bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of DNA versus RNA NGS-based Methods in MET Exon 14 skipping mutation detection.
Authors: Jurkiewicz Magdalena , Saqi Anjali , Mansukhani Mahesh M , Hodel Vaishali , Krull Anamaria , Shu Catherine A. , D’Silva Fernandes Helen 
Published: May 2020

9036 Background: Exon 14 skipping mutations in the mesenchymal-epithelial transition ( MET) gene are reported in 2-5% of lung adenocarcinomas and are mutually exclusive of other driver mutations. Small-molecule MET tyrosine kinase inhibitors, capmatinib and tepotinib, showed durable responses in previously treated and treatment-naïve patients harboring MET-exon-14 skipping mutations. Studies suggest that for detection of MET-ex14 mutations, DNA-based assays alone may be sub-optimal when compared to RNA-based NGS assays. We compared the performance of DNA and RNA-based assays for detection of MET-ex14 variants. Methods: We examined NGS-based profiling data of lung adenocarcinomas (or when this diagnosis could not be excluded) to identify MET-ex14 mutations missed by DNA but identified by RNA analysis. The carcinomas were profiled by a DNA-based NGS panel that targets MET exons 2, 14, 16, 18 and 19. Cases without driver mutations were reflexed to an NGS-based RNA fusion panel (Archer’s Anchored Multiplex PCR). Results: Over a 21-month period, MET-ex14 skipping events were detected in 16/644 (2.5%) lung carcinomas by DNA profiling. RNA analysis on driver-negative cases identified 9 additional MET-ex14 mutations. All 16 MET-ex14 DNA variants occurred at or around the intron 14 splice donor site, as the assay did not include the intron 13 splice acceptor site. Clinical characteristics of the MET positive cohort include a male to female ratio of 0.8:1.0, an average age of 76.5 years and 52% non-smoker status. All tumors were adenocarcinomas (including one with a < 10% spindle/pleomorphic component) with the exception of 3 adenosquamous carcinomas and 1 squamous cell carcinoma. Conclusions: DNA based NGS-panels can potentially miss MET-ex14 skipping events in lung carcinomas, when the primers do not target both 3′ splice site of intron 13, and the 5′ splice site of intron 14. A reflex work flow interrogating RNA fusions can potentially capture such events. The clinical and molecular characterization of the variants detected only by RNA NGS assays warrants further exploration.
Clinical characteristics, genomic features, and recurrence risk of early-stage MET exon 14 mutant non-small cell lung cancer (NSCLC).
Authors: Recondo Gonzalo , Guo Robin , Cravero Paola , Ricciuti Biagio , Falcon Christina , Vokes Natalie , Kris Mark G. , Leonardi Giulia Costanza , Lamberti Giuseppe , Nguyen Tom , Venkatraman Deepti , Sholl Lynette Marie , Drilon Alexander E. , Awad Mark M. 
Published: May 2020

9042 Background: MET exon 14 alterations occur in ~3% of patients (pts) with NSCLC. Although clinical and genomic features of MET exon 14 mutant (mut) NSCLC are better characterized in the metastatic setting, less is known about early-stage disease for this molecular subtype. Methods: Clinicopathologic and genomic data were collected from patients (pts) with resected stage I-III MET exon 14 mutant NSCLC at the Dana-Farber Cancer Institute (DFCI) and the Memorial Sloan Kettering Cancer Center (MSKCC). We estimated the disease-free survival (DFS) and overall survival (OS) of patients from the date of surgical resection. The prevalence of MET exon 14 mutations in stage I-III NSCLC was assessed using OncoPanel NGS v3.0 at DFCI. Results: The prevalence of MET exon 14 alterations in resected tumors of pts with stage I-III NSCLC at DFCI using Oncopanel v3 was 2.8% (17/613) overall: 2.9% (16/542) in non-squamous and 1.4% (1/71) in squamous histology. We identified 131 pts with resected stage I-III (I = 73, II = 28, III = 30) MET exon 14 mut NSCLC at DFCI (Oncopanel v1-v3) and MSKCC (MSK-IMPACT), with a median age of 71 years (yrs) (range: 43-88). There were no significant differences in sex, smoking status, or type of MET alteration across stages. In stage I resected tumors there was a higher proportion of adenocarcinoma histology compared to stages II and III (p = 0.009). The median harmonized TMB (mTMB) was similar across stages (p = 0.43). Common genomic co-alterations included MET amplification (amp) (5.3%), CDK4/ 6 amp (19.1%), MDM2 amp (35.1%), TP53 mut (17.6%) and CDKN2A/ B loss (9.2%). The median DFS in stage I, II, and III NSCLC was 8.3 yrs (95% CI: 3.1-8.3), 2.6 yrs (95% CI: 1.0-2.6), and 2.1 yrs (95% CI: 0.7-2.7), respectively (p = 0.017). The median OS in stage I, II, and III NSCLC was 9.2 yrs (95% CI: 8.5 -10.5), not reached (NR) (95% CI: NR-NR), and 4.1 yrs (95% CI: 3.6-4.1), respectively (p = 0.052). Concurrent MET amp was independently associated with worse DFS (HR: 4.9, 95% CI: 1.8-13.1; p = 0.002) in multivariate analysis. Conclusions: MET exon 14 mutations are present in 2.8% of resected stage I-III NSCLCs. Given the prevalence of this molecular alteration in early-stage NSCLC, clinical trials exploring the role of adjuvant and neoadjuvant MET targeted therapies in this population may be warranted.
CCTG BR.34: A randomized trial of durvalumab and tremelimumab +/- platinum-based chemotherapy in patients with metastatic (Stage IV) squamous or nonsquamous non-small cell lung cancer (NSCLC).
Authors: Leighl Natasha B. , Laurie Scott Andrew , Goss Glenwood D. , Hughes Brett Gordon Maxwell , Stockler Martin R. , Tsao Ming Sound , Kulkarni Swati , Blais Normand , Joy Anil A. , Mates Mihaela , Rana Punam , Yadav Sunil , Underhill Craig , Lee Christopher W. , Bradbury Penelope Ann , Hiltz Andrea , Dancey Janet , Ding Keyue , Vera Badillo Francisco Emilio ,   Canadian Cancer Trials Group, Australasian Lung Cancer Trials Group
Published: May 2020

9502 Background: First-line therapy for advanced NSCLC includes PD-1 checkpoint inhibitor (ICI) monotherapy, and in combination with chemotherapy. Combination ICI have also demonstrated better survival compared to chemotherapy (CM-227). In CCTG BR.34, we compared overall survival (OS) in patients with advanced NSCLC receiving first-line durvalumab plus tremelimumab (DT) with or without platinum doublet chemotherapy (CT). Methods: This international, open-label, randomized trial accrued 301 participants from Canada and Australia, with stage IV NSCLC, EGFR/ALK wildtype, ECOG PS 0/1. Patients were randomized to DT for 4 cycles or DT+CT (pemetrexed- or gemcitabine-platinum), with ongoing D or D + pemetrexed (non-squamous) maintenance until disease progression. Stratification factors included histology, stage IVA v. IVB and smoking status. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR = CR + PR) and adverse events (AEs). Results: At a median follow up of 16.6 months, no significant difference in OS was seen between the two treatment arms, with a median OS of 16.6 months with DT+CT v. 14.1 months with DT, (estimated HR 0.88, 90% CI 0.67-1.16). PFS was significantly improved in the DT+CT arm (stratified HR 0.67, 95% CI 0.52-0.88; medians 7.7 v. 3.2 months). ORR was higher in the DT+CT arm, 28% v. 14%, (odds ratio 2.1, p=0.001). Preplanned subgroup analysis demonstrated no significant differences in treatment outcomes by plasma TMB (<20 v. ≥20 mut/Mb, Guardant OMNI), age, sex, or smoking status. There was a trend to improved OS with DT+CT in the subgroup with PD-L1 TPS≥50%, (HR 0.64, 95% CI 0.40-1.04, p=0.07). Plasma TMB<20 mut/Mb was associated with shorter survival in both treatment groups (HR 1.99, 95% 1.3-3.1). Toxicity was greater in the DT+CT arm, with grade≥3 adverse events in 82% v. 70%, (p=0.02), most commonly dyspnea, nausea and cough. The incidence of immune-related adverse events was similar between arms (colitis 11%, pneumonitis 6%, endocrinopathy 21%). Grade 5 events occurred in 2.7%, (5 with DT+CT, 3 with DT). Conclusions: The addition of CT to first-line DT did not improve OS in advanced NSCLC. CT+DT improved ORR and PFS, and was associated with greater toxicity. No differential effects were seen by PD-L1 TPS nor bTMB. These data suggest that adding chemotherapy to ICI may be beneficial in those with PD-L1 TPS >=50%, and warrant further analysis in independent datasets. Clinical trial information: NCT03057106 .
Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial.
Authors: Subbiah Vivek , Gainor Justin F. , Oxnard Geoffrey R. , Tan Daniel Shao-Weng , Owen Dwight Hall , Cho Byoung Chul , Loong Herbert H. F. , McCoach Caroline Elizabeth , Weiss Jared , Kim YuJung , Bazhenova Lyudmila , Park Keunchil , Daga Haruko , Besse Benjamin , Gautschi Oliver , Ng Sarah , Huang Xin , Drilon Alexander E. 
Published: May 2020

9516 Background: Patients with RET fusion-positive NSCLC have an ~50% lifetime prevalence of developing central nervous system (CNS) metastases. Selpercatinib is a highly selective oral RET inhibitor with CNS penetration. Its intracranial antitumor activity was previously demonstrated in an orthotopic RET fusion-positive preclinical model. The activity of selpercatinib in RET fusion-positive NSCLC patients with CNS metastases was evaluated as a prespecified subgroup analysis in LIBRETTO-001, a registrational phase 1/2 trial (NCT03157128). Methods: This global (89 sites, 16 countries) trial enrolled patients with advanced RET-altered solid tumors, including patients with RET fusion-positive advanced NSCLC with baseline CNS metastases. The selpercatinib recommended phase 2 dose was 160 mg twice daily, dosed orally in 28-day cycles. CNS metastases were assessed by MRI/CT scan at baseline, then every 8 weeks for 1 year, and every 12 weeks thereafter. The primary endpoint for this analysis was intracranial objective response rate (ORR, confirmed; RECIST v1.1) as assessed by independent review committee (IRC). Secondary endpoints included intracranial duration of response (DoR) by IRC. To be included in the efficacy analysis, patients were required to have adequate follow-up time (opportunity for ≥6 months follow-up from the first dose). Analyses were based on 17Jun2019 data cutoff date. Results: 79 patients with RET fusion-positive NSCLC and baseline CNS metastases were enrolled. Per IRC, 22 of 79 patients had measurable (≥10 mm) CNS disease; 14 of the 22 patients had adequate follow-up time for analysis. This efficacy-evaluable population had a median age of 64 yrs (range 43-80), ECOG PS 0/1 = 21% / 79%, and all had prior systemic therapy. 5 of the 14 patients received prior intracranial radiotherapy; all radiotherapy was completed > 2 months prior to selpercatinib. The intracranial ORR in the 14 patients was 93% (n = 13; 95% CI = 66.1 – 99.8), including 2 complete responses (14%) and 11 partial responses (79%). The median intracranial DoR was 10.1 months (95% CI = 6.7 – NE), with CNS progression events (n = 5) or death (n = 1) reported in 6 of 13 responders. The remaining responders (n = 7) were ongoing and censored. Presentation will include updated IRC data as of 16Dec2019. Conclusions: Selpercatinib had marked intracranial anti-tumor activity in RET fusion-positive NSCLC patients with CNS metastases. Tumor responses were durable, independently-confirmed, and observed in patients with prior systemic chemotherapy. Clinical trial information: NCT03157128 .
Capmatinib in patients with METex14-mutated or high-level MET-amplified advanced non–small-cell lung cancer (NSCLC): results from cohort 6 of the phase 2 GEOMETRY mono-1 study.
Authors: Groen Harry J.M. , Akerley Wallace L. , Souquet Pierre Jean , Laack Eckart , Han Ji-Youn , Smit Egbert F. , Mansfield Aaron Scott , Garon Edward B. , Wolf Juergen , Tan Daniel Shao-Weng , Heist Rebecca Suk , Waldron-Lynch Maeve , Le Mouhaer Sylvie , Nwana Ngozi , Giovannini Monica , Orlov Sergey 
Published: May 2020

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]
Tumor antigen expression and survival of patients with previously treated advanced non-small cell lung cancer (NSCLC) receiving viagenpumatucel-L (HS-110) plus nivolumab.
Authors: Morgensztern Daniel , Waqar Saiama Naheed , Bazhenova Lyudmila , McDermott Lori , Hutchins Jeff , Taylor David H , Robinson Fred L , Dowdell Alexa K , Piening Brian , Harb Wael A. , Pennell Nathan A. , Cohen Roger B. 
Published: May 2020

9546 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with gp96-Ig fusion protein. Gp96-Ig functions as an antigen chaperone for dendritic cell activation and direct CD8+T cell expansion via cross presentation. DURGA is a multi-cohort study evaluating HS-110 plus anti-PD-1 mAbs in patients (pts) with advanced NSCLC. We report on Cohort A, which enrolled previously-treated pts who had not received an anti-PD(L)1 prior to study entry. Methods: Primary objectives were safety and objective response rate (ORR). Overall Survival (OS) was a secondary endpoint. Pts received 1 X 107 HS-110 cells intradermally every week for 18 wks and nivolumab until tumor progression. To determine cancer testis antigen (CTA) overexpression from baseline pt tumor samples, hybrid-capture RNA-seq libraries were prepared from macrodissected formalin fixed paraffin embedded tumor tissue and sequenced on an Illumina NovaSeq 6000. Gene-level transcripts were quantified using the Salmon software package. Results: 47 pts were enrolled into Cohort A. ORR and clinical benefit rate (CR + PR + SD) were 21% and 43%, respectively, with a 17.2 month median duration of response. Median OS was 28.7 months (mos), with a median follow up of 15.7 mos. One and 2-year survival were 57% and 36%, respectively. A prespecified exploratory analysis of CTA expression level in baseline pt tumor tissue was performed. 50% of pts shared at least 8 of the 39 total antigens overexpressed by HS110. Although there was no difference in ORR between these groups, mOS was higher in pts with tumors that shared ≥ 8 antigens with HS-110 (not reached (NR) [95%CI: 10.3 mos, NR] vs 6.7 mos [95%CI: 1.4 mos, NR]), p = 0.028. Pts whose tumors expressed the ZNF492 antigen also had improved OS (NR [95%CI: 11.6 mos, NR] vs 7.2 mos [95%CI: 1.6 mos, NR]), p = 0.03. All pts experienced at least one adverse event (AE), and the most common AEs were fatigue (28%), arthralgia (19%) and cough (17%). There were 2 grade 5 AEs not related to treatment. Conclusions: The combination of HS-110 and nivolumab appears safe and well tolerated. OS was improved in pts whose tumors express ≥ 8 shared antigens with HS110, as well as in those who specifically expressed ZNF492. Further exploration of antigen expression as a predictor for treatment outcome with HS110 plus nivolumab is ongoing. Clinical trial information: NCT02439450 .
Primary efficacy and biomarker analyses from the VISION study of tepotinib in patients (pts) with non-small cell lung cancer (NSCLC) with METex14 skipping.
Authors: Le Xiuning , Felip Enriqueta , Veillon Remi , Sakai Hiroshi , Cortot Alexis B. , Garassino Marina Chiara , Mazieres Julien , Viteri Ramirez Santiago , Senellart Helene , Van Meerbeeck Jan , Reinmuth Niels , Conte Pier Franco , Kowalski Dariusz , Cho Byoung Chul , Straub Josef , Scheele Jürgen , Juraeva Dilafruz , Bruns Rolf , Heymach John , Paik Paul K. 
Published: May 2020

9556 Background: Preliminary tepotinib data showed durable activity in pts with NSCLC with METex14 skipping prospectively identified by liquid (L+) or tissue (T+) biopsy. Having met target enrollment of ≥60 L+ pts & ≥60 T+ pts, we report primary data. Methods: VISION Cohort A enrolled pts with advanced EGFR/ALK wt, METex14 skipping NSCLC (asymptomatic brain metastases [BM] allowed), who received oral tepotinib 500 mg QD. On-study treatment decisions were based on investigator assessment (INV) of response. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) analyzed in 3 primary ITT sets: L+ and/or T+, L+, T+. 2ary endpoints included ORR by INV, duration of response (DOR), disease control rate (DCR), PFS, OS, & safety. Preplanned analyses were performed in pts with BM at baseline (BL). BL/on-treatment ctDNA plasma samples (L+) were analyzed using a 73-gene NGS panel (Guardant360). Deep molecular responses (MR), defined as > 75% depletion of METex14, were compared with objective responses (OR). Results: By data cut-off (1 Oct 19) 151 pts received tepotinib (safety set); 99 L+/T+, 66 L+, 60 T+ pts comprised the 3 ITT sets with ≥6-month [m] follow-up. Across treatment lines (n = 44 1L, n = 55 ≥2L), primary ORR & mPFS [95% CI] in 99 L+/T+ pts were 43% [34–54] & 8.6 m [6.9–11.0] by IRC and 56% [45–66] & 9.5 m [6.7–13.5] by INV. ORR was similar in L+ or T+ pts (table) or in T+L− pts (n = 25): 40% [21–61] by IRC and 48% [28–69] by INV. Only 2 pts were T−L+. Outcomes were also comparable in pts with BM (n = 11): IRC ORR 55% [23–83] & mPFS 10.9 m [8.0–ne]. 34/51 pts (67%) with matched BL/on-treatment L+ samples had deep MR strongly associated with clinical response: 32/34 pts (94%) with MR had disease control (INV), including 29/34 pts (85%) with OR; 2/34 pts had progressive disease. Further biomarker data will be presented. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 37/151 pts (25%). 13 pts (9%) discontinued due to TRAEs. Conclusions: Tepotinib is a promising targeted therapy with durable clinical activity and manageable toxicity in pts with METex14 skipping NSCLC L+ or T+, including pts with BM. High ORR & DCR in pts with ctDNA molecular responses support that MET inhibition in METex14+ tumor cells can lead to clinical benefit. Clinical trial information: NCT02864992 . [Table: see text]
RELAY+: Exploratory study of ramucirumab plus gefitinib in untreated patients (pts) with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC).
Authors: Nishio Makoto , Nishio Kazuto , Reck Martin , Garon Edward B. , Imamura Fumio , Kawaguchi Tomoya , