bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes in extensive stage small cell lung cancer patients treated with thoracic radiation.
Authors: Higgins Kristin Ann , Zhang Xinyan , Jiang Renjian , Pillai Rathi Narayana , Owonikoko Taofeek Kunle , Steuer Conor Ernst , Saba Nabil F. , Pakkala Suchita , Patel Pretesh R , Belani Chandra Prakash , Khuri Fadlo Raja , Curran Walter John , Ramalingam Suresh S. , Behera Madhusmita
Published: September 2018

8565

Background: The benefit of consolidation thoracic radiation in extensive stage small cell lung cancer (E-SCLC) remains unclear. This study utilized the National Cancer Database (NCDB) to evaluate overall survival outcome (OS) for patients receiving chemotherapy (CT) alone for E-SCLC versus CT + thoracic radiation (TRT). Methods: The NCDB was queried to capture patients (pts) with stage E-SCLC from 2010-2013. Patients with brain metastases at diagnosis were excluded, as were patients receiving radiation prior to initiation of chemotherapy. Univariate association of OS was assessed using Cox proportional hazards models and log-rank tests. A multivariable Cox proportional hazard model and Kaplan-Meier analyses were performed to compare treatment with CT only to CT + TRT. Propensity score matching method was also implemented to reduce treatment selection bias. All analyses were performed using SAS Version 9.4. Results: A total of 14,367 (12,019 received CT, 2,348 received CT + TRT) pts were included in the analysis. Patient characteristics included a median age of 66 years; 66 years for pts receiving CT, and 63 for pts receiving CT + TRT (p < 0.001). Male gender comprised 51% of pts; 52% in CT group versus 49% in CT + TRT (p < 0.001). Charlson-Deyo comorbidity score was zero in 53% of all patients; 52% in the CT group versus 57% of CT + TRT group (p < 0.001). In the CT + TRT group, the median total thoracic radiation dose was 45 Gy. On multivariate analysis, CT only was associated with an increased risk of death relative to CT+ TRT (HR 1.74 [1.65 – 1.84], p < 0.001). 5 year OS was 7% vs. 2% for CT + TRT versus CT alone (p < 0.001). On propensity matched analysis, CT + TRT was associated with better 5-year OS compared to CT alone (8% vs. 2%; p < 0.001). On multivariate analysis of propensity matched samples, chemotherapy alone continued to be associated with worse survival (HR 1.76 [1.62 – 1.91], p < 0.001). Conclusions: For E-SCLC, CT alone as standard of care is associated with worse survival relative to CT + TRT.
Comparing treatment strategies for stage I small cell lung cancer: A National Cancer Database study.
Authors: Paximadis Peter Alexander , Beebe-Dimmer Jennifer Lynn , George Julie , Schwartz Ann G. , Wozniak Antoinette J. , Gadgeel Shirish M.
Published: September 2018

8566

Background: Concurrent chemoradiotherapy is the standard of care for limited stage small cell lung cancer (SCLC). The ideal treatment strategy for stage I SCLC, however, is less clear. The purpose of this study is to compare outcomes for patients receiving definitive surgery, stereotactic body radiation therapy (SBRT), or external beam radiation therapy (EBRT) for stage I SCLC using the National Cancer DataBase (NCDB). Methods: Patients with a first primary diagnosis of stage I (T1-2 N0 M0) SCLC treated between 2004 and 2013 were identified in the NCDB. Patients were defined as having a first course of treatment of either definitive surgery, EBRT (45-74 Gy in 15-40 fractions) or SBRT (40-60 Gy in ≤5 fractions). Other recorded information included age, gender, race, T stage, Charlson-Deyo score, and use of chemotherapy. Overall survival (OS) was determined using the Kaplan-Meier method and Cox proportional hazards regression methods were used to estimate risk of overall mortality. Results: A total of 5944 patients with stage I SCLC were identified; of those, 2681 fit the study criteria. The median age of patients in the cohort was 68 years and median follow up was 26.6 months. Definitive surgery was performed in 944 (35%), EBRT in 1597 (60%), SBRT in 140 (5%), and chemotherapy was delivered in 2067 (77%). The 2- and 3-yr OS for the whole cohort was 62% and 50%; 72% and 62% for surgery, 56% and 44% for EBRT, and 56% and 40% for SBRT. Patient age, female gender, Charlson-Deyo score < 2, tumor size ≤3 cm, receipt of surgery and receipt of chemotherapy were all associated with improved OS. Comparing treatment strategies in a multivariate model, surgical resection demonstrated improved OS over EBRT (HR 2.0, p < 0.001) and SBRT (HR 1.66, p < 0.001). When excluding patients who underwent surgery, SBRT demonstrated improved OS compared with EBRT (HR 1.28, p = 0.04). In addition, receipt of chemotherapy resulted in improved OS (HR 0.66, p < 0.001). Conclusions: In this hospital-based registry study, definitive surgical resection and use of chemotherapy resulted in improved survival outcomes for patients with stage I SCLC. For patients who are not candidates for surgery, SBRT may offer a survival benefit compared with standard EBRT.
Using circulating tumor DNA analysis to depict genomic profiles and predict survival outcomes in patients with small-cell lung cancer.
Authors: Wang Jinghui , Nong Jingying , Gong Yuhua , Sun Shuai , Yi Yuting , Guan Yan-Fang , Yang Ling , Jia Hongyan , Zhang Shucai , Xia Xuefeng , Yi Xin , Liao Zhongxing X.
Published: September 2018

