bluuebunny/crossref_metadata_2025 huggingface dataset:
Total lesion glycolysis (TLG) at baseline FDG-PET/CT compared with maximum standard uptake value (SUVmax) to predict survival in non-small cell lung cancer (NSCLC).
Authors: Li Ling , Kong Feng-Ming (Spring) , Bi Nan , Wang Jingbo , Mahasittiwat Pawinee , Stanton Paul , Ritter Timothy
Published: March 2020

7579

Background: SUVmaxat baseline FDG-PET has been reported as a significant prognostic factor while recent studies suggest that metabolic tumor volume (MTV) may be more important factor in patients with NSCLC. We hypothesized that TLG is a better prognostic factor than either SUVmax or MTV alone for overall survival (OS) and progression free survival (PFS) in NSCLC because it integrates both volumetric and biologic activity. Methods: The study population included a prospectively recruited cohort of stage I-III NSCLC patients treated with chemoradiation. FDG PET/CT scans were performed within 2 weeks from treatment start. The SUV in the tumor was normalized to that of the background level in the middle of ascending aorta to minimize the confounding effect from inter-scan variation in SUV measurement. MTV was delineated by auto-threshold at 1.5 times background level in the aorta followed by knowledge based manual editing. Mean and maximum SUV normalized to the background level were computed. TLG was calculated as the product of lesion SUVmean and MTV. Results: A total of 96 patients with minimum follow-up of 1 year were eligible. The median follow-up among survivors was 30 months. Univariate analysis demonstrated that MTV and TLG were significant factors for both OS and PFS (all P<0.05). There was a significant correlation between SUVmean and PFS (P=0.013), but there was no significant association between SUVmean and OS. SUVmax was not a significant factor for either OS or PFS (all P>0.05). Under multivariate Cox regression analysis, MTV (HR= 2.62, P= 0.003) and NSUVmean (HR=0.351, P=0.003) were significantly associated with PFS; but only TLG was significantly associated with OS (HR=2.14, P=0.006)adjusted by of TNM stage and other clinical factors. Conclusions: These results support our hypothesis that metabolic tumor volume and biologic average glucose metabolic activity of this volume are more important prognostic factors for overall prognosis than SUVmax in NSCLC patients treated with chemoradiation. Should this be validated by independent studies, future clinical trial should take this into consideration for individualized care.
Independent validation of progression-free survival rate at 9 and 18 weeks (PFSR-18, PFSR-9) as predictor for overall survival (OS) in patients with malignant pleural mesothelioma (MPM): EORTC 08052 study.
Authors: Hasan Baktiar , Pallis Athanasios G. , Gaafar Rabab Mohamed , Greillier Laurent , Van Meerbeeck Jan P. , O'Brien Mary
Published: March 2020

7584

Background: The increasing incidence and the plateau of current treatment outcomes in MPM necessitates development of new therapeutic approaches. Reliable and meaningful response assessment is difficult in phase II trials thus a primary endpoint based on progression free survival (PFS) rate at certain time point has been proposed (Greillier et al, 2011). EORTC 08052 was a phase II study in MPM where independent validation of PFSR-18 weeks was foreseen. We extend this to PFSR-9. Methods: Association of PFS and response with OS was assessed at two distinct time points; 9 and 18 weeks after registration. Landmarks method was used, PFS status (CR/PR/SD vs. PD) and response status (CR/PR vs. PD/SD) were determined at those time points. Cox regression and logrank test were performed and the corresponding c-indexes were calculated. Results: Of 82 registered patients, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-18 and PFSR-9 were both strongly correlated with OS. Patients with no progression at 18 weeks had median OS of 16.9 months compared to 11.9 months in those who progressed at 18 weeks. Hazard ratio [HR] (95 confidence interval [CI]) was 0.46 (0.32-0.67), logrank test was 0.007 and C-index = 0.60. Adjusting for 3 important baseline prognosis factors, histology, performance status and disease stage resulted in PFS-18 as the only significant factor. When 9 weeks landmark was chosen, patients with no progression had median OS of 16.9 months vs. 6.8 months in those who progressed with HR (CI), logrank test and C-index 0.35(0.25-0.49), < 0.0001 and 0.66 respectively. When adjusted by 3 important baseline prognosis factors PFS-9 remained the only significant factor. The results also confirmed that response at 18 weeks and 9 weeks was correlated with OS. Conclusions: PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier endpoint, PFSR-9 was also strongly correlated to OS and had a better discriminating capacity. Previous results on correlation between PFSR-9 and PFSR-18 and OS were independently validated.
Genetic analysis of the separate morphologic components in combined small cell lung cancer.
Authors: Lu Hongyang , Ling Zhiqiang , Cheng Qiao-Yuan , Chen Bo , Cai Ju-Fen , Jia Wang Xiao , Lei Lei , Lou CaiJin , Qin Jing , Ye Wei-Wu , Mao Weimin
Published: March 2020

