bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of radiologic features of pneumonitis induced by anti-PD-1 therapy.
Authors: Watanabe Satoshi , Ota Takeshi , Hayashi Masachika , Ishikawa Hiroyuki , Miyabayashi Takao , Terada Masaki , Sato Kazuhiro , Ishida Takashi , Tanaka Hiroshi , Iwashima Akira , Shoji Satoshi , Nozaki Koichiro , Ichikawa Kosuke , Kondo Rie , Yoshizawa Hirohisa , Kikuchi Toshiaki 
Published: March 2020

9065 Background: Anti-PD-1 therapy is now a standard treatment for patients with NSCLCs. Pneumonitis induced by immune-check point inhibitors is potentially fatal; however, some studies have shown that antitumor effects were enhanced in patients with pneumonitis. Although several radiologic patterns of pneumonitis induced by anti-PD-1 therapy have been reported, the association between radiologic features and clinical outcomes, especially enhancement of antitumor effects remains unclear. Methods: We retrospectively evaluated data of NSCLC patients treated in 1st to 3rd line with anti-PD-1 antibodies (nivolumab or pembrolizumab) at Niigata Lung Cancer Treatment Group. Pneumonitis was diagnosed by the treating investigators. The chest CT scans of patients with pneumonitis were independently reviewed by one radiologist and two pulmonologists to classify pneumonitis into 5 subtypes: cryptogenic organizing pneumonia-like (COP), ground glass opacities (GGO), interstitial, hypersensitivity and pneumonitis not otherwise specified (NOS). Results: Of 231 patients who received anti-PD-1 antibodies, pneumonitis developed in 33 patients (14.3%) at 7 institutions between January 2016 to October 2017. Of 33 patients with pneumonitis, the median age was 66 (range 45 to 82 years), 7 were female, 25 received nivolumab, and 8 received pembrolizumab. Sixteen patients were classified as GGO, 16 patients had COP-like appearance and one patient had NOS. The median survival time was significantly longer among patients with COP than among those with GGO (not reached vs. 7.8 months; HR 0.29, 95% CI 0.09-0.81; p = 0.0071). Pneumonitis improved in 94% (31 of 33) of cases, and one patient died from pneumonitis. The overall response ratio (CR+PR) was 44% in patients with COP and 31% in patients with GGO (p = 0.47). There was no statistical difference in OS between patients with systemic corticosteroid therapy for pneumonitis and those without (not reached vs. 14.8 months; HR 1.4, 95% CI 0.52-4.1; p = 0.51). Conclusions: Patients with pneumonitis classified as COP had significantly longer survival time than those with pneumonitis classified as GGO. Radiologic features of pneumonitis may reflect clinical outcomes after anti-PD-1 therapy.
Longitudinal analysis of plasma ALK mutations during treatment with next-generation ALK inhibitors.
Authors: Dagogo-Jack Ibiayi , Rooney Marguerite , Nagy Rebecca , Digumarthy Subba , Chin Emily , Ackil Jennifer , Gainor Justin F. , Lin Jessica Jiyeong , Lanman Richard B. , Shaw Alice Tsang 
Published: March 2020

