bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of prior radiation on survival in metastatic lung cancer ECOG-ACRIN trials.
Authors: Khan Saad A. , Puligandla Maneka , Dahlberg Suzanne Eleanor , Masters Gregory A. , Langer Corey J. , Brahmer Julie R. , Hanna Nasser H. , Bonomi Philip , Gerber David E. , Johnson David H. , Schiller Joan H. , Ramalingam Suresh S. 
Published: September 2018

9051 Background: Up to 50% of advanced NSCLC patients receive radiation therapy at some point in their course. We sought to determine whether patients with prior radiation demonstrate altered outcomes on subsequent metastatic clinical trials. Methods: We reviewed 8 ECOG-ACRIN advanced non-small cell lung cancer studies conducted between 1993 and 2011 in which information was collected about receipt of prior radiation. Whether radiotherapy was given with curative or palliative intent, or to specific sites was not recorded. Median follow-up among all trials was 66 months. We used the log-rank, Wilcoxon and Fisher’s exact tests to compare patients, and Cox Model and Kaplan-Meier method to calculate survival. Results: 574/3041 (18.9%) patients had received prior radiation. These patients were more likely to be male (64% vs 58%), have squamous histology (20% vs 14%) and have had prior surgery (48% vs 33%) compared to those with no prior radiation. At registration, prior radiation patients were more likely to have an ECOG PS of 1 (66% vs 58%), while they were less likely to have a PS of 0 (24% vs 36%) or have a pleural effusion (23% vs 37%). Patients who received radiation were more likely to have been registered on to studies between 1993-1999 than 2000-2011 (69% vs 31%) (all p < 0.001). Median Overall Survival (OS) for patients with prior radiation was 7.6 months (range 7-8.3) vs 9.5 (9.1-9.8) for those without (p < 0.001). Median Progression Free Survival (PFS) for those with prior radiation was 3.5 months (3-3.9) vs 4.2 (4.1-4.4) for those without (p < 0.001). In multivariable analysis controlling for stage IIIB/IV, sex, PS, histology, and prior surgery, the impact of prior radiation on overall survival remained significant (p = 0.042, HR (95% CI) = 1.11 (1.00, 1.22)). Conclusions: Almost one-fifth of lung cancer patients on systemic therapy trials for advanced disease previously received radiation. They are more likely to be male, have squamous histology, have an ECOG PS of 1 and have had prior surgery. Prior radiation is significantly associated with inferior OS and PFS. For advanced NSCLC clinical trials, documentation of whether curative intent/palliative intent radiation was given and stratification by prior radiation exposure should be considered.
Phase II study of the FGFR inhibitor AZD4547 in previously treated patients with FGF pathway-activated stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400D.
Authors: Aggarwal Charu , Redman Mary Weber , Lara Primo , Borghaei Hossein , Hoffman Philip C. , Bradley Jeffrey D. , Griffin Katie , Miao Jieling , Mack Philip C. , Papadimitrakopoulou Vassiliki , Herbst Roy S. , Kelly Karen , Gandara David R. 
Published: September 2018

