by Stenzinger et al, should use more comprehensive characterization of molecular alterations to overcome limitations of existing histology-based and single genetic alteration–based approaches. The CUSTOM trial is a necessary first step toward identifying better clinical trial designs to investigate in parallel the clinical efficacy of multiple targeted therapies in multiple cancers.

TPS8584 Background: The first-line standard of care for the majority of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide, but survival outcomes remain poor (median OS, < 1 year) despite initial response rates ranging from 50-70%. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents the binding of PD-L1 with its receptors PD-1 and B7.1 and restores anticancer T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemotherapy in NSCLC, whereby durable responses may translate into improved survival over atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC. Methods: Pts with measurable (RECIST v1.1) ES-SCLC, who have ECOG PS 0-1 and no prior systemic anticancer treatment, are eligible for the study. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. The study requires submission of tumor tissue, but pts will be enrolled regardless of biomarker status. Pts will be stratified by sex, ECOG PS and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m2 IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled. Clinical trial information: NCT02763579.

Platinum-based chemotherapy has been the standard first-line treatment for patients with advanced non-small-cell lung cancer for decades. However, a recent study has shown the superiority of gefitinib treatment in comparison with chemotherapy in a molecularly selected cohort of patients harboring sensitizing EGFR mutations. These results demonstrate the importance of incorporating molecular selection into the design of lung cancer trials that use EGFR tyrosine kinase inhibitors.

Summary Background No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Methods Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. Findings 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1–46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3–36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5–29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0–26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3–4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

Aims Among lung cancer patients, depression has been associated with increased mortality, although the mechanisms are unknown. We evaluated the association of depression with mortality and receipt of cancer therapies among depressed veterans with lung cancer. Materials and methods A retrospective, cohort study of lung cancer patients in the Veterans Affairs-Northwest Health Network from 1995 to 2010. Depression was defined by ICD-9 coding within 24 months before lung cancer diagnosis. Multivariable Cox proportional analysis and logistic regression were used. Results In total, 3869 lung cancer patients were evaluated; 14% had a diagnosis of depression. A diagnosis of depression was associated with increased mortality among all stage lung cancer patients (hazard ratio = 1.14, 95% confidence interval: 1.03–1.27, P = 0.01). Among early-stage (I and II) non-small cell lung cancer (NSCLC) patients, the hazard ratio was 1.37 (95% confidence interval: 1.12–1.68, P = 0.003). There was no association of depression diagnosis with surgery (odds ratio = 0.83, 95% confidence interval: 0.56–1.22, P = 0.34) among early-stage NSCLC patients. A depression diagnosis was not associated with mortality (hazard ratio = 1.02, 95% confidence interval: 0.89–1.16, P = 0.78) or chemotherapy (odds ratio = 1.07, 95% confidence interval: 0.83–1.39, P = 0.59) or radiation (odds ratio = 1.04, 95% confidence interval: 0.81–1.34, P = 0.75) receipt among advanced-stage (III and IV) NSCLC patients. Increased utilisation of health services for depression was associated with increased mortality among depressed patients. Conclusions Depression is associated with increased mortality in lung cancer patients and this association is higher among those with increased measures of depression care utilisation. Differences in lung cancer treatment receipt are probably not responsible for the observed mortality differences between depressed and non-depressed patients. Clinicians should recognise the significant effect of depression on lung cancer survival.

Although tumor molecular-profile-directed therapy appears promising in early clinical studies, there are many practical challenges to its successful clinical application in non-small-cell lung cancer (NSCLC). These challenges may be broadly classified as those relating to tumor (heterogeneity), tissue (acquisition and processing), testing (assays for molecular profiling) and trials (clinical evaluation of molecular markers and drugs). Strategies to overcome these challenges include (i) understanding the biological basis of tumor heterogeneity and of carcinogenesis in the large subset of patients with no currently evident driver events; (ii) technological advances in minimally invasive acquisition of tumor and next-generation sequencing (NGS) which would enable single-platform analysis of molecular alterations in limited tissue at a reasonable turnaround time (TAT); (iii) deliberation in early stages of drug development as well as clinical trial design to identify, validate and assess the clinical utility of biomarkers in conjunction with drugs and (iv) collaboration to improve understanding of and accrual to trials enrolling patients with rare molecular alterations.

Purpose Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat. Patients and Methods Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had failed were eligible for this study. Other eligibility criteria included adequate organ function and good performance status. Belinostat was administered intravenously at 1 g/m2 on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance. The primary objective was response rate in patients with thymoma. Results Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of two previous systemic regimens (range, one to 10 regimens). Treatment was well tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects. Two patients achieved partial response (both had thymoma; response rate, 8%; 95% CI, 2.2% to 25%), 25 had stable disease, and 13 had progressive disease; there were no responses among patients with thymic carcinoma. Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached v 12.4 months; P = .001). Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome. Conclusion Belinostat has modest antitumor activity in this group of heavily pretreated thymic malignancies. However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.