9068 Background: Next-generation ALK tyrosine kinase inhibitors (TKIs) are the cornerstone of management of ALK-positive (ALK+) lung cancer. Each ALK TKI has a unique spectrum of activity against distinct ALK kinase domain mutations (muts). Plasma genotyping is a promising strategy for identifying ALK muts at relapse on ALK TKIs. Methods: To detect ALK muts, we performed next-generation sequencing (Guardant360) of circulating tumor DNA from patients (pts) with ALK+ lung cancer relapsing on a second-generation (2nd-gen) ALK TKI (n = 65) or the third-generation (3rd-gen) TKI lorlatinib (n = 26). Results: Among 65 pts progressing on a 2nd-gen TKI, 49 (75%) had only received one 2nd-gen ALK TKI prior to analysis: n = 42 alectinib, n = 3 each brigatinib/ceritinib, and n = 1 ensartinib. We detected an ALK mut in 42/65 (65%) specimens at relapse, among which ALK G1202R (32%) and I1171X (23%) were the most common. Sixteen (25%) pts had ≥2 ALK muts at progression on a 2nd-gen TKI. Among 26 pts progressing on lorlatinib (all of whom had previously relapsed on a 2nd-gen ALK TKI), we identified ALK muts in 20 (76%), including 14 (54%) with ≥2 ALK muts. Detection of ≥2 ALK muts was more common at relapse on lorlatinib compared to a 2nd-gen TKI (p = 0.013). To assess the evolution of ALK muts during treatment with different TKIs, we analyzed serial plasma specimens from 20 pts treated with sequential 2nd-gen/2nd-gen or 2nd-gen/3rd-gen TKIs. Among six pts who received alectinib followed by brigatinib, repeat plasma analysis at brigatinib progression revealed persistence of pre-brigatinib ALK muts in two pts (one L1196M and one G1202R), expansion of G1202R in one pt, and acquisition of new ALK muts in three pts. Among 14 pts who received a 2nd-gen TKI followed by lorlatinib, 11 had persistence of pre-lorlatinib ALK muts and 8 acquired ≥1 additional ALK muts at lorlatinib progression. The most frequently acquired ALK mut was D1203N in four of eight cases. Conclusions: ALK resistance muts are prevalent at relapse on next-generation ALK TKIs and increase with each successive generation of ALK TKIs. These findings suggest that sequential therapy with increasingly potent ALK TKIs may select for compound ALK muts and/or fuel tumor heterogeneity.
Time-to-treatment discontinuation (TTD) and real-world progression-free survival (rwPFS) as endpoints for comparative efficacy analysis between entrectinib trial and crizotinib real-world ROS1 fusion-positive (ROS1+) NSCLC patients.
Authors: Doebele Robert Charles , Perez Laura , Trinh Huong , Martinec Michael , Martina Reynaldo , Riehl Todd , Krebs Matthew , Meropol Neal J. , Wong William Bruce , Crane Gracy 
Published: March 2020

9070 Background: Entrectinib is an oral tyrosine kinase inhibitor for ROS1+ NSCLC. Three phase 1/2 single-arm studies showed entrectinib efficacy in this population (Doebele WCLC 2018). Due to the rarity of ROS1+ pts generating direct comparative evidence in prospective randomized trials is difficult. We identified a retrospective real-world cohort of ROS1+ NSCLC pts from electronic health records (EHR), to compare crizotinib, the current standard of care, to entrectinib as reported in clinical trials. Methods: Crizotinib-treated pts with advanced ROS1+ NSCLC diagnosed 1 Jan 2011 to 30 Jun 2018, were identified with technology-enabled abstraction in the Flatiron Health EHR-derived database ( > 2.1 million cancer pts from US oncology practice). Entrectinib trial inclusion/exclusion criteria were applied to match the crizotinib cohort as closely as possible. Primary endpoint: TTD, adapted from Gong (ASCO 2018); rwPFS (physician/scan report) and OS were secondary outcomes. Time-to-event analyses used Kaplan-Meier survival curves and Cox proportional hazard models on propensity score weighted populations; age, gender, race/ethnicity, smoking status, brain metastasis and previous lines of therapy were prognostic factors. Results: We analyzed 53 entrectinib and 69 crizotinib ROS1+ NSCLC pts. Median weighted TTD: entrectinib, 14.6 mo (95% CI: 8.3–23.8); crizotinib, 8.8 mo (95% CI: 8.2–9.9). When rwPFS from crizotinib was compared to trial PFS, entrectinib had longer PFS vs crizotinib (weighted HR: 0.44; 95% CI: 0.27–0.74). Median OS with entrectinib was not reached (median follow-up: 15.5 mo); weighted median OS with crizotinib was 18.5 mo (95% CI: 15.1–19.9). Findings were consistent across multiple sensitivity analyses. Conclusions: Entrectinib was associated with longer TTD and PFS in ROS1+ NSCLC pts vs a matched real-world crizotinib population. Control populations derived from real-world cohorts can supplement evidence from clinical trials in settings where new standards of care are needed, but where only limited data are available and randomization is not feasible.
DNA damage response gene alterations are associated with high tumor mutational burden and clinical benefit from programmed death 1 axis inhibition in non-small cell lung cancer.
Authors: Ricciuti Biagio , Cheng Michael L. , Recondo Gonzalo , Nishino Mizuki , Umeton Renato , Sholl Lynette M. , Awad Mark M. 
Published: March 2020