8567

Background: Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. Most patients have extensive-stage disease with widespread metastases and poor survival. Understanding the molecular mutation profile of each SCLC patient would allow precision treatment and improved clinical outcome. However, tumor tissues from surgery are not available for most SCLC patients and biopsy specimens are often have limited quantities. Several studies have provided evidence of circulating tumor DNA (ctDNA) in detecting somatic variants of multiple solid tumors. This study evaluated utility of ctDNA to depict genomic profiles and predict survival outcomes in SCLC patients. Methods: 22 Plasma samples were obtained before initial treatment from 22 patients with SCLC enrolled between 2012 and 2016. Targeted-capture deep sequencing was performed to identify somatic variants in 465 cancer-related genes. Genomic mutation profiles were described and the clinical implications were further analyzed. Results: Tumor DNA can be detected in all 22 plasma samples collected from patients with SCLC. In total, 340 variants were identified, and the mean and median mutation rate were 6.3 and 6.6 per Mb. TP53 and RB1 are the most frequently mutated genes, detected in 90.9% (20/22) and 59.1% (13/22) patients, respectively. Further analysis showed that high ctDNA fraction in cell-free DNA (cfDNA) was associated with heavy tumor burden (R = 0.7, p = 0.0017). Moreover, patients with high ctDNA fractions (ctDNA fraction > = 18.3%) had poor progression free survival (PFS) (HR, 17.2; p = 0.0019). The median PFS of patients with high versus low ctDNA fractions was 5.2 months (95% CI 4.6 to 5.8 months) versus 10.0 months (95% CI 9.3 to 10.7 months), respectively. Conclusions: In this study, ctDNA analysis offers a promising way to depict the molecular profile in patients with SCLC. Moreover, these findings highlight the potential clinical utility of ctDNA to predicate clinical outcome in SCLC.
IFCT-GFPC-1101 trial: A multicenter phase III assessing a maintenance strategy determined by response to induction chemotherapy compared to continuation maintenance with pemetrexed in patients (pts) with advanced non-squamous (NSQ) NSCLC.
Authors: Perol Maurice , Audigier-Valette Clarisse , Molinier Olivier , Cortot Alexis B. , Margery Jacques , Moreau Lionel , Westeel Virginie , Dô Pascal , Barlesi Fabrice , Pichon Eric , Zalcman Gerard , Dumont Patrick , Girard Nicolas , Poudenx Michel , Mazieres Julien , Cadranel Jacques , Debieuvre Didier , Dauba Jérôme , Moro-Sibilot Denis , Souquet Pierre Jean ,   French Cooperative Thoracic Intergroup (IFCT)
Published: September 2018

9003

Background: Benefit coming from maintenance treatment appears greater for switch maintenance in pts with disease stabilization (SD) while it might be larger for continuation maintenance in pts with objective response (OR). This study assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG): continuation maintenance with G for pts with OR and switch maintenance with pemetrexed (P) for pts with SD compared with a control arm using P continuation maintenance following cisplatin-pemetrexed (CP) induction regimen. Methods: Eligibility criteria included age 18-70 years, PS of 0-1, untreated stage IV NSQ NSCLC without EGFR mutation or ALK rearrangement, ineligibility to bevacizumab. Pts were randomized 1:1 to receive either experimental CG arm: CG (4 cycles) followed by G maintenance in case of OR followed by second-line P or switch maintenance with P for pts with SD, or standard CP arm: 4 cycles CP induction regimen followed by maintenance P. Overall survival (OS) was the primary endpoint; secondary endpoints included PFS, response rate and safety. Results: Between Jul 2012 and Jun 2016, 932 pts were randomized (CG: 467, CP: 465). Pts characteristics were balanced between the arms. 255 pts (54.6%) in the CG arm received maintenance treatment (G: 142, P: 113) while 274 pts (58.9%) received P maintenance in the CP arm. Median number of maintenance cycles was 5 for G and 4 for P in both arms. The OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p=0.72); median OS: 10.9m CG vs. 10.4m CP. The HR for PFS was 0.96 (95% CI 0.84, 1.10; p=0.56); median PFS: 5.0m CG vs. 4.7m CP. Safety profile was as expected during induction chemotherapy. During maintenance, grade ≥3 hematological AEs occurred in 28% and 31% of pts in CG and CP, respectively, with febrile neutropenia (2.4% vs. 1.1%), anemia (9.4% vs. 11.7%), thrombocytopenia (6.7% vs. 5.8%). No grade ≥3 non-hematological AEs occurred in >5% of pts except for asthenia (3.9% CG vs. 5.1% CP). Conclusions: Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome. Clinical trial information: NCT01631136.
Characteristics and outcomes of patients (pts) with metastatic KRAS mutant lung adenocarcinomas: Lung Cancer Mutation Consortium (LCMC) database.
Authors: El Osta Badi Edmond , Behera Madhusmita , Kim Sungjin , Berry Lynne D , Sica Gabriel , Pillai Rathi Narayana , Owonikoko Taofeek Kunle , Kris Mark G. , Johnson Bruce E. , Kwiatkowski David J. , Bunn Paul A. , Khuri Fadlo Raja , Ramalingam Suresh S.
Published: September 2018