9055 Background: LungMAP is a National Clinical Trials Network umbrella trial for previously-treated SqNSCLC. S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibitor AZD4547 in patients (pts) with FGFR positive chemo-refractory SqNSCLC. Methods: Eligible pts had tumor FGFR alteration and/or mutation by next generation sequencing (Foundation Medicine), measurable disease, Zubrod PS 0-2, progression after 1 line of systemic therapy, and adequate end organ function. Receipt of prior immunotherapy was allowed. Eligible pts received AZD4547 80 mg bid orally. Primary endpoint was overall response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS) and duration of response (DoR). Originally designed as a randomized trial of AZD4547 versus docetaxel, it was redesigned to be a single arm AZD4547 trial with the emergence of immunotherapy as standard 2ndline therapy. Forty pts were required to rule out an ORR of < = 15% if the true ORR was > 35% (90% power, alpha 0.05). Results: 93 pts (13% of pts screened on S1400) were assigned to S1400D; 43 were enrolled with 28 receiving AZD4547. Pt characteristics: median age 66.3 y (49-88), female (n = 8, 29%), & Caucasian (n = 25; 89%). Biomarker profile: FGFR1 amplification (n = 38; 86%); FGFR3 S249C (n = 4; 9%); FGFR3 amplification (n = 3; 7%); and FGFR3 fusion (n = 2; 5%). Nine pts (26%) had more than one biomarker alteration. The study was closed at interim analysis for futility in October 2016. Treatment related Grade 3 AEs were seen in 5 pts (dyspnea, fatigue, hyponatremia, lung infection & retinopathy); 1 pt had Grade 4 sepsis. There were no Grade 5 AEs. Median follow up among alive pts was 4.3 months (mos). Of 25 response evaluable pts, one with FGFR3 S249C had unconfirmed PR (4%, 95% CI 1-20%) with DoR of 1.5 mos. Median PFS was 2.7 mos (95% CI 1.4 - 4.3 mos). Conclusions: This is the first Phase II trial to evaluate AZD4547 as a targeted approach in pts with previously treated FGFR-altered SqNSCLC. AZD4547 had an acceptable safety profile but minimal activity in this biomarker-enriched cohort. Evaluation of other targeted agents in LUNG-MAP is currently ongoing. Clinical trial information: NCT02965378.
Retinoblastoma mutation to predict poor outcomes in non-small cell lung cancer (NSCLC).
Authors: Bhateja Priyanka , Wildey Gary , Fu Pingfu , Lipka Mary Beth , Ardeshir-Larijani Fatemeh , Sharma Neelesh , Dowlati Afshin 
Published: September 2018

9060 Background: Genomic profiling of tumor DNA has revealed the diversity in NSCLC. The retinoblastoma gene ( RB1) encodes for RB pocket protein that plays an important role in cell cycle progression by interacting with various transcriptional factors. Here we determine the frequency and prognostic significance of RB1mutation in NSCLC and compare it to that in small cell lung cancer (SCLC). Methods: This IRB-approved retrospective review on NSCLC patients included Stage III and IV patients with genomic and clinical data. Primary outcome was median overall survival (OS) and secondary outcome was progression-free survival (PFS). OS and PFS were calculated by the Kaplan-Meier method and compared between mutant and wild-type (wt) RB1using the Log-Rank test. The effect of RB1mutation status on OS and PFS was further evaluated using the multivariable Cox model, controlling the effects of age, sex, stage, smoking history and chemotherapy. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified RB1 mutation in 8.2% of NSCLC patients (16 of 195 patients). With a median follow-up of 15.1 months, the median OS for wt RB1was 28.3 months and for mutant RB1 was 8.3 months (HR = 2.59, p-value = 0.002). The median PFS for wt RB1 was 21.8 months vs 6.4 months for mutant RB1 (HR = 2.85, p-value = 0.0002). RB1 mutation was associated with worse OS ( p= 0.017, HR = 2.17) and PFS ( p= 0.005, HR = 2.37) in multivariate analyses after adjusting for traditional risk factors like, age, sex, stage, smoking history and chemotherapy. Interestingly, a previously described benign deletion (A16-A18) in RB1 protein was identified in 5 of the 16 RB1 mutant patients and was associated with far worse outcomes compared to other RB1 mutations. In contrast to NSCLC, RB1 mutation was identified in 75% of 64 SCLC patients. Furthermore, wt RB1 was associated with significantly shorter OS ( p= 0.002), PFS ( p= 0.004) and chemotherapy refractoriness ( p= 0.033) in SCLC. Conclusions: RB1 mutation is present in a minority of patients with advanced NSCLC and is associated with poor prognosis. In contrast, RB1 mutation is present in the majority of SCLC patients and is associated with a favorable prognosis.
Targeted therapy for non-small cell lung cancer (NSCLC) with HER2, BRAF, or hedgehog alterations: Interim data from MyPathway.
Authors: Hainsworth John D. , Bose Ron , Sweeney Christopher , Meric-Bernstam Funda , Hurwitz Herbert , Swanton Charles , Burris Howard A. , Kurzrock Razelle , Yoo Bongin , Beattie Mary Stanley , Gupta Ravindra , Patel Rajesh D. , Schulze Katja , Spigel David R. 
Published: September 2018