9077 Background: DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. Methods: Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. DDR positive (DDRpos) cases were defined as those with pathogenic DDR alterations (per COSMIC and ClinVar databases). DDR negative (DDRneg) cases were defined as either DDR wild-type or those with non-pathogenic DDR alterations. Results: Of 468 pts with successful NGS who received ICIs, 242 (51.7%) were identified as having any DDR alteration. Of them, 74 (15.8% in the entire cohort) were defined as DDRpos with pathogenic alterations in the following genes: ATM (41.9%), MLH1/MSH2/MSH6 (18.9%), BRCA1/2 (16.2%), CHEK1/2 (9.4%), FANC genes (9.4%), BAP1 (5.4%), RAD genes (5.4%), ERCC4/6 (4.0%), POLE (2.7%), ATR (2.7%). DDRpos and DDRneg groups were balanced in terms of age, performance status, gender, histology, oncogenic driver mutation, smoking status, ICI line, baseline brain metastases. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.1 vs 9.8 mutations/megabase, P = 0.007). No difference in median PD-L1 tumor proportion score was observed between groups (30% vs 25%, P = 0.33). Compared to DDRneg pts (N = 394), DDRpos pts had a significantly higher objective response rate (31.1% vs 19.1%, P = 0.03), and longer median progression-free survival (4.3 vs 2.6 months, HR: 0.71 [95%CI: 0.53-0.95], P = 0.02) and overall survival (16.3 vs 9.8 months, HR: 0.63 [95%CI: 0.45-0.89], P = 0.009) with PD-(L)1 therapy. Conclusions: Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC pts treated with PD-1 axis inhibition.
Phase II randomized trial of afatinib with or without cetuximab as first-line treatment for EGFR mutated non-small cell lung cancer (NSCLC) patients (IFCT-1503 ACE-Lung).
Authors: Cortot Alexis B. , Madroszyk Anne , Giroux Leprieur Etienne , Molinier Olivier , Quoix Elisabeth A. , Berard Henri , Otto Josianne , Rault Isabelle , Raimbourg Judith , Hureaux Jose , Moreau Lionel , Debieuvre Didier , Morel Hugues , Denis Marc G. , Amour Elodie , Morin Franck , Moro-Sibilot Denis , Cadranel Jacques ,   French Cooperative Thoracic Intergroup (IFCT)
Published: March 2020

9079 Background: First-line treatment of metastatic EGFR-mutated NSCLC relies on EGFR-TKIs. However, all patients (pts) eventually develop progression. Dual inhibition of EGFR with afatinib (A), an irreversible pan-erbB TKI, and cetuximab (C), an EGFR monoclonal antibody, has shown activity in EGFR-mutated pts with acquired resistance to TKIs, regardless of the T790M status. Methods: We conducted a phase II randomized trial in advanced NSCLC pts harboring an activating EGFR mutation, who had not received prior therapy. Pts were treated with A (40 mg/d) until progression alone or with C 500 mg/m² every 2 weeks during 6 months (mos) (beginning at D15 at 250 mg/m²). Primary endpoint was time-to-treatment failure (TTF) at 9 mos for pts with del19 and L858R mutations. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS). Prospective monitoring of the T790M mutation was performed on circulating tumoral DNA (ctDNA) by digital PCR. Results: Trial was stopped early due to futility analysis after 118 pts were enrolled (59 in each arm). Baseline characteristics were balanced between the 2 arms, and especially for the types of EGFR mutation (del19, 55.9 vs 50.8%; L858R, 39 vs 40.7%; others, 5.1 vs 8.5% in AC and A arms, respectively). Treatment-related AEs of any grades were similar, although there was an excess of grade 3 AEs in the AC arm (50 vs 37.3%), but no of grade 5. The excess in grade 3-5 AEs was essentially due to cutaneous (96.6 vs 81.4%), eyes (32.8 vs 27.1%), hematological (22.4 vs 15.3%) but not to digestive toxicities (89.7 vs 98.3%). Among the 117 pts included in the efficacy analysis, 9-months TTF was 63.3% (47.5-75.6) in arm A and 65.8% (50.1-77.66) in arm AC. Median TTF was 11.1 mos (8.3-not reached [NR]) and 10.8 mos (9.2-13.7) in arms A and AC, respectively. Median PFS was 11.1 mos (8.3-NR) and 12.8 mos (9.2-13.7), respectively. Median OS was 20.8 mos (17.5-NR) and NR (17-NR), respectively. Conclusions: Efficacy of AC was similar to that of A alone. These results don’t support further evaluation of this combination in this setting. Results of ctDNA monitoring will be reported during the meeting. Clinical trial information: NCT02716311.
Health-related quality of life (HRQoL) results from ALTA-1L: Phase 3 study of brigatinib vs crizotinib as first-line (1L) ALK therapy in advanced ALK+ non-small cell lung cancer (NSCLC).
Authors: Campelo Rosario Garcia , Lin Huamao Mark , Perol Maurice , Jahanzeb Mohammad , Popat Sanjay , Zhu Yanyan , Zhang Pingkuan , Camidge D. Ross 
Published: March 2020