8051 Background: Heregulin induced activation of ErbB3 has been implicated as a mechanism of resistance to many targeted therapies such as EGFR-TKIs in preclinical models. MM-121 is a monoclonal an...

8050 Background: In NSCLC, the PDGF-PDGFR axis mediates angiogenesis, local invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3), a fully human monoclonal antibody, selectively binds hum...

TPS8126 Background: KRAS mutations have been associated with poor prognosis in NSCLC and resistance to epidermal growth factor (EGFR) tyrosine kinase inhibitors. FAK represents a therapeutic target...

e19141 Background: Advances in genetic analysis have created a successful paradigm shift in the treatment of advanced lung cancer. Prior studies characterizing molecular profiles in lung cancer have been limited by analysis of a restricted number of genes and lack of clinical outcomes correlation. To overcome these limitations, this study investigates a prospective cohort of lung cancer patients using an expanded molecular profile and evaluates clinical outcomes. Methods: Non-small cell lung cancer (NSCLC) patients enrolled from April 1, 2011 through December 31, 2012 are included in this analysis. Formalin-fixed, paraffin-embedded tumor tissue was analyzed, using mass spectrometry-based panel of multiplexed assays (through July 31, 2012) or using next-generation sequencing detecting hydrogen-ions generated during DNA polymerization (using Ion Torrent from August 1 through December 31, 2012). Clinical information was collected at enrollment and throughout the study. Results: Analysis of 229 enrolled patients revealed 52% women, 95% had ECOG performance status 0-2, 89% Caucasian, and 28% never smokers. Successful molecular analysis (at least one successful analysis) occurred in 178 patients. Fifty-one patients had insufficient tissue for any successful molecular analysis. One hundred twenty-five mutations were detected among ninety-seven patients. The most frequent mutations included KRAS (28%), TP53 (20%), EGFR (13%), ALK translocations (6%), and BRAF (3%). At the time of analysis, 49% of the study population was deceased. Of the deceased, 37% harbored at least one genetic mutation within their tumor sample. Overall survival for those with mutations was 22.7 months, compared to overall survival for those without mutations of 23.3 months. Conclusions: Our analysis contributes to the growing body of data on molecular abnormalities in NSCLC by expanding the knowledge of common and less-commonly documented mutations, as well as characterizing the clinical outcomes associated with the mutations documented. These data emphasize the diversity of mutations and outcomes for NSCLC, and highlight the need for additional research of prognostic genetic markers and improvements in targeted therapies.

6524 Background: Traditionally, the structure of clinical trials has relied upon histology as the top eligibility criterion for enrollment. While more modern trial designs (i.e. BATTLE and I-SPY2) have implemented molecular selection for treatment assignment, histology has remained at the top of the clinical trial structure (1. Histology 2. Molecular selection 3. Treatment assignment). CUSTOM is the first completed prospective clinical trial designed by implementing the ideas of mass customization and product postponement into its structure. This report discusses CUSTOM’s innovative clinical trial design strategy. Methods: In CUSTOM, the task of differentiating a particular treatment’s efficacy by statistical analysis based on histology was postponed until the latest possible point in the trial’s structure (1. Molecular selection 2. Treatment assignment 3. Histology). An optimal two-stage phase II design was used to identify compounds with high clinical activity defined by a response rate of more than 40%. Patients were eligible for enrollment regardless of performance status, previous number of therapies or organ function. Results: CUSTOM was able to enroll 668 patients in only 18 months at 2 academic institutions and conduct a parallel and simultaneous evaluation of multiple targeted therapies (5) in molecularly selected patients in 3 cancer histological types. Its design allowed for the inclusion of rare cancers resulting in the largest prospective molecularly based clinical trial in patients with thymic malignancies and small cell lung cancer. Overall, its design resulted in a more rapid, cost-effective and efficient strategy for pharmaceutical development compared to traditional approaches. Conclusions: The traditional methodology used to design and execute clinical trials (i.e., histology-driven, single treatment vs. SOC) is dated, inefficient and expensive. The CUSTOM’s clinical trial design is one approach to increase the efficiency, reduce the cost, and increase the speed of the early phase pharmaceutical development process. Clinical trial information: NCT01306045.