9021

Background: To better understand outcome heterogeneity in pts with KRAS mutant lung cancers, we analyzed the largest multi-institutional database of pts with metastatic KRAS mutant lung adenocarcinomas. Methods: We reviewed data of all pts who consented to LCMC between 2009-2015. Pts with known KRAS status were included in analyses. Mutation data along with co-mutations were obtained along with clinical outcomes. We evaluated baseline characteristics and association of KRAS data with overall survival (OS), calculated from date of distant metastasis to death, in a univariate and multivariable analyses. The median follow-up was 2.15 years (95% CI: 2.01-2.27). Results: 1655 (86%) of 1918 pts’ data were analyzed. Comparative characteristics are summarized in the Table. Among 450 (23%) pts with KRAS mutations: 58% female, 93% ever smokers, and median age 65 years. Main KRAS subtypes: G12C 39%, G12D and G12V were 18% each. Never smokers with KRAS mutation were more likely to have G12D subtypes (18%; p < 0.001). Pts with KRAS mutation, the median OS was 1.96 years, with 2-year OS rate of 49%. Co-mutations (1-16) were checked in all KRAS mutant pts. Co-mutations were rare (14 pts; 3%). KRAS co-mutations were associated with improved OS in multivariable analyses (HR 0.35; 95% CI: 0.13-0.97; p = 0.04), but not KRAS main subtypes / codons. Co-mutation STK-11 in particular (17 of 92 pts; 18%) was associated with poor OS in univariate (HR 2.16; 95% CI: 1.03-4.54; p = 0.04) and multivariable analyses (HR 2.31; 95% CI: 1.18-5.50; p = 0.02). Pts with KRAS mutations had a trend towards a shorter survival (median OS 1.96 vs. 2.22 years; p = 0.08) and a decreased 2-year OS when compared to KRAS wildtype [49% (95% CI: 44-54%) vs. 55% (95% CI: 52-58%)], respectively. Conclusions: KRAS mutation is a significant predictor of worse survival outcomes in pts with metastatic lung adenocarcinomas. The presence of STK-11 co-mutation was associated with especially poor OS. [Table: see text]
Lung cancers with mutations in EGFR exon 18: Molecular characterization and clinical outcomes in response to tyrosine kinase inhibitors.
Authors: Lai Wei-Chu Victoria , Ni Ai , Arcila Maria E. , Huang James , Sabari Joshua K. , Arbour Kathryn Cecilia , Rudin Charles M. , Kris Mark G. , Riely Gregory J. , Yu Helena Alexandra
Published: September 2018

9029

Background: Little data is available to guide clinical management of individuals with less common oncogenic drivers such as exon 18 mutations (ex18m) in EGFR. To better understand the impact of these rare mutations on treatment outcomes, we reviewed clinicopathologic data in patients (pts) with ex18m treated with tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancers. Methods: Pts with EGFR ex18m were detected via molecular diagnostics using Sequenom™, FoundationOne™ or MSK IMPACT™ NGS testing from 2003-2016. We reviewed their clinical data for molecular alterations in EGFR, treatment outcomes in response to TKI (time on treatment) and median overall survival (OS). Results: We identified mutations in EGFR ex18m in 63 pts. Median age at diagnosis was 68; 63% were women; 29% never smokers. Overall, 74 ex18m were found in 63 pts, including: G719A = 38, G719S = 11, G719C = 8, E709K = 6, E709_T710delinsD = 6, E709A = 3, G719D = 2. E709 and G719 co-mutations in ex18 were found in 9 pts, and 1 pt was found to have 3 separate tumors, each with a distinct ex18m. 29/63 (46%) patients with ex18m had a co-occurring EGFR mutation: 9 with another ex18m; 20 with ex19-21m. Using our IMPACT NGS, the median number of co-mutations was 8 (range 1-17). Two out of 63 pts had a pre-treatment T790M mutation. The 25 pts with non-metastatic disease presented in the following stages: IA = 19; IB = 3; IIB = 1; IIIA = 2; IIIB = 2. 34/38 pts with metastatic disease were treated with the following first-line EGFR-TKIs: erlotinib = 28, afatinib = 5, osimertinib = 1. Median duration on TKI treatment in months was: erlotinib = 10 mo, (range 1-25), afatinib = 3 mo (range 2-9), osimertinib = 4 mo. Median OS from the date of diagnosis of metastatic disease was 22 months (95% CI 18-29). In comparison, a similar cohort of pts with sensitizing EGFR exon19del/L858R mutations had a median OS of 31 months (95% CI 28-33) (Naidoo Cancer2015). Conclusions: Almost half of ex18m occur concurrently with another EGFR mutation. Overall, ex18m pts have a shorter median OS when compared to similar patient cohorts. EGFR-TKIs appear to be an effective treatment for pts with ex18m in EGFR-mutant lung cancers.
A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated non-squamous non-small cell lung cancer.
Authors: Becerra Carlos , Hanna Wahid Tewfik , Richey Stephen Lane , Cote Gregory Michael , Laurie Scott Andrew , Langleben Adrian , Gao Yuan , Li Wei , Li Youzhi , Hitron Matthew , Li Chiang
Published: September 2018

9052

Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for pts with advanced non-small cell lung cancer (NSCLC). Methods: Pts with metastatic non-squamous NSCLC were enrolled to confirm safety and preliminary anti-cancer activity. Prior platinum-based systemic therapy was required, and patients with an EGFR or ALK mutation required appropriately targeted therapy. Napabucasin was administered orally at a starting dose of 240 or 480 mg BID with PTX 80 mg/m2 IV weekly 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed every 8 weeks per RECIST 1.1. Results: A cohort of 23 pts with advanced non-squamous NSCLC was evaluated. The median number of prior systemic treatment lines was 3, including taxane-based therapy in 100% and immune checkpoint inhibitor in 48% (n = 11). Treatment was well tolerated; related grade 3 AE included diarrhea (n = 4) and fatigue (n = 1). The objective response rate was 26% (6 partial responses [PR]) and the disease control rate (DCR; proportion with SD at 8 weeks plus PR per RECIST) was 70% (n = 16). Tumor regression, including PR, occurred in 35% (n = 8). The median progression-free survival (mPFS) was 5.4 months, and 43% (n = 10) of pts were alive and free of progression at the 24 week time-point or longer. The median overall survival (mOS) was 11.0 months, and 30% (n = 7) of pts were alive for 52 weeks or longer. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with heavily pretreated non-squamous NSCLC who received napabucasin plus weekly paclitaxel. The objective response rate, progression free survival, and overall survival in this population warrant further clinical evaluation and a controlled phase 2/3 trial (CanStem43L) has been initiated. Clinical trial information: NCT01325441.
Differential crizotinib efficacy among ROS1 fusion partners in ROS1-positive non-small cell lung cancer.
Authors: Lu Shun , Li Ziming
Published: September 2018