7590

Background: Combined small cell lung cancer (CSCLC) is currently considered a subset of SCLC and have been reported to account for less than 1-3.2% of all SCLCs. Accurate understanding of CSCLCs is of great importance because treatment strategies are significantly different for NSCLC and SCLC. To address molecular features of different components in CSCLC we analyzed mutation status in CSCLC tumor samples in EGFR signal pathway. Methods: Seven CSCLC samples were included in direct sequencing for mutation analysis of EGFR, KRAS, PIK3CA, BRAF, and PTEN. Results: Mutations were detected in 4 of 7 (57.1%) CSCLC patients. EGFR Exon 18 mutations were identified in two patients among whom the mutation was identified in both adenocarcinoma component and SCLC combined adenocarcinoma component of one patient. The similar situation also happened in another one with PTEN C511T mutations both conventional SCLC component and SCLC combined adenocarcinoma component. Both KRAS and PIK3CA were detected in one SCLC combined adenocarcinoma patient and no mutation in BRAF was identified. Conclusions: Our result is consistent with previous work that the individual components of CSCLC are closely related, despite their distinct morphologic appearances.
A gene signature to determine metastatic behavior in thymic carcinoma.
Authors: Gokmen-Polar Yesim , Cook Robert W. , Wilkinson Jeffrey , Maetzold Derek , Stone John F , Oelschlager Kristen M. , Lu Wei , Vladislav Ioan Tudor , Kesler Kenneth , Loehrer Patrick J. , Badve Sunil S.
Published: March 2020

7605

Background: Thymomas and thymic carcinomas (TC) are rare epithelial tumors derived from the thymic gland in the anterior mediastinum. Although all histological types of thymomas, albeit with different frequencies, can give rise to metastases, TC have a more aggressive behavior and metastasize earlier and more frequently than thymomas. We previously developed a prognostic gene signature able to accurately determine metastatic behavior of thymomas (Gökmen-Polar et al. ASCO 2012). The signature is currently used in clinical practice to identify patients at high or low risk for metastatic disease. In the current study, we sought to evaluate the utility of this signature for determining risk from TC tumors. Methods: FFPE tissue sections were macrodissected from 35 primary TC. RNA was isolated and RT-PCR was performed to assess the expression of 23 genes (19 test and four reference genes). Predictive modeling was performed using Radial Basis Machine (RBM) software from JMP Genomics (SAS), and survival analysis was done using the Kaplan-Meier method. Results: Samples from the TC cohort ranged from stage II through IVB, with a median age of 54 years. 26 samples had evidence of metastatic progression, while nine samples did not. Prediction of metastasis, based upon comparison to the previously developed thymoma training set and using a 19-gene signature, yielded an ROC = 0.66. Independent analysis of the TC cohort with the thymoma 19-gene signature resulted in a predictive model with an ROC = 0.97 (overall accuracy = 87%, sensitivity = 73% and specificity=100%). Further modeling and gene set reduction revealed a separate ten-gene signature able to segregate metastatic from non-metastatic cases with 100% accuracy. All the cases classified as high risk (n= 26) developed metastasis within 5 years while none of the cases categorized as low-risk (n= 9) had any events at 5 years of follow-up. Conclusions: A ten-gene signature was established that appears to predict metastatic behavior of TC with a high degree of accuracy; however, validation in an independent cohort is necessary. Our data suggests that the biologic determinants of the clinical course of TC maybe distinct from thymoma and could be used to improve patient management.
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: Spigel David R. , Gettinger Scott N. , Horn Leora , Herbst Roy S. , Gandhi Leena , Gordon Michael S. , Cruz Cristina , Conkling Paul , Cassier Philippe Alexandre , Antonia Scott J. , Burris Howard A. , Fine Gregg Daniel , Mokatrin Ahmad , Kowanetz Marcin , Shen Xiaodong , Chen Daniel S. , Soria Jean-Charles
Published: March 2020

8008

Background: Human lung cancer expresses high levels of PD-L1, which may inhibit anti-cancer immune responses. MPDL3280A, a human monoclonal Ab containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with squamous or nonsquamous NSCLC received MPDL3280A IV q3w at doses between 1-20 mg/kg in a Ph I expansion study. Pts were treated for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 53 NSCLC pts were evaluable for safety and treated at doses of ≤1 (n=2), 10 (n=10), 15 (n=19) and 20 mg/kg (n=22). Pts had a median age of 61 y (range 24-83 y), 98% were PS 0-1, 89% had prior surgery and 55% had prior radiotherapy. 98% of pts received prior systemic therapy. Pts received treatment for a median duration of 106 days (range 1-324) of MPDL3280A. The incidence of all G3/4 AEs, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%) and fatigue (4%). No G3-5 pneumonitis or diarrhea was reported. 37 NSCLC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses were observed at dose levels between 1 and 20 mg/kg, with all responses ongoing or improving. An ORR of 24% (9/37) was observed in pts with squamous and nonsquamous histologies, including several with rapid tumor shrinkage. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). The 24-week PFS was 48%. Analysis of biomarker data from archival tumor samples demonstrated a correlation between PD-L1 status and efficacy. Pts who were PD-L1 tumor status–positive showed an ORR of 100% (4/4) and a PD rate of 0% (0/4), while pts who were PD-L1 tumor status–negative showed an ORR of 15% (4/26) and a PD rate of 58% (15/26). Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A. Clinical trial information: NCT01375842.
Different-dose docetaxel plus cisplatin as first-line chemotherapy and then maintenance therapy with single-agent docetaxel for advanced non-small cell lung cancer (TFINE study, C-TONG 0904).
Authors: Zhang Li , Lu Shun , Cheng Ying , Hu Zhihuang , Chen Zhiwei , Chen Gongyan , Liu Xiaoqing , Yang Jinji , Zhang Li , Chen Jia , Huang Meijuan , Tao Min , Cheng Gang , Huang Cheng , Zhou Caicun , Zhang Weimin , Zhao Hong
Published: March 2020