7513 Background: CUSTOM is the first completed prospective clinical trial using molecular selection for treatment assignments into multiple targeted therapy arms and in multiple cancer histological subtypes concurrently. Methods: All patients with advanced NSCLC, SCLC or TM were eligible to participate in the study. Oncogenic mutations, amplifications or translocations in 12 genes detected in CLIA-certified laboratories were used to assign patients to 1 of 5 biomarker/treatment groups per histological subtype: EGFR mutations/erlotinib; KRAS, NRAS, HRAS or BRAF mutations/AZD6244; PIK3CA, AKT or PTEN mutations/MK2206; ERBB2 mutations or amplifications/lapatinib; and KIT or PDGFRA mutations/sunitinib; or to standard-of-care therapy. For each arm, the study was conducted as an optimal two-stage phase II trial in favor of a response rate of 40% or more. Results: 668 patients were enrolled at two academic institutions. The most frequent genetic alterations in NSCLC were KRAS and EGFR mutations (25.2 and 19.7% respectively), ALK rearrangements 7.8%, HER2 amplifications 2.7% and mutations in PIK3CA 2.5%, BRAF 1.9%, HRAS 1.5%, ERBB2 1.7%, AKT1 0.4%, and NRAS 0.7%. PTEN mutation analysis was only feasible in 13 patients with NSCLC of which 3 were positive (23%). The most frequent genetic alterations in SCLC were mutations in PIK3CA 6.5%, ERBB2 amplifications 5.3% and mutations in HRAS 3.4%, AKT1 2.2%, BRAF 2% and KRAS 2%. The most frequent genetic alterations in TMs were HER2 amplifications 7.7% and mutations in HRAS 4.7%, PIK3CA 1.4% and EGFR 1.4%. Only 6.2% (n=42) of patients met criteria for enrollment into the treatment arms of the study. Efficacy analyses including response rates will be presented. Conclusions: CUSTOM is the first completed prospective clinical trial demonstrating the feasibility of conducting efficacy analyses of multiple biomarker-matched therapies in multiple cancer histological subtypes concurrently. CUSTOM is also the largest prospective molecular profiling study of patients with SCLC and TMs. Clinical trial information: NCT01306045.

TPS7609 Background: For decades, clinical trial design strategies have relied upon the broad classification of tumors into tumor site and histopathology. Several lines of evidence have shown that a molecular approach to patient selection may be better in its capacity to improve patient outcomes. CUSTOM is an innovative clinical trial that allows for the parallel evaluation of multiple targeted therapies in molecularly selected patients with multiple cancer histological subtypes and the prospective evaluation of multiple molecular biomarkers. Methods: All patients with advanced lung cancer and thymic malignancies and a good performance status are eligible independently of previous lines of treatment. The trial begins with tumor biopsy and molecular profiling using a multi-platform approach to identify oncogenic alterations in more than 34 genes for treatment allocation (12 genes) and exploratory purposes. Depending upon the specific biomarker identified, patients are then triaged into 5 experimental arms. Erlotinib for sensitizing EGFR mutations; AZD6244 for KRAS, NRAS, HRAS and BRAF mutations; MK2206 for PIK3CA, AKT and PTEN mutations and PIK3CA amplification; Lapatinib for ERBB2 mutations or amplification; Sunitnib for KIT mutations and PDGFRA mutations and amplification. Patients not eligible for the experimental treatment arms are enrolled into a standard treatment arm. Upon disease progression patients are eligible for repeat biopsy and molecular profiling in order to identify molecular changes and mechanisms of resistance. All patients are followed until death. The primary endpoint is response rate and secondary endpoints include progression-free survival, duration of response and overall survival. With three disease types and five experimental drugs, there are 15 possible treatment arms which will be under active consideration. For each of these, the study will be conducted as an optimal two-stage phase II trial in order to rule out an unacceptably low 10% clinical response rate in favor of a modestly high response rate of 40%. As of January 11, 2012, two hundred and sixteen patients have been enrolled.

e17511 Background: TETs are very rare anterior mediastinal tumors. Methods: We performed a retrospective review of patients (pts.) with TETs presenting to the NCI for enrollment in ongoing clinical trials, standard-of-care therapy or a second opinion. Results: Seventy-three pts. were seen between 12/2007 and 12/2010; 43 males (41%), median age at diagnosis: 48 years (range, 17 – 81). Fifty-four pts. were Caucasian (74%), 7 (10%) African-American, 8 (11%) Asian and 4 (6%) Hispanic. Histology: B1 5 (7%), B2 13 (18%), B2/B3 1 (1%), B3 9 (12%), thymic carcinoma (TC) 35 (48%), atypical carcinoid 2 (3%) and unclassified thymoma 8 (11%). Fifty pts. were enrolled in clinical trials: 28 on a phase II study of the HDAC inhibitor, belinostat (B), 27 on a phase II study of the IGF -1R inhibitor cixutumumab (C) (including 10 previously on B), 3 on a phase I study of chemotherapy (PAC) plus B and 2 on a phase II study of the cyclin-dependant kinase inhibitor PHA-848125AC. Median number of previous systemic therapy regi...

3090 Background: To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155 (Y), a small-molecule selective su...