9067

Background: ROS1 rearrangement non–small-cell lung cancers can be effectively treated with ALK inhibitor such as crizotinib, but the response magnitude and duration are heterogeneous. Several ROS1 fusion partners have been identified, but few studies have focused on the effects of different fusion partners on the efficacy of crizotinib. Methods: Among 49 RT-PCR assay ROS1 rearrangement patients treated with crizotinib between April 2014 and November 2016, we identified 36 patients with tumor specimens that could be evaluated for the presence of different ROS1 fusion partners by Sanger sequencing. Patients continued crizotinib until RECIST-defined progression. We retrospectively evaluated the efficacy of crizotinib on the basis of the objective response rate(ORR), progression-free survival (PFS) and overall survival (OS) according to the different ROS1 fusion partners. Results: The most frequent ROS1 fusion partner was CD74-ROS1 (CD74-E6; ROS1-E34) in 16 patients (44.4%), followed by EZR-ROS1 (EZR-E10; ROS1-E34) in 7 patients (19.4%), SDC4 (SDC4-E2; ROS1-E32) in 4 patients (12%), SLC34A2-ROS1 (SLC34A2-E14del; ROS1-E32) in 2 patients (5.6%) and TPM3 (TPM3-E8; ROS1-E35) in 2 patients (5.6%). We also found that SDC4+EZR (SDC4-E2; ROS1-E32/EZR-E10; ROS1-E34) in 2 patients (5.6%), dual CD74-ROS1 (CD74-E6; ROS1-E32/34) in 2 patients (5.6%), CD74+SDC4 (SDC4-E2; ROS1-E32/CD74-E6; ROS1-E34) in 1 patient (2.8%). ORR was 83.3% in all patients, whereas it was 70.58% and 92.35% in the CD74 and non–CD74 groups, respectively (P = 0.17). The median PFS was longer in non–CD74 than in those with CD74 (median PFS, 17.67 months [95% CI, 12.14 to 23.19 ] vs 19.30 months [95% CI, not reached], respectively; P = 0.405) with no statistical significance. The median OS was significantly longer in patients with non–CD74 than in those with CD74 (median OS, 28.07 months [95% CI, 23.93 to 32.1] vs not reached, respectively; P = 0.043). Multivariable analysis identified 1 significant factor associated with OS, brain metastasis before crizotinib treatment (P < 0.001). Conclusions: Our results indicate the better OS of crizotinib in patients with non–CD74 vs CD74. The ROS1 fusion partnerS might affect the efficacy of ALK-TKIs.
Nivolumab-induced interstitial lung disease (ILD) in Japanese patients with non-small cell lung cancer: A study on risk factors using interim results of post-marketing all-case surveillance.
Authors: Kenmotsu Hirotsugu , Sakai Fumikazu , Kato Terufumi , Kusumoto Masahiko , Baba Tomohisa , Kuwano Kazuyoshi , Gemma Akihiko , Nakagawa Kazuhiko , Nakanishi Yoichi , Yamamoto Nobuyuki , Ito Yoshihiko , Tahara Yasuhiro , Ohe Yuichiro
Published: September 2018

9078

Background: We investigated case reports of ILD in patients receiving nivolumab for the treatment of unresectable, advanced or recurrent non-small cell lung cancer to identify risk factors for the occurrence of nivolumab-induced ILD. Methods: In Japan, post-marketing all-case surveillance of nivolumab is currently underway in patients with non-small cell lung cancer who received nivolumab from December 17, 2015 to March 31, 2016. The data were retrospectively analyzed using a multivariate stepwise logistic regression analysis with a level of significance of 5% to identify risk factors for the occurrence of nivolumab-induced ILD. Results: A total of 3,648 patients received nivolumab during the surveillance period, and data from 1,005 patients whose case report forms were available by November 30, 2016 were analyzed. Among them ILD was reported in 58 (5.8%). The median time to onset in 42 patients who were recovering or recovered from ILD was 50 days (range: 2 to 246 days). Eleven patients died of ILD. The following table summarizes univariate and multivariate analyses of risk factors for the occurrence of ILD. Conclusions: In this interim analysis of Japanese lung cancer patients treated with nivolumab, incidence of ILD as immune-related AE was 5.8%. Age, abnormal findings of chest CT, and treatment line were identified as risk factors for the occurrence of ILD during treatment with nivolumab. [Table: see text]
Impact of immune-related adverse events (irAE) on overall survival (OS) in patients treated with immunotherapy for non-small cell lung cancer (NSCLC).
Authors: Owen Dwight Hall , Wei Lai , Villalona-Calero Miguel Angel , Bertino Erin Marie , He Kai , Shields Peter G. , Carbone David P. , Otterson Gregory Alan
Published: September 2018