8015

Background: Docetaxel (75 mg/m2) has been reported as first-line and maintenance treatment for Western population with advanced NSCLC. Different doses of docetaxel (60 mg/m2) are currently delivered in Asian population. Pharmacogenomics alterations in taxanes disposition in different ethnic groups may explain this difference. TFINE study was to evaluate the efficacy, safety, and tolerability of docetaxel in the maintenance setting, and to identify the preferable dose of docetaxel in Asian population. Methods: Previously untreated patients, aged between 18 and 75 years, histologically or cytologically confirmed advanced NSCLC with PS of 0-1 were included. Patients were initially randomized (R1, 1:1) to receive cisplatin (75 mg/m2) plus docetaxel of 75 mg/m2 or 60 mg/m2 for 4 cycles. Patients with disease control after the initial treatment were subsequently randomized (R2, 1:2) to best supportive care (BSC) or maintenance docetaxel of 60 mg/m2 for up to 6 cycles. Genomic DNA was prospectively collected from all enrolled patients. The primary endpoint was PFS since R2, and the secondary endpoints included ORR, overall survival, and toxicity. This study is registered with ClinicalTrials.gov (NCT01038661). Results: This randomized study was undertaken in 15 centers in China. A total of 378 patients were enrolled to R1 and 184 patients (48.7%) were enrolled to R2 (61 vs. 123). Maintenance docetaxel plus BSC significantly prolonged PFS compared with BSC (5.4 months [95% CI 2.8, 7.0] vs. 2.8 months [1.8, 3.1]; P=0.002). The difference of ORR during initial chemotherapy was not significant, with 32.4% in the 60 mg-group and 33.7% in 75 mg-group (P=0.80).The data concerning the overall survival and toxicity, together with the information of pharmacogenomics alterations, will be presented in the meeting subsequently. Conclusions: Maintenance therapy with docetaxel is well tolerated and offers improved PFS in patients with advanced NSCLC.The dose of 60 mg/m2 of docetaxel demonstrated similar efficacy and better tolerability than that of 75 mg/m2 and should be preferred in Asian population. Clinical trial information: NCT01038661.
Response to erlotinib and prognosis for patients with de novo epidermal growth factor receptor (EGFR) T790M mutations.
Authors: Riely Gregory J. , Yu Helena Alexandra , Arcila Maria E. , Hellmann Matthew David , Ladanyi Marc , Kris Mark G.
Published: March 2020

8018

Background: A secondary mutation in exon 20 of EGFR, T790M, is the most common cause of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR mutant lung cancers. De novo EGFR T790M mutations in TKI-naïve patients are rare when assessed by standard genotyping methods. The response to EGFR TKIs in patients with de novo EGFR T790M mutations is unknown. Methods: Patients with EGFRmutations were identified through routine testing, using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing. Clinical characteristics, progression free survival (PFS) from start of EGFR TKI and overall survival (OS) were obtained from the medical record. Results: From 2008-2012, we observed EGFR T790M in 21 tumors from 20 patients who had not previously been treated with an EGFR TKI representing <2% of all tumors with identified EGFR mutations. Two patients are included in reports from the Lung Cancer Mutation Consortium. The median age at lung cancer diagnosis was 57 (range 35-90). 55% presented with stage IV disease. 60% were women. 65% were never-smokers. In all cases, T790M occurred concurrently with another EGFR mutation, L858R (76%, 16/21) or exon 19 deletion (24%, 5/21). Compared to a contemporary cohort of 593 patients with EGFR mutations, in these patients with de novo EGFR T790M, L858R was more frequent than exon 19 deletion (p=0.003). Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. Their response rate (CR+PR) was 9% (1/11, 95% Confidence Interval: 0-40%). SD was observed in 36% (4/11). The median progression-free survival was 3 months and the median overall survival was 16 months. Conclusions: De novo EGFR T790M mutations are rare and occur most commonly with EGFR L858R. Overall survival for patients with de novo EGFR T790 mutations is shorter than what is seen in patients with EGFR exon 19 deletions or L858R, and appears more similar to EGFR wild-type patients. Response rate to EGFR TKI in these patients is low. EGFR TKI therapy for patients with de novo EGFR T790M appears to have limited objective benefit and should be considered only after standard cytotoxic chemotherapy.
A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC).
Authors: Johnson Bruce E. , Kris Mark G. , Berry Lynne D , Kwiatkowski David J. , Iafrate Anthony John , Varella-Garcia Marileila , Wistuba Ignacio Ivan , Franklin Wilbur A. , Ladanyi Marc , Su Pei-Fang , Sequist Lecia V. , Khuri Fadlo Raja , Garon Edward B. , Pao William , Rudin Charles M. , Schiller Joan H. , Haura Eric B. , Giaccone Giuseppe , Minna John D. , Bunn Paul A.
Published: March 2020

8019

Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p<0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.
An analysis of the prevalence of HER2 and KRAS mutations, and ALK rearrangements and clinical outcomes in Cancer and Leukemia Group B [CALGB (Alliance)] trial 30406 in advanced non-small cell lung cancer (NSCLC).
Authors: Stinchcombe Tom , Sholl Lynette M. , Wang Xiaofei F. , Gu Lin , Socinski Mark A. , Rodig Scott J. , Capelletti Marzia , Crawford Jeffrey , Edelman Martin J. , Villalona-Calero Miguel Angel , Kratzke Robert Arthur , Vokes Everett E. , Miller Vincent A. , Janne Pasi Antero ,   Alliance
Published: March 2020