9084 Background: Results from ALTA-1L (NCT 02737501 ), an international, multicenter trial, showed that brigatinib vs crizotinib as 1L ALK therapy significantly prolongs progression-free survival (PFS; HR: 0.49, 95% CI, 0.33, 0.74) in advanced ALK+ NSCLC. HRQoL was evaluated as a secondary objective. Methods: ALK+ NSCLC patients were randomized 1:1 to brigatinib 90 mg daily for 7 days, then 180 mg daily or crizotinib 250 mg twice daily as 1L ALK therapy; treatment cycles were 28 days. HRQoL was assessed with the EORTC QLQ-C30 and LC13. Change from baseline, duration of improvement and time to worsening were analyzed in the ITT-PRO population (n = 131 for both groups). Results: HRQoL compliance was > 90% for brigatinib and crizotinib. Global health status (GHS)/QoL improved starting at cycle 2, with clinically meaningful improvement (≥10-point increase) noted with brigatinib at cycles 5−8, 10−13, 17 and 19 and crizotinib at cycle 6. Brigatinib substantially improved overall HRQoL vs crizotinib, as demonstrated by the estimated mean difference on change from baseline (4.1, P< 0.05) and duration of improvement for GHS/QoL (HR = 0.16, P< 0.001). Improved GHS/QoL with brigatinib vs crizotinib was also supported by improvement in several functional domains (Table) and for these symptoms ( P< 0.05): fatigue, nausea/vomiting and appetite loss. No domains significantly favored crizotinib. Brigatinib showed a trend to prolong time to worsening of dyspnea vs crizotinib (HR 0.65, 95% CI 0.38, 1.12). Table: HRQoL results brigatinib vs crizotinib Clinical trial information: NCT02737501. Conclusions: Consistent with the prolongation of PFS seen in 1L treatment of advanced ALK+ NSCLC, brigatinib improved HRQoL and prolonged the duration of improvement in GHS/QoL, and the majority of functional and symptom domains vs crizotinib.[Table: see text]
Pembrolizumab alone or with chemotherapy for PD-L1 positive NSCLC: A network meta-analysis of randomized trials.
Authors: Doherty Mark , Delos Santos Seanthel , Rahmadian Amanda Putri , Everest Louis , Chan Kelvin K. 
Published: March 2020