9080

Background: Immunotherapy (IO) has brought dramatic clinical benefit to patients with NSCLC. Most patients tolerate IO, but serious irAE have been reported. In melanoma, a correlation between development of irAE and clinical benefit has been suggested. For NSCLC, the risk of irAE including pneumonitis has been described in clinical trials but not for the wider population. Risk factors for irAE and the impact of irAE on OS are unknown. Methods: A retrospective review of patients with NSCLC treated with single-agent IO between September 2014 and June 2016 was carried out at The Ohio State University. Patients had confirmed pathologic disease and received IO either on clinical trial or as standard of care. IrAE were assessed based on the treating physician diagnosis. OS was calculated from the date of initiation of IO to death from any cause or date or last follow-up. Results: A total of 90 patients met criteria. Median age was 67. Histology was nonsquamous in 58 (64%) and squamous in 32 (35%). Most patients received nivolumab (n = 87). Median months of IO was 2.6 (95% CI 1.9 – 4.2). IrAE occurred in 24 patients (26.67%). The most common irAE were pneumonitis (n = 8), thyroid dysfunction (n = 6), and rash/pruritus (n = 5). Other irAE included colitis in 2 patients and new onset diabetes and autoimmune hepatitis in 1 patient each. Development of pneumonitis did not have a statistically significant impact on overall survival (median OS 5.8 vs 8.1 months, p = 0.11). Prior thoracic radiation (TR) was not associated with pneumonitis (11.54% vs 8.33%, p = 0.69), but was associated with shorter survival (median OS 3.9 vs 8.7 months, p = 0.018). Development of irAE was not associated with histology (p = 1.00), KRAS mutation (p = 0.10), TP53 mutation (p = 0.09), or recent flu vaccination (p = 1.00). Patients with irAE had longer median OS (13.2 vs 5.8 months, p = 0.018). Conclusions: The incidence of irAE and pneumonitis match that seen in published clinical trials. The development of irAE was associated with better prognosis, whereas patients with prior TR had worse outcomes. Further prospective research is warranted to investigate the correlation of irAE with clinical benefit from IO in patients with NSCLC.
STREAM: A randomized discontinuation, blinded, placebo-controlled phase II study of sorafenib (S) treatment of chemonaïve patients (pts) with metastatic uveal melanoma (MUM).
Authors: Scheulen Max E. , Kaempgen Eckhart , Keilholz Ulrich , Heinzerling Lucie , Ochsenreither Sebastian , Abendroth Annalena , Hilger Ralf A. , Grubert Matthias , Wetter Axel , Guberina Nika , Bauer Sebastian , Schuler Gerold , Bornfeld Norbert , Schuler Martin H. , Richly Heike
Published: September 2018

9511

Background: There is no established systemic treatment for pts with MUM. The STREAM study evaluated the efficacy of the oral multikinase inhibitor S in chemonaïve pts with MUM with the primary endpoint progression-free survival (PFS). Methods: During the initial 56d run-in period all pts received oral S 400 mg bid with concomitant monitoring by magnetic resonance imaging including diffusion weighted imaging (DWI-MRI). Pts with partial remission (PR) on d56 according to RECIST 1.1 were further treated with open-label S and monitored, pts with progressive disease (PD) were taken off study, and pts with stable disease (SD) were randomly assigned to blinded S or placebo (P) and were further monitored every 8 wks and unblinded in case of PD. Pts on S were taken off study and pts on P were offered S with further monitoring. Results: Altogether, 118 (79.2%) of 149 pts entering the run-in period were evaluable for response on d56. Two pts had PR (1.7%), 78 pts had SD (66.1%) and 38 pts had PD (32.2%), respectively. Median PFS from randomization was significantly longer with S (5.5 mths) than P (1.9 mths, HR = 0.527, p = 0.0079). S was readministered to 23 pts with PD under P (59.0%) with a median PFS of 2.0 mths (range 1.2-15.7 mths). Overall survival (OS) was not different between the S group (median 14.8 mths, range 3.7-38.3 mths) and the P group (median 14.4, range 3.3-37.3 mths). During the entire study there were 43 NCI-CTCAE grade 3 and 9 grade 4 adverse events requiring dose reduction of S to 200 mg bid or treatment discontinuation, respectively. No pt died from toxicity. The evaluation of the apparent diffusion coefficient (ADC) ratio derived from DWI-MRI in 47 pts of the run-in period showed a significant difference between pts with SD and pts with PD (p < 0.05). Conclusions: The primary endpoint of STREAM was reached. S is clinically active and tolerable in first-line treatment of pts with MUM with an increase of median PFS from 1.9 mths for P to 5.5 mths for S (p = 0.0079). The median OS of 14.8 mths compares favorably with previous findings in pts with MUM. Besides morphological MRI features, ADC ratio may be used as an additional functional response criterion. Clinical trial information: NCT01377025.
Incidence, features and management of radionecrosis (RN) in melanoma patients (pts) treated with cerebral radiotherapy (RT) and anti-PD-1 antibodies (PD1).
Authors: Pires Da Silva Ines Esteves Domingues , Johnpulle Romany Anne Nilanthi , Banks Patricia Diana , Grass G. Daniel , Smith Jess Louise , Everett Ashlyn S. , Goldinger Simone M. , Roberts-Thomson Rachel , Millward Michael , Glitza Isabella Claudia , Haydu Lauren Elaine , Atkinson Victoria , Wang Tim , Eroglu Zeynep , Conry Robert Martin , Shackleton Mark J. , Hong Angela , Long Georgina V. , Johnson Douglas Buckner , Menzies Alexander M.
Published: September 2018

9513

Background: Melanoma brain metastases confer poor prognosis, with various treatments used including RT and PD1. While RT and PD1 may have a synergistic effect to improve efficacy, RN may complicate RT, and whether PD1 potentiates this is unknown. We examined the incidence and features of RN and other neurotoxicities in melanoma pts treated with PD1 and whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS). Methods: Pts treated with PD1 who received WBRT/SRS during or within 1 year (y) of PD1 who survived > 1y were examined for short and long term neurotoxicity. 2 cohorts were included: (A) consecutive pts fulfilling eligibility criteria from 8 melanoma centers, (B) additional cases of RN from 3 centers. Pt demographics, disease features, treatment details, neurotoxicity, and outcome data were collected. Results: Cohort A included 118 pts, with median follow-up of 24.3 months (mo). Median age was 56yo, 51% had mutant BRAF, 41% elevated LDH and 65% were ECOG 1-2 at PD1 start. 58% had prior ipilimumab and 43% prior MAPK inhibitors. 85% were treated with pembrolizumab, 10% nivolumab and 5% combination ipilimumab/nivolumab. Most pts (82, 69%) had SRS, 22 (19%) had WBRT alone and 14 pts (12%) had both. Median PFS was 24mo and OS was 45.8mo. 21 pts (18%) developed RN, (14/82) 17% after SRS, (2/22) 9% after WBRT and (5/14) 36% after both. With 13 further cases from cohort B (total 34), all had radiological signs on MRI, 78% had neurological symptoms and 56% had pathological confirmation of RN. Median time to symptom onset and to first radiological sign was 9.8mo and 10.8mo, respectively. 52% were treated with steroids and 30% had bevacizumab, with clinical improvement in 64% and 100%, respectively. Updated analysis including clinical variables associated with RN development will be presented, including RT dose and schedule. Conclusions: RN is a significant toxicity in melanoma pts with brain metastases treated with RT and PD1, particularly in long term survivors. Further research to identify those at risk of RN, those who do not require RT, and studies exploring RT and PD1 schedules are required.
Incidence, patterns of progression and outcomes of melanoma brain metastasis (MBM) during programmed-death 1 inhibitor (PD1i) therapy.
Authors: Schvartsman Gustavo , Ma Junsheng , Bassett Roland L. , Haydu Lauren Elaine , Amaria Rodabe Navroze , Hwu Patrick , Hwu Wen-Jen , Diab Adi , Patel Sapna Pradyuman , Davies Michael A. , Tawbi Hussein Abdul-Hassan , Glitza Isabella Claudia
Published: September 2018