8039

Background: CALGB (Alliance) 30406 was a randomized phase II trial that investigated erlotinib alone or in combination with carboplatin and paclitaxel in patients (pts) with a never or light smoking history with advanced NSCLC. Tissue collection was mandatory. Methods: Between August 2005 and April 2009 188 pts were enrolled. Tumor specimens were assessed using ALK immunohistiochemistry (IHC; clone D5F3; Cell Signaling); KRAS and HER2 mutations were tested. Results: The rate of mutations was: KRAS 10% (17/164), HER2 2% (3/164), and ALK + 7% (8/114). Given the small numbers of KRAS, HER2 and ALK positives, the analysis combines data from both arms. Pts with ALK + compared to ALK- NSCLC had an inferior ORR and PFS (Table). No statistically significant differences in ORR, PFS, OS between pts with KRAS or HER2 mutant and wild-type NSCLC were observed. In multivariate analysis pts with ALK+ compared to ALK- tumors experienced a statistically significant worse PFS (HR=2.67, p=0.0114) but not OS (HR=1.48, p=0.3217). One pt was identified as having an EGFR exon 21 mutation and ALK +; the pt experienced a best response of progressive disease, a PFS of 2.9 months, and OS of 17.4 months. Conclusions: (1) Pts with ALK+ compared to ALK- NSCLC have a lower ORR, worse PFS, but not OS with erlotinib alone or with carboplatin and paclitaxel. (2) The prevalence ALK+, KRAS and HER2 mutations observed was 7%, 10% and 2%, respectively. Clinical trial information: 00126581. [Table: see text]
Serum and tumor biomarkers to predict outcome in the eLung trial, a multicenter, randomized phase IIb study of standard platinum doublets (PD) plus cetuximab (CET) as first-line treatment of advanced non-small cell lung cancer (NSCLC).
Authors: Miller Paul J. E. , Walker Mark S. , Tauer Kurt W. , Atkins James , Sivarajan Kulumani M , Patel Vipul M. , Bastos Bruno R. , Meyer Krista , Roder Joanna , Uyeda Lisa , Salazar Suzanne , Langer Corey J. , Socinski Mark A. , Spigel David R. , Schwartzberg Lee Steven
Published: March 2020

8044

Background: The eLung trial randomized chemotherapy naïve advanced NSCLC patients (pts) to 1 of 3 PD and concurrent CET followed by CET maintenance until progression, stratified by non-squamous (NSQ) and squamous (SQ) histology. Primary outcome results were reported (ESMO, Schwartzberg 2012). Pre-treatment tumor tissue and serum samples were prospectively collected. Methods: Tumor samples were analyzed for H-score (graded 0-300), calculated by the intensity and number of cells expressing EGFR by IHC; a score of >200 was considered high (Pirker 2011). Mutation analysis of EGFR and KRAS was performed by PCR. The VeriStrat multivariate serum protein test was performed on available serum samples assigning good and poor classifications (Taguchi 2007). Results: Of 601 pts enrolled on the trial, 378 consented to blood/tissue or both. The available tissue (N=210) and serum subsets (N=203) had similar demographics and survival outcome to the full trial set. Results for biomarkers/cohorts in the Table demonstrate that VeriStrat was highly significant for OS in all pts and NSQ, while H-score and EGFR mutations were significant only in NSQ. In adjusted Cox analysis VeriStrat was an independent predictor for OS, HR=.665, p=.026; H-score was not. Conclusions: VeriStrat classification significantly correlated with survival outcome in all pts treated with PD and CET and the NSQ subset; tissue biomarkers correlated in NSQ only. Further evaluation of these markers is warranted. [Table: see text]
Impact of aggressive therapy in patients with non-small cell lung carcinoma presenting with brain-only oligometastatic disease.
Authors: Gray Phillip J. , Sher David , Yeap Beow Y. , Cryer Sarah K , Mak Raymond H. , Weiss Stephanie E. , Alexander Brian Michael , Jackman David Michael
Published: March 2020

8069

Background: Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain metastases as their only metastatic site is not well defined. We investigated whether aggressive therapy directed to the primary site or whole-brain radiotherapy (WBRT) were associated with improved outcomes in this subset of patients. Methods: We conducted a retrospective analysis of patients seen at the Dana-Farber Cancer Institute between 1/2000 and 1/2011. Patients with NSCLC, 1-4 synchronous brain metastases and no other sites of metastatic disease confirmed by CT or PET scan were included. Patients with poor performance status were excluded. Aggressive thoracic therapy (ATT) was defined as surgical resection of the primary disease or radiotherapy to a dose of greater than 45 Gy. A Cox proportional hazards model was used to analyze effects on survival and a competing risks model was constructed to analyze the risk of recurrence in the brain. Results: 66 patients met the study criteria. Median follow-up for survivors was 32.3 months. Excluding the metastatic disease, 9 patients had stage I disease, 10 stage II and 47 stage III. 38 patients received ATT. Patients receiving ATT were significantly younger (median age 55 vs. 60.5 years) but otherwise had a similar distribution of sex, performance status and number of brain metastases. Receipt of ATT was associated with significantly prolonged overall survival (OS) (median 26.8 vs. 10.9 months; p<0.001). Actuarial 5-year survival was 28% for those who received ATT vs. 0%. ATT remained significantly associated with OS after controlling for age, stage, performance status and receipt of WBRT (HR 0.42, p=0.016). On multivariate analysis, receipt of ATT (HR 3.14, p=0.048) and WBRT (HR 0.10, p=0.005) were the only factors predictive of first failure in the brain. Receipt of initial WBRT did not improve OS. Conclusions: Patients with NSCLC presenting with synchronous brain-only metastases may still benefit from aggressive therapy directed to the thoracic primary site. Use of WBRT for this subgroup does not improve OS but significantly reduces future brain recurrences.
Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): Analyses based on age in the phase III PointBreak and E4599 trials.
Authors: Langer Corey J. , Socinski Mark A. , Patel Jyoti D. , Sandler Alan , Schiller Joan H. , Leon Larry , Uttamsingh Shailaja , Ramalingam Suresh S.
Published: March 2020