9073 Background: Treatments targeting critical molecular alterations (EGFR, ALK, and ROS1) in NSCLC are highly effective. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatment in non-indicated tumor types harboring alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. Interim results in NSCLC are presented. Methods: Patients with previously treated advanced NSCLC and alterations in the HER2 (amplification and/or mutation), BRAF (V600E or other mutations), Hh (SMO or PTCH-1 mutations), or EGFR (mutations other than known activating mutations) pathways received standard doses of pertuzumab + trastuzumab, vemurafenib, vismodegib, or erlotinib, respectively, until disease progression or unacceptable toxicity. The HER2, BRAF, and Hh cohorts are included in this analysis. The primary endpoint is investigator-assessed objective response rate (ORR, defined as complete response [CR] + partial response [PR]) by RECIST v1.1. Results: As of November 30, 2016, 61 patients with NSCLC and HER2 (n = 36), BRAF (n = 22), or Hh (n = 3) alterations have been treated (median age of 64 years, 49% male, 85% adenocarcinoma, and a median of 2 previous regimens). Median treatment duration was 1.8 (range, 0–21.4) months. Efficacy in the 55 patients with the minimum required follow-up for efficacy analysis is summarized in the table. Conclusions: Targeted therapy is active in patients with previously treated NSCLC harboring BRAF V600E mutations or HER2 alterations (amplifications and/or mutations). These cohorts have been expanded as MyPathway accrual continues. Additional efficacy data and details regarding molecular alterations will be presented. Clinical trial information: NCT02091141. [Table: see text]
Clinical outcomes of patients with non-small cell lung cancer (NSCLC) receiving chemotherapy after immune checkpoint blockade.
Authors: Grigg Claud , Reuland Brian D. , Sacher Adrian G. , Yeh Randy , Rizvi Naiyer A. , Shu Catherine A. 
Published: September 2018

9082 Background: Objective response rates (ORR) to chemotherapy beyond the first-line for advanced NSCLC are low (5-10%). Pre-clinical studies suggest that some chemotherapies may act, in part, through immune mediated mechanisms. Additionally, results from phase I/II studies of chemotherapy combined with immune checkpoint inhibitors (ICIs) suggest high response rates ( > 50%) and potential synergy. It is unknown whether chemotherapy is more efficacious when given after ICIs. Methods: We reviewed demographics, imaging, treatment history, and clinical course for all patients at our institution with a diagnosis of metastatic NSCLC who received at least one dose of nivolumab, pembrolizumab, atezolizumab, or durvalumab prior to December 8, 2016. Patients who received any subsequent chemotherapy were included for analysis. Objective response was determined by RECIST v1.1, and date of progression was determined radiographically or clinically (treatment discontinuation with documented clinical deterioration). Results: 145 patients received at least one dose of any ICI, and 38 patients received subsequent chemotherapy. The median age was 68 years (range 44-88). Six chemotherapy-naïve patients received carboplatin + pemetrexed +/- bevacizumab. There were 3 partial responses (PR) including one exceptional response that is ongoing after 2 years. Among 32 chemotherapy non-naïve patients, the median number of prior chemotherapy regimens was 2 (range 1-6). Post-ICI chemotherapy included docetaxel + ramucirumab (n = 12), vinorelbine (n = 7), gemcitabine-based chemotherapy (n = 6), carboplatin doublets (n = 4), pemetrexed + bevacizumab (n = 2), and paclitaxel (n = 1). Six patients had documented poor performance status and died within 1 month of starting treatment. The ORR was 25% (1CR, 7PR), median time to progression was 116 days, and 9 patients (28%) experienced stable disease (SD) or better lasting > 150 days. Exceptional responses occurred across regimens. Nine patients received a further line of chemotherapy, with 3 ongoing PR or SD lasting > 100 days. Conclusions: For NSCLC, chemotherapy response rates may be higher when administered after an ICI.
Response to single-agent (SA) chemotherapy (CTx) after immunotherapy exposure in non-small cell lung cancer (NSCLC).
Authors: Schvartsman Gustavo , Peng S. Andrew , Bis Giorgios , Lee J. Jack , Benveniste Marcelo Felipe Kuperman , Zhang Jianjun , Rinsurongkawong Waree , Lewis Jeff , Roarty Emily , Lacerda Lara , Roth Jack A. , Swisher Stephen , Heymach John , Fossella Frank V. , William William Nassib 
Published: September 2018

9083 Background: Overall response rates (ORR) to 2nd-line SACTx in NSCLC have consistently not exceeded 15%. Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in ORR to CTx after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if SACTx (3rd-line or beyond) would yield improved ORR when given after exposure to programmed-death-(ligand)1 inhibitors (PD1i) in metastatic NSCLC. Methods: Eligibility criteria - patients registered in the Thoracic GEMINI database of MD Anderson treated between 06/12 and 11/16 who received at least one SACTx as 3rd-line or beyond, following progression after platinum-based CTx and PD1i. We computed efficacy outcomes to each therapy, including ORR by RECIST v1.1, progression-free survival (PFS) and overall survival (OS). Results: Of 306 PD1i-treated patients registered in the database, 28 met eligibility criteria - 54% were male, median age 66 years, 82% adenocarcinoma, 29% never smokers. The PD1i and SACTx most commonly used were nivolumab (82%) and docetaxel (54%). ORR to SACTx after exposure to PD1i was 39% (11/28 patients, 8 confirmed). In contrast, ORR to 1st-line CTx in this cohort was 30% (Table). Liver metastasis and pembrolizumab as the PD1i of choice were the only factors associated with response to SACTx on univariate analysis (p < 0.05). Conclusions: In NSCLC patients, ORR to SACTx after immunotherapy exposure was higher compared to historical data from the pre-PD1i era, and approached ORR to 1st-line platinum-based CTx. Further investigation of a possible chemosensitization effect by immunotherapy is warranted. [Table: see text]
Tumor response dynamics of advanced non-small-cell lung cancer (NSCLC) patients (pts) treated with commercial PD-1 inhibitors in the clinical setting.
Authors: Nishino Mizuki , Dahlberg Suzanne Eleanor , Adeni Anika E , Lydon Christine A. , Hatabu Hiroto , Janne Pasi A. , Hodi F. Stephen , Awad Mark M. 
Published: September 2018

9087 Background: PD-1 inhibitors have shown promising activity in advanced NSCLC, with increasing clinical use. We evaluated tumor burden dynamics in advanced NSCLC pts treated with commercial PD-1 inhibitors to identify imaging markers for clinical benefit. Methods: The study included 160 advanced NSCLC pts (79 males; median age: 65) treated with commercial nivolumab or pembrolizumab monotherapy at DFCI as a part of routine clinical care. Tumor burden dynamics were assessed on serial CT scans during therapy by irRECIST1.1, which uses unidimensional measures and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. Results: Tumor burden change at best overall response (BOR) ranged from -100% to +278% (median: +3.5%). Objective response rate (ORR) was 18% (29/160). Current and former smokers had higher ORR than never smokers (ORR:14% (8/58), 25% (20/79), 4% (1/23); Fisher p = 0.04). Durable disease control with tumor burden < 20% increase from baseline for at least 6 months was noted in 27 pts (17%), which included 11 pts with stable disease as their irBOR. Using an 8-week landmark analysis, pts with < 20% tumor burden increase from baseline at 8 weeks had longer OS than pts with ≥20% increase (median OS:12.4 vs. 4.6 months, p < 0.001). In Cox models using a time varying covariate, pts with < 20% tumor burden increase during therapy had significantly reduced hazards of death (HR = 0.24, p < 0.0001) after adjusting for smoking (HR = 1.77, p = 0.016) and baseline tumor burden (HR = 1.66, p = 0.032). Two pts (1.3%) had atypical response pattern or “pseudoprogression”, where tumor burden showed initial increase and subsequent decrease, which was noted after confirmed irPD on consecutive scans in both pts. Conclusions: An objective response or durable disease control was noted in 25% of advanced NSCLC pts treated with PD-1 inhibitors in the clinical setting. Tumor burden increase of < 20% from the baseline during therapy was associated with longer OS, proposing a practical marker of clinical benefit. Pseudoprogression was uncommon, with tumor decrease noted after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluation.
A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).
Authors: Long Georgina V. , Atkinson Victoria , Menzies Alexander M. , Lo Serigne , Guminski Alexander David , Brown Michael Paul , Gonzalez Maria Magdalena , Diamante Katrina , Sandhu Shahneen Kaur , Scolyer Richard A. , Emmett Louise , McArthur Grant A. 
Published: September 2018

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]
Association of distinct baseline tissue biomarkers with response to nivolumab (NIVO) and ipilimumab (IPI) in melanoma: CheckMate 064.
Authors: Rodig Scott , Gusenleitner Daniel , Jackson Donald , Gjini Evisa , Giobbie-Hurder Anita , Jin Chelsea , Chang Han , Lovitch Scott , Horak Christine , Weber Jeffrey S. , Shipp Margaret Ann , Hodi F. Stephen 
Published: September 2018

9515 Background: CheckMate 064 (open label, phase 2) randomized advanced melanoma pts to NIVO 3 mg/kg Q2W for 6 doses then IPI 3 mg/kg Q3W for 4 doses (n = 70; cohort A), or the reverse (IPI then NIVO; n = 70; cohort B). More cohort A than cohort B pts had complete or partial response (54% and 31%, respectively). We sought to determine whether common or distinct baseline biomarkers were associated with response for each cohort. Methods: Protein expression of biomarkers identifying a broad array of cell lineages and immunoregulatory factors was determined by IHC and evaluated by 2 pathologists, with concordance. Global transcript expression was determined by RNAseq from frozen tissue. An elastic net predictor was trained on cohort A (α = 0.1, λ = 0.05) using leave-one-out cross-validation. RECIST v1.1 was used to assess tumor response. Results: Patients with tumors showing a pro-inflammatory transcriptional signature at baseline had superior overall response in cohort A, but not cohort B. Consistent with this observation, a parsimonious classifier of 10 immune/IFNγ-related genes predicted BOR (AUC 0.87) and OS (CPH log-likelihood P= 0.0003) for patients in cohort A, but not cohort B. In contrast, low baseline expression of MHC class I protein by malignant cells ( < 50% positive) was associated with disease progression (MHCI < 50% vs ≥50%: 12/13 vs 16/28 progressed) and inferior OS for patients in cohort B (MHCI < 50%: 6.42 mo [2.20, 9.66]; MHCI ≥50%: mOS 18.02 mo [7.98, not reached]: P= 0.0021, log-rank test), but not cohort A. Conclusions: Different pre-treatment biological characteristics of melanoma are associated with clinical response to NIVO followed by a planned switch to IPI (cohort A) and clinical response to IPI followed by NIVO (cohort B). Improved outcome with initial NIVO is strongly associated with a pro-inflammatory signature enriched for IFNγ targets. Inferior outcome with initial IPI is associated with reduction/loss of MHC I antigen presentation machinery. These data imply that NIVO broadly activates innate and adaptive immunity, whereas IPI is reliant upon CD8/MHC class I mediated adaptive immunity to effect clinical response. Clinical trial information: NCT01783938.