9532

Background: MBM are common in patients (pts) with metastatic melanoma (MM) and represent a frequent site of treatment failure with current therapies. Little is known, however, about the incidence, patterns of progression and outcomes of MBM pts treated with PD1i and in conjunction with central nervous system (CNS) focused therapy. Methods: Outcomes of mm pts treated with PD1i at MD Anderson from 01/12 to 07/16 were reviewed. The association between clinical variables and development of MBM and overall survival (OS) were assessed using logistic regression and Cox regression analyses. Results: We identified 324 mm pts, including 77 pts (24%) who had MBM prior to first dose of PD1i. Median follow-up from start of therapy was 16.3 months, median OS for pts without MBM at the start of PD1i 3.37 years, as compared to 2.85 years in pts with prior MBM (p = 0.268). Of the 247 pts without prior MBM, 64 (26%) developed MBM after exposure to PD1i. Of those, 21 pts (8.5%) developed MBM during therapy or within 30 days of discontinuation, with 12 (4.5%) having CNS-only progression, while 9 (3.6%) had both systemic and CNS progression. Pts with MBM prior to PD1i (n = 77) had CNS-only progression in 22 pts (28.6%) during therapy. Progression occurred in systemic and systemic plus CNS in 12 pts (15.6%) and 19 pts (24.7%), respectively. 24 pts (31.2%) had stable disease (SD). On multivariate analysis, pts with lung metastases (OR, 2.16; 95% CI, 1.25 - 3.78; p = 0.006) and NRAS-mutated tumors (OR, 2.17; 95% CI, 1.14 - 4.18; p = 0.02) were more likely to develop MBM; pts who had liver metastases at the start of PD1i (HR, 1.77; 95% CI, 1.09 - 2.87; p = 0.002) and those who developed MBM during PD1i (HR, 4.81; 95% CI, 3.00 - 7.71; p < 0.0001) had increased risk of death. Conclusions: We found a 26% incidence of MBM after PD1i exposure. Pts that develop MBM are still at higher risk of death despite advances in systemic and local CNS therapy. CNS-only progression was substantially higher in patients with MBM prior to PD1i, supporting a change in the natural history of the disease after PD1i. These findings support the use of CNS imaging to monitor disease during PD1i therapy.
Safety of resuming anti-PD-1 (aPD1) in patients (pts) with immune-related adverse events (irAEs) during combined anti-CTLA-4 (aCTLA4) and aPD1 in metastatic melanoma (MM).
Authors: Pollack Megan , Betof Allison Shayna , Rappazzo Katherine , Valentine Ian , Eroglu Zeynep , Johnson Douglas Buckner , Shoushtari Alexander Noor
Published: September 2018

9544

Background: Combination aPD1 and aCTLA4 has demonstrated greater response rates (RR) than aPD1 alone in MM. However, aPD1 + aCTLA4 also leads to more frequent and severe irAEs compared to aPD1. The safety of resuming aPD1 following these irAEs is not known. We characterized the safety and efficacy of resuming aPD1 following severe irAEs during aPD1 + aCTLA4 in pts with MM. Methods: We retrospectively reviewed mm pts from 3 academic centers who had a severe irAE with aPD1 + aCTLA4 (defined as CTCAE v4.03 G3-4 or leading to early discontinuation of aPD1 + aCTLA4) and who resumed aPD1 thereafter. We assessed for frequency, timing, and spectrum of irAEs as well as RR, progression free survival (PFS) and overall survival (OS). Results: We identified 64 pts who received aPD1 + aCTLA4 for a median of 2 doses (range, 1-4). The most frequent irAEs that led to aPD1 + aCTLA4 discontinuation were: colitis (36%), hepatitis (23%), hypophysitis (8%), pneumonitis (5%), nephritis (3%), neurologic complications (3%), and pancreatitis (3%); eight pts (13%) had > 1 concurrent severe irAEs. aPD1 was resumed at a median of 55 days after last dose of aCTLA4 + aPD1 (range, 17-289); 23% experienced recurrence of the same irAE with aPD1 monotherapy, 16% experienced a distinct irAE, and 60% did not experience any severe irAE after resuming aPD1. Hepatitis recurred in 6 of 18 pts, pancreatitis in 2 of 2, dermatitis in 1 of 4, nephritis in 1 of 2, pneumonitis in 1 of 3, hypophysitis in 1 of 5, and colitis in 1 of 27; the grade of these recurrent irAEs was: 46% grade 1-2, 33% grade 3, 13% grade 4, and 7% grade 5 (n = 1). One death from irAEs occurred related to Toxic Epidermal Necrolysis (TEN). No difference was observed in time prior to resuming aPD1 in those that had recurrent irAEs vs. those without (median 56 days each). The RR in this cohort was 73% (30% CR; 44% PR); median PFS (range, 2.2-not reached (NR)) and OS (range, 2.4-NR) were not reached. Conclusions: In our experience, pts who resume aPD1 following irAEs with aPD1 + aCTLA4 exhibit variable toxicity profiles with most experiencing no irAEs, but a minority experiencing severe or life-threatening irAEs. We observed excellent efficacy in this cohort.
Safety and results of anti-PD1 combined with radiosurgery for the treatment of melanoma brain metastases.
Authors: Gaudy Marqueste Caroline , Carron Romain , Amatore Florent , Malissen Nausicaa , Muracciole Xavier , Loundou Anderson , Troin Laura , Monestier Sandrine , Mallet Stéphanie , Richard Marie-Aleth , Regis Jean , Grob Jean Jacques
Published: September 2018

9552

Background: Anti-PD1 are now pivotal in the treatment of metastatic melanoma (MM). Some concerns have emerged regarding the risk/benefit ratio of their combination with stereotactic radiosurgery. Methods: Retrospective assessment of the interaction between Gamma-Knife radiosurgery (GKRS) and anti-PD1 in terms of toxicity and OS in mm patients (pts) with BM. Patients were included if they were under anti-PD1 (PRE) at time of GKRS, or if they had started anti-PD1 concomitantly with GKRS (CO), or had received anti-PD1 within 3 months after GKRS (POST). Results: Among 47 pts who received GKRS and anti-PD1 during their disease course, 35 fulfilled PRE or CO or POST criteria (anti PD1 1st line therapy in 10 pts and 2d or more in 25 pts). One pt died before radiological evaluation. GKRS targeted a single BM in 10 pts and multiple BMs in 24 (max 19 BMs). Out of the 128 BMs treated, 6 cases of increase of preexisting edema (4.7%) and 8 hemorrhages (6.25%) occurred in 12 pts, but only 5 events (5%) were regarded as Adverse Radiation effects (ARE), being symptomatic in 3 pts (8% of pts). One BM had to be resected because of the occurrence of a symptomatic hemorrhage with hemiparesis 9 month after treatment. Median follow- up from GKRS was 13.7 mths. Median overall survival (OS) from GKRS and 1st BM were 14.8 and 26.5 mths respectively, with 6 and 12 mths 0S rates from GKRS of 65.7% and 57%, respectively. Local failure was observed in 5 pt. Median time to new BM was 12.6 mths. There was no significant difference in outcomes in pts, depending on PRE, CO and POST conditions. Conclusions: In this series, the largest to date of pts with BMs treated by GKRS and anti-PD1,ARE were within the expected range and survival rates appear promising. Given the natural propensity of MM-BMs for bleeding and edema our data do not support an increased risk with the combination of GKRS and anti-PD1. Regarding the timing between anti-PD1 administration and GKRS our data do not support a higher efficacy or higher toxicity among the 3 following potential mechanisms: immuno- sensitization to radiation (PRE), immuno-radio direct synergy (CO) or radiosensitization to immunotherapy (POST).
A phase Ib study of napabucasin plus weekly paclitaxel in patients with advanced melanoma.
Authors: Edenfield William Jeffery , Becerra Carlos , Braiteh Fadi S. , Spira Alexander I. , Sullivan Ryan J. , Panella Timothy J. , Li Wei , Huang Janet , Li Youzhi , Flaherty Keith , Hitron Matthew , Li Chiang
Published: September 2018

9553

Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity with paclitaxel was observed in pre-clinical testing, and a favorable clinical safety profile was established in a phase I/II trial in patients (pts) with advanced solid tumors. A phase 1b trial was established to evaluate the safety and preliminary signs of anti-cancer activity of the combination regimen in pts with advanced melanoma. Methods: Pts with melanoma were enrolled after failure of standard therapies for advanced disease. Napabucasin 480 or 500 mg orally twice daily was administered with paclitaxel 80 mg/m2 IV weekly for 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks and evaluated per RECIST 1.1 criteria. Results: A total of 12 pts with advanced melanoma were enrolled after a median 3 prior lines of therapy (including immune checkpoint inhibitors, BRAF-inhibitor if presence of BRAF V600E mutation). Protocol therapy was well tolerated with grade 3 AEs including diarrhea (n = 3), abdominal pain (n = 1), and fatigue (n = 1). Partial response (PR) was observed in 1 pt. Stable disease of at least 24 weeks or more was achieved by 33% of patients (n = 4) and the median progression-free survival (mPFS) was 3.7 months. Prolonged survival of 1 year or more was achieved by 33% of pts (n = 4), with a median overall survival (mOS) of 10.4 months. Conclusions: Napabucasin plus weekly paclitaxel has shown clinical safety and encouraging anti-tumor activity in a cohort of pts with previously treated advanced melanoma. The RP2D in combination with weekly paclitaxel was established to 480 mg orally bid. The data suggest that targeting stemness pathways with napabucasin may be a novel therapeutic strategy for melanoma. Clinical trial information: NCT01325441.
Evaluation of the Melanoma Tumor Burden Score (MTBS) in a real-world setting.
Authors: Weichenthal Michael , Senel Gamze , Both Marcus , Senkpiehl Ilka , Lekic Dragana , Kähler Katharina C. , Ugurel Selma , Leiter Ulrike M. , Mohr Peter , Hauschild Axel , Schadendorf Dirk
Published: September 2018

9565

Background: Clinical cancer registration is increasingly important for healthcare delivery and outcome research in oncology. As compared to clinical trial data, information from clinical routine is often limited regarding the granularity and quality of measures for individual tumor load and distribution. Methods: In an effort to implement a robust and useful measure of tumor burden for patients with metastatic melanoma in a German national skin cancer registry (ADOReg) we evaluated the melanoma tumor burden score (MTBS), originally developed for analyzing chemotherapy data in melanoma patients. The MTBS contains a simple categorization of size, number an distribution of metastatic lesions in individual patients. It is aimed at being used on routine radiologic report allowing for a certain level of uncertainty and imprecise quantification of metastatic lesions. Basically, the lesions are categorized per affected organ with respect to number (solitary, few, multiple) and size (≤1cm, >1- 5cm, >5cm). For evaluation of prognostic significance the summary score was calculated and included in univariate and multivariate survival analysis. We performed extensive sensitivity analyses for a variety of different model settings. Results: In the primary analysis set we re-evaluated 898 radiologic reports in a total of 235 various chemotherapies in n=128 stage IV melanoma patients. The confirmatory data sets consisted of n=384 stage IV melanoma patients with various treatments including chemotherapy, BRAF inhibitor treatment, and immune checkpoint blockade. MTBS categorization could be applied on routine radiologic reports in the majority of cases (95.7 %). In a multivariate model MTBS remained significantly correlated with outcome when adjusted for age, sex, LDH, and number of metastatic sites. Moreover, change in MTBS correlated to a formal response evaluation according to RECIST. Conclusions: The MTBS appears to be a promising tool for meaninful quantification of metastatic tumor load in metastatic melanoma for real life data collection like in clinical cancer registries. [Table: see text]
Exploratory analysis of multiprotein serum predictors at baseline of progression-free survival of ipilimumab or ipilimumab and nivolumab in the Checkmate-069 study.
Authors: Homicsko Krisztian , Cuendet Michel A. , Mlynska Agata , Moura Bianca , Horak Christine , Hanahan Douglas , Michielin Olivier
Published: September 2018

9571

Background: Checkpoint inhibitors have revolutionized the treatment of stage IV melanoma patients. Selection of patients for PD-1 monotherapy or CTLA4/PD1 combination remains an important challenge. We set out to perform a discovery study of pretreatment serum protein biomarkers to identify predictors of progression free survival (PFS) for ipilimumab (IPI) or ipilimumab/nivolumab (IPI/NIVO). Methods: We performed an exploratory analysis of baseline serum samples from 135 treatment-naive patients with metastatic melanoma included in the randomized phase II clinical trial, CheckMate 069 (NCT01927419). We used the RayBiotech 440 human cytokine array and evaluated the relationship of serum protein levels with 44 clinical parameters. R, Prism 7.0 and TensorFlow were used for analyses. Results: We focused on correlation of serum protein markers with PFS as a predictor of long-term benefit. In the IPI arm (n = 46), high FGF4 correlated with worse PFS outcome (p = 0.0012). However, FGF4 levels alone were unable to select responsive vs. non-responsive patients. In contrast, a set of three markers consisting of FGF4 ( < 760pg/ml), CCL15 ( > 2.7 ng/ml), and TACE ( > 600pg/ml) separated non-progressing versus progressing patients. Moreover a small group of FGF4-high patients who were concomitantly TIM-3-low also had longer PFS (combined of both: p = 0.0004, HRlogrank: 0.07, 95% CI: 0.03279 to 0.1533). The same markers did not discriminate between IPI/NIVO patients (p = 0.467, HR: 15). In the IPI/NIVO arm, three different markers could select patients. Patients either with low CCL2 ( < 72 pg/ml) or alternatively with high CCL2 combined with high PDGF-AA ( > 8.2 ng/ml) and low GASP-1 ( < 1.3 ng/ml) had longer PFS (p < 0.0001, HR: 0.115, 95% CI: 0.03848 to 0.3408). Conversely, these markers did not predict benefit for IPI-monotherapy. Conclusions: In this study we identified protein signatures in baseline serum that correlate with PFS for therapies with IPI or IPI/NIVO. The markers were exclusive for IPI or IPI/NIVO but not for both. Additional research is warranted to substantiate these results and evaluate the possibility of incorporating into clinical practice.
Performance of a prognostic 31-gene expression profile test in stage III cutaneous melanoma subjects.
Authors: Fleming Martin D. , Middlebrook Brooke , Covington Kyle R. , Gerami Pedram , Wayne Jeffrey D. , Zager Jonathan S.
Published: September 2018

9578

Background: The management of stage III cutaneous melanoma (CM) patients has changed significantly with the introduction of contemporary therapies. A 31-gene expression profile (GEP) test that provides a prediction of low or high risk of melanoma metastasis has been validated as an independent prognosticator of distant metastasis-free (DMFS) and melanoma-specific survival (MSS). We examine the prognostic accuracy of the test in a cohort of stage III, and particularly stage IIIA, subjects from a multicenter validation study. Methods: 207 primary CM tumors from 16 centers were analyzed as part of an IRB-approved study. Quantitative RT-PCR and predictive modeling were performed to classify metastasis and survival risk as Class 1 (low risk) or Class 2 (high risk). Results for Kaplan-Meier and Cox regression survival analysis are reported. Results: Of the 207 subjects with stage III melanoma, 76 were stage IIIA. The table shows 5-year DMFS and MSS rates for all stage III and stage IIIA groups. Patients with Class 2 GEP had significantly worse outcomes compared to Class 1. In univariate analyses, GEP was a significant predictor of DMFS and MSS with a hazard ratio for DMFS of 2.8 (95%-CI; 1.7-4.6) and for MSS of 4.0 (95%-CI; 1.7-9.4) for all stage III, while HR of 2.2 for DMFS (95%-CI; 1.0-4.7) and 4.3 for MSS (95%-CI; 1.2-15.2) were observed for the stage IIIA group. For all stage III cases, Breslow thickness and GEP were significant predictors of DMFS and MSS in multivariate models including ulceration and mitotic rate (p < 0.05). Conclusions: The results support the capability of the GEP to accurately predict stage III distant metastasis and survival, and that the test complements existing prognostic factors. GEP testing may be useful in identifying stage IIIA patients who are appropriate for adjuvant therapies and/or enrollment in clinical trials. [Table: see text]