8073

Background: A post hoc analysis of NSCLC (pts) ≥70 y in the pivotal E4599 trial found increased adverse events (AEs) and numerically decreased survival benefit associated with bevacizumab (BEV) vs pts <70 y. We evaluated the efficacy and safety of BEV by age in pts in a pooled dataset from the E4599 and PointBreak (PB) trials. Methods: Pts randomized to the PC (paclitaxel and carboplatin ) + BEV arms of E4599 and PB received P 200 mg/m2, C AUC 6, and BEV 15 mg/kg q3w for 6 (E4599) or 4 (PB) cycles; 1 pt in PB received 6 cycles. Eligible pts received maintenance BEV q3w until disease progression or unacceptable toxicity. Overall survival (OS), progression-free survival (PFS), and safety were assessed in pts grouped according to age (<65 y, 65–75 y, 70–75 y, <75 y, and ≥75 y). Pt-level data from the PC + BEV arms of E4599 and PB were pooled and compared with data from pts in the PC-alone arm of E4599. Results: PB and E4599 randomized 467 pts and 434 pts to PC + BEV, respectively. Baseline characteristics were balanced between age groups. OS and PFS hazard ratios (HRs) and increases in grade ≥3 AEs for the pooled pt cohort relative to E4599 PC-alone arm are shown (Table). Outcomes were similar in pts <70 y and ≥70 y, and data from the pooled population were similar to those seen in each individual trial (data not shown). Conclusions: In a pooled exploratory analysis of pt data from E4599 and PB, the statistically significant benefit associated with the addition of BEV to PC appeared consistent across all age groups <75y. Pts ≥75 y receiving BEV had a higher incidence of grade ≥3 AEs relative to PC alone with no statistically significant survival benefit, although an increase in grade ≥3 AEs was observed in all age groups. Clinical trial information: NCT00762034 and NCT00021060. [Table: see text]
A phase I/II study combining dasatinib (D) and erlotinib (E) in non-small cell lung cancer.
Authors: Johnson Faye M. , Tang XiMing , Tran Hai T. , Mc Intyre Chelsey , Price Justina , Lee J. Jack , Harun Nusrat , Wistuba Ignacio Ivan , Gold Kathryn A.
Published: March 2020

8102

Background: In preclinical models, combining EGFR and Src inhibition has been shown to have at least additive and possibly synergistic effects. In this phase I/II (phI/II) trial, we combined EGFR inhibitor E with D, a multi-targeted tyrosine kinase inhibitor with activity against Src. Primary endpoint of PhI was to determine maximum tolerated dose (MTD) of the combination of E and D; primary endpoint of PhII was progression free survival (PFS) at 12 weeks. Methods: In preclinical models, combining EGFR and Src inhibition has been shown to have at least additive and possibly synergistic effects. In this phase I/II (phI/II) trial, we combined EGFR inhibitor E with D, a multi-targeted tyrosine kinase inhibitor with activity against Src. Primary endpoint of PhI was to determine maximum tolerated dose (MTD) of the combination of E and D; primary endpoint of PhII was progression free survival (PFS) at 12 weeks. Results: 53 pts were enrolled between 2/09 and 4/12. 6 were not eligible. Of the 47 eligible pts (12 in PhI, 35 in PhII): median (range) age was 62 yrs (44-88), 26 pts (45%) were female. 6 pts in PhI and all 35 pts in PhII had NSCLC: adeno 25 pts, squamous 11, NSCLC NOS 5. Other tumor types enrolled in PhI: head and neck cancer (2), adenoid cystic carcinoma (1), mesothelioma (2), small cell lung cancer (1). 47% of pts were chemo-naïve. 8 pts had activating EGFR mutations (6 exon 19 deletions, 2 L858R mutations). The PhI starting dose E150/D100 was not well tolerated as 2 of 3 pts experienced grade 3 hypophosphatemia as a dose limiting toxicity. MTD was found to be E150/D70. 11% achieved PR and 44% SD. All observed responders had EGFR mutations. 9 pts (19%) stopped treatment early and were unevaluable. Median time on treatment was 43 days (range 1-262). Median time on treatment for the 8 pts with activating EGFR mutations was 144 days. Conclusions: Combination of E and D is safe and feasible in NSCLC, with MTD E 150 mg PO daily and D 70 mg PO daily. Rate of PR and SD were 11%,and 44%, respectively. Biomarker and pharmacokinetic studies will be reported. Clinical trial information: NCT00826449.
Dynamic changes in circulating tumor cell levels as a prognostic marker in stage IV non-small cell lung cancer.
Authors: Carlsson Anders , Bazhenova Lyudmila , Kolatkar Anand , Luttgen Madelyn , Bethel Kelly , Nieva Jorge J. , Kuhn Peter
Published: March 2020

8109

Background: We have previously reported the performance of our immuno-enrichment free HighEDefinition CTC (HDECTC) assay in the enumeration and characterization of circulating tumor cells (CTCs) in lung cancer patients. In the HD-CTC assay, nucleated cells are fluorescently labeled and imaged using automated microscopy. CTCs are defined as morphologically distinct, cytokeratin positive, CD45 negative cells. Here, we investigate further how CTCs numbers and physical properties relate to prognosis in NSCLC patients. Methods: The HD-CTC assay was applied for CTC enumeration in 362 blood samples collected longitudinally from 81 Stage IV NSCLC patients. Blood was collected at time 0, 3 weeks, and every 3 months thereafter. The collection protocol was restarted at disease progression, resulting in a sample number ranging between one and 12 samples per patient. Results: Eighty-one patients were enrolled, with 41 patients in 1st line therapy, 11 in 2nd, 17 in 3rd, 7 in 4th, 3 in 5th and 2 in 6th line therapy. Average age was 63, range 33 to 90; male to female ratio was 1:1.19. Eighty-six percent of patients had CTCs in at least one blood sample; CTC counts ranged from 0 to 885 CTCs/ml with a mean of 23.5 CTCs/ml across all samples. While no correlation was found between the absolute CTC concentration and survival, it was observed that for the 26 patients that had samples collected both at the start and during firstEline chemotherapy, an increase in CTC level between the two time points was significantly associated with longer survival (p < 0.001). Conclusions: As detected with our assay, it is the change in CTC level upon entering 1st line chemotherapy and not the absolute CTC concentration that carries prognostic information. This observation highlights not only the importance of CTCs as prognostic biomarkers, but also that of access to serially collected specimens. The latter is here made possible only by the fact that the HDECTC assay samples tumor cells from peripheral blood.
DDR2 mutations in lung cancer in adenocarcinoma and squamous cell carcinoma and association with MET activation.
Authors: Windham Justin P , Wang Yongbao , Hilferty Rebecca A , Sanidad Marc A , Jones Daniel
Published: March 2020

8115

Background: The discoidin domain receptor tyrosine kinase 2 (DDR2) gene is mutated in a small subset of squamous cell carcinomas (SQCAs) of the lung. Targeting of DDR2 with the inhibitor dasatinib inhibits DDR2-mutated cell line growth and is being investigated in clinical trials for treatment of DDR2-mutated lung tumors. We investigated the frequency and type of DDR2 mutations and their association with other targetable growth factor pathway alterations in non-small cell lung carcinoma (NSCLC). Methods: DNA was extracted from macro-dissected FFPE sections of 105 advanced stage lung carcinomas. Next-generation sequencing was performed using a 36-amplicon panel including the coding regions of DDR2 and exons 11 and 15 of BRAF. DDR2 mutations were confirmed by bidirectional Sanger sequencing. Lung tumors were classified using a standard immunohistochemistry panel. MET pathway activation was assessed with immunohistochemistry using an activation-specific phospho-antibody (pMET, Try1234/1235). MET amplification and ALK rearrangement were assessed using FISH. Mutational analysis for EGFR (exon 18-21), PIK3CA (exons 9 and 20), and KRAS(exons 1-2) was performed using PCR-based DNA sequencing. Results: Heterozygous DDR2 point mutations were identified in 7/105 (6.7%) NSCLCs, including 3/29 (10.3%) SQCAs and 4/69 (5.8%) ACAs, but not in neuroendocrine/large cell carcinomas (0/7). DDR2 mutations were scattered throughout the gene, with 4 present in the discoidin domain and 3 in the kinase domain. MET pathway activation, seen in 25% of DDR2-unmutated cases, was found in 3/6 (50%) DDR2-mutated cases, including 1 SQCA with high-level MET gene amplification. DDR2 mutations were mutually exclusive with BRAF or EGFR mutation or ALK rearrangement, with 1 KRAS-mutated case. Conclusions: DDR2 mutations occur in lung carcinomas with a range of histologic features and in association with MET activation. Dual targeting of the MET and DDR2 kinases in such cases may warrant further investigation.
Magnetic resonance guided focused ultrasound surgery for palliation of painful bone metastasis: Results of a multicenter phase III trial.
Authors: Hurwitz Mark , Meyer Joshua E. , Iozeffi Dimitri , Ghanouni Pejman , Gianfelice David , Fennessy Fiona M. , Kuten Abraham , LeBlang Suzanne , Roberts Anne C. , Choi Junsung , Napoli Alessandro , Turkevich Vladimir , Tempany Clare M. , Inbar Yael , Pfeffer Raphael M. , Larner James Mitchell , Kanaev Sergy
Published: March 2020

9500

Background: Pain due to bone metastases is a common cause of cancer-related morbidity. Magnetic resonance guided focused ultrasound surgery (MRgFUS) is a non-invasive approach to thermal tissue ablation. This multi-center phase III trial assessed efficacy of MRgFUS compared with sham treatment to alleviate pain due to bone metastases. Methods: Subjects with a painful bone metastasis amenable to MRgFUS treatment for whom radiation therapy was ineffective or contraindicated were randomized 3:1 to MRgFUS or sham treatment in a single blind design. Un-blinding of sham subjects who did not experience significant pain relief within 2 weeks was permitted with crossover allowed to salvage MRgFUS treatment. Pain response and impact on quality of life (QOL) were assessed using the numerical rating scale (NRS) and Brief Pain Inventory-Quality of Life (BPI-QOL). Safety was also assessed. Results: 142 randomized subjects were included in an intent-to-treat analysis. 67% (95%CI: 57.5-76.0%) of 107 subjects in the MRgFUS arm experienced clinically significant pain relief, equating with an anchor descriptor of “much improved” or better at 3 months compared to 20% of 35 sham arm subjects (p<0.0001). Median baseline and 3 month NRS scores were 7.0 and 2.0 for the MRgFUS arm vs. 7.0 and 6.0 for the sham arm. A clinically significant improvement at 3 months in BPI-QOL score for MRgFUS but not sham treatment was noted [average change: 2.4 vs. 0.2 respectively, (p<0.0001)]. MRgFUS treatment was well tolerated. Conclusions: MRgFUS, as demonstrated by this phase III trial, results in excellent rates of pain relief and improvement in QOL for patients with oncologic related bone pain who are not candidates for radiation therapy. Given these excellent results coupled with a favorable side effect profile, MRgFUS should be considered a primary choice for this patient population. Clinical trial information: NCT00656305.
A randomized trial of single versus multiple fractions (Fx) for re-irradiation (RE-RT) of painful bone metastases (PBM): NCIC CTG SC.20.
Authors: Chow Edward , van der Linden Yvette , Roos Daniel , Hartsell William F. , Hoskin Peter , Wu Jackson S.Y. , Brundage Michael , Nabid Abdenour , Wilson Carolyn F. , Meyer Ralph M. , Chen Bingshu E , Wong Rebecca
Published: March 2020

9502

Background: The optimal RE-RT dose and fractionation schedule for PBM is uncertain. Methods: Patients (pts) with PBM after previous radiation (RT) to the same site were stratified by previous Fx schedule and pain response and randomized to 8 Gy in 1 Fx or 20 Gy in 5 Fx (8 Fx if previous RT was to spine/whole pelvis in multiple Fx). The primary endpoint was overall response rate (RR) at 2 months using the International Consensus schema (Chow 2002) which combines Brief Pain Inventory worst pain score and opioid analgesic use. We tested if 8Gy was non-inferior (NI), analyzed by intention to treat (ITT) and a per-protocol (PP) sensitivity analysis excluding those who were ineligible, inevaluable or received non-allocated therapy. Sample size was calculated using an expected RR of 70% with 20Gy and a NI margin of 10% (i.e. upper boundary of 1-sided 95% CI for the RR difference). Pts reported adverse events (AEs) by questionnaire on Day 14. Quality of life (QoL) was assessed using the EORTC QLQ C30. Results: Between 01/2004 and 06/2012, we enrolled 850 pts from 9 countries. Most common cancers were prostate (27%), breast (26%) and lung (22%). Before the 2 month assessment, 98 (11%) pts died. By ITT, the 2-month RR was available in 66% (557/850) and was 119/425 (28%) with 8Gy and 136/425 (32%) with 20Gy (P=0.2); the upper boundary of the 95% CI for RR difference = 9.2% and is less than the pre-specified NI margin. By PP analysis, 2-month RR was available in 521 and was 117/258 (45.3%) with 8Gy and 135/263 (51.3%) with 20Gy (P=0.17); the upper boundary of the 95% CI for RR difference = 13.2%, which exceeds 10% non-inferiority boundary. Day 14 AEs differing by treatment were: lack of appetite (P=0.01), vomiting (P= 0.001), diarrhea (P=0.02) and skin reddening (P=0.002); all were worse with 20Gy. There were 30 vs 20 pathological fractures and 7 vs 2 spinal cord compressions with 8Gy and 20Gy, respectively (P=NS). No difference in QoL existed between arms. Conclusions: In pts with PBM receiving RE-RT, the 2-month RR obtained with 8Gy is non-inferior to 20 Gy when assessed by ITT but findings were not robust to a PP sensitivity analysis. When choosing between options tested, trade-offs exist between pain response and acute toxicity. Clinical trial information: NCT00080912.
The course of depression, inflammation in the serum and tumor microenvironment, and survival in the context of advanced cancer.
Authors: Steel Jennifer Lynne , Kim Kevin H , Gamblin T. Clark , Fraser Danyelle , Biala Michelle , Savkova Alexandra , Butterfield Lisa , Geller David A. , Marsh J. Wallis , Tsung Allan
Published: March 2020

9507

Background: The aims of the present study were to study the course of depression in patients diagnosed with cancer and the link with biomarkers of inflammation in the serum or tumor microenvironment and survival. Methods: A total of 474 patients diagnosed with advanced cancer were administered the Center for Epidemiological Studies-Depression (CES-D) scale every 2-months and blood samples were drawn to assess biomarkers of inflammation in the serum and tumor microenvironment. The course of depression was estimated using a semi-parametric trajectory analyses and cross-lagged panel analyses were performed to assess the link between depression and biomarkers of inflammation. Cox regression analysis was use to test the link between depression and survival while adjusting for demographic and disease specific factors. Results: A three-class solution was chosen based on Bayesian information criterion and theory. The first class, “not depressed,” with a mean CES-D score of 6.7 at baseline contained 32% of patients and no significant change in depression scores across time. The second class, “mildly depressed” (53% of sample) had a significant increase in the mean CES-D from 14.5 at baseline to 18.0 at 12 months and 20.0 at 16 months [B = .35, z = 3.12, p = .002]. The third class, “severely depressed,” with a mean of 31.5 at baseline (15% of patients) and no significant change win depression over 24 months. Depression predicted serum levels of Tumor Necrosis Factor (TNF)-alpha and Interleukin-1alpha at subsequent time points and was associated with High Mobility Group Box 1 in the tumor microenvironment. Trajectory group assignment significantly predicted survival after demographic and disease specific factors were adjusted (p=0.04). The non-depressed trajectory group had a median survival of 13 months (95%CI=8.9-17.1), the mildly depressed group median survival was 10 months (95% CI 7.1-12.9) and the severely depressed group median survival was 6 months (95% CI=7.6-12.4). Conclusions: These findings may facilitate the targeting of psychosocial and biological interventions to reduce depression symptoms, improve quality of life, and potentially slow disease progression.
The role of age on dose-limiting toxicities (DLTs) in phase I dose-escalation trials.
Authors: Schwandt Anita , Harris Pamela Jo , Hunsberger Sally , Deleporte Amélie , Smith Gary L , Vulih Diana , Anderson Barry Douglas , Ivy S. Percy
Published: March 2020

9517

Background: Elderly oncology patients are not enrolled on phase I trials in proportion to the prevalence of cancer in the age-matched population. They are excluded from these trials based on the perception that these patients will have an increased number of and more severe toxicities, per dose level, than younger patients. We hypothesize that if other patient characteristics are accounted for, then age will not be an independent predictor of dose limiting toxicities (DLTs). Methods: We retrospectively reviewed data from 162 single- agent dose-escalation phase I clinical trials performed at the Cancer Therapy Evaluation Program/National Cancer Institute. Several baseline patient characteristics, including age, were collected. Patient dose levels were described as %MTD and an analysis of age, dose and DLTs was performed. Results: Data was obtained from 5,401 patients who were divided into five age groups, with 556 pts < 40 years old, 2,438 between 40-59, 1,481 between 60-69, 836 between 70-79 and 90 pts > 79. Proportion of DLT occurring in each age group and %MTD are described in the Table. Conclusions: This analysis of DLTs occurring in nearly 1000 patients over 70 years of age on phase I dose-escalation trials is the largest reported. A logistic regression model will be performed to determine if age, by itself, predicts for DLTs and what concurrent patient characteristics contribute to their occurrence. [Table: see text]
Prognostic information (PI), psychological well-being, and quality of life for advanced cancer patients (ACP) in phase I trials and their spousal caregivers (SC).
Authors: Hlubocky Fay J. , Cella David , Sher Tamara , Yap Bonnie , Ratain Mark J. , Daugherty Christopher
Published: March 2020

9520

Background: The impact of the physician’s (MD) disclosure of PI on the psychological well-being and quality of life (QoL) of clinical trial subjects with terminal disease on Phase I trials has not been formally evaluated. Methods: A prospective cohort of ACP enrolling in phase I trials was assessed at baseline (T1) and one month (T2) utilizing various measures including: state-trait anxiety (STAI-S/T), depression (CES-D), quality of life/QoL (FACIT-Pal), and global health (SF-36). Semi-structured interviews of ACPs also evaluated MD-Pt communication re prognosis and worry about ACP death. Results: 100 subjects (50 Phase I ACPs and 50 SC) were separately interviewed at T1 and T2. For the population as a whole: median age 62 (28-78y); 51% male; 100% married; 88% Ca; 68% > HS educ; 56% GI dx; 54% income <$65,000 yr. At T1, 45% of ACPs acknowledged having a discussion re life expectancy with MD; 35% stated the MD gave a prognostic timeframe; and 41% reported worry re death. For SC at T1, 62% recalled a prognosis discussion with the MD; 50% stated MD gave a timeframe; 53% reported PI disclosure was initiated by the MD; 66% reported worry re ACP death. At T2, rates remained consistent for both ACP and SC with the exception of increased reported worry re ACP death at 55% and 70% respectively. At T2, ACP who denied a prognosis was given by the MD had higher STAI-S (35 ± 10 v 29 ± 9, p=0.03) and CES-D scores (16 ± 12 v 7 ± 4, p=0.01); and lower FACT-Pal scores (128 ± 18 v 153 ± 24, p=0.01). SC with acknowledgement of a prognostic timeframe given by the MD had higher STAI-S anxiety (39 ± 16 v 35 ± 14, p=0.04) at T2. Regression analyses revealed that ACP with acknowledgement of a prognostic timeframe given by the MD had poorer FACIT-Pal QoL over time. Also, SC with acknowledgement of a prognostic timeframe at T2 was negatively associated with SF-36 scores. ACP and SC qualitative responses re PI disclosure revealed salient themes: hope for a positive outcome or prolonged survival; stabilization of disease; emotional distress; ambivalence/fear; acceptance. Conclusions: Physician disclosure of a prognostic timeframe is negatively associated with QoL among clinical trial subjects and SC in phase I trials.