9087 Background: Pembrolizumab (P) has replaced chemotherapy (C) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression > / = 50%. Among PD-L1 unselected patients, P+C is superior to C alone. This network meta-analysis compared P alone with P+C in patients with > / = 50% PD-L1 positive NSCLC. Methods: An indirect network was constructed to compare P and P+C through the control arms of the Keynote 024, 189 and 407 (PD-L1 > / = 50% subgroup) trials. Baseline characteristics and chemotherapy outcomes were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicities including immune-related adverse events (irAE) were extracted from trial results. Toxicity results were unavailable for the PD-L1 > / = 50% subgroups of KN 189 & 407, so overall study results were used. Survival outcomes are expressed as hazard ratios (HRs) or restricted mean survival time (RMST) ratios, and toxicity and ORR as risk difference (RD). Results: 507 patients were included: 154 on P, 430 on C and 483 on P+C. Patient characteristics across trials were similar in age, sex, performance status and smoking history. All trials had similar chemotherapy outcomes (PFS 6, 4.9, 4.8 mos) suggesting similar populations. Network meta-analysis showed no difference between P+C and C alone in OS (HR 0.85, 95%CI 0.45-1.59, p = 0.60) or PFS (HR 0.73, 95%CI 0.48-1.1, p = 0.13), but P+C was associated with higher ORR (+16.9%, 95%CI 0.7-33%, p = 0.04). RMST analysis suggested fewer early PFS events with P+C (0-6 mo RMST ratio 1.25, RMST difference 1.02 mo, p = 0.002), with the difference disappearing at 1 year (0-12 mo RMST ratio 1.16, p = 0.07). No difference in RMST for OS was found. Overall toxicities, hematologic and grade 3-5 toxicities were higher with P+C compared with P alone (table). Conclusions: Among patients with > / = 50% PD-L1 positive NSCLC, P+C did not improve OS or PFS compared with P alone, but was associated with higher ORR. RMST analysis suggested fewer early progression events using P+C. [Table: see text]
A plasma miRNA signature classifier identifies PD-L1 ≥ 50% NSCLC nonresponders to immune checkpoint inhibitors.
Authors: Proto Claudia , Prelaj Arsela , Verri Carla , Signorelli Diego , Lo Russo Giuseppe , Ferrara Roberto , Galli Giulia , Trevisan Benedetta , Mavis Mensah , De Braud Filippo G. , Garassino Marina Chiara , Sozzi Gabriella , Boeri Mattia 
Published: March 2020

9096 Background: A sizable proportion of PD-L1≥50% NSCLC patients (pts) do not respond to single agent immune checkpoint inhibitors (ICI) and no biomarker is able to identify non responders. A three levels plasma microRNA signature classifier (MSC), reflecting an immunosuppressive profile of immune cell subsets, has already shown its ability to identify pts treated with ICI with a worse prognosis independently from PD-L1 expression. Aim of this trial is to prospectively test the ability of MSC to identify at diagnosis PD-L1≥50% non responders to ICI. Methods: we prospectively collected baseline plasma samples from 41 consecutive advanced EGFR/ALK/ROS1 wild-type NSCLC pts with PD-L1 TPS ≥50% treated with ICI as first (n = 28) or further line treatment to run the MSC molecular test. Pts were stratified in high (H) vs intermediate/low (I/L) risk levels. Overall response rate (ORR) and the relative risk of response (RR) were evaluated by 2x2 contingency table using Fisher exact test. Cox proportional hazard models were used to define crude and adjusted hazard ratio (HR). Results: According to RECIST 1.1 criteria, 14 (34%) pts respond to ICIs. With a global median follow-up of 9.8 months, median progression free survival (PFS) and overall survival (OS) were 7.9 months and not reached, respectively. Ten (24%) NSCLC pts were MSC H risk level. ORR was 0% in MSC H vs 45% in MSC I/L risk pts (RR = 0.10; 95%CI = 0.00-0.90; p = 0.0080). Median PFS was 11.4 months for MSC I/L pts vs 2.3 months for MSC H risk (HR = 0.26 95%CI = 0.11-0.62; p = 0.0021). Median OS was not reached for MSC I/L vs 2.7 months for MSC H risk pts (HR = 0.17 95%CI = 0.06-0.48; p = 0.0008). Data remained significant adjusting for age, sex, pack-years and ECOG performance status at the baseline: PFS HR = 0.24 (95%CI = 0.09-0.66; p = 0.0054) and OS HR = 0.15 (95%CI = 0.05-0.51; p = 0.0023). Conclusions: plasma MSC shows promising results for treatment selection with ICI. So far, MSC is the only molecular test able to identify a group of NSCLC pts with PD-L1≥50% who do not respond to single agent immunotherapy. Ongoing trials are validating these results and testing the possible predictive effect of MSC in chemotherapy plus immunotherapy combinations.
DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).
Authors: Mamdani Hirva , Chen Jerry , Kim Seongho , Ibrahim Yahya , Asad Mohammad Fahad Bin , Nieva Jorge J. , Feldman Rebecca , Naqash Abdul Rafeh , Liu Stephen V. , Ma Patrick C. , Portnoy David Craig , Borghaei Hossein , Abdel Karim Nagla Fawzy , Boumber Yanis , Vanderwalde Ari M. , Spira Alexander I. , Jalal Shadia Ibrahim 
Published: March 2020

9100 Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as ≥10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high (≥50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( < 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with ≥3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of ≥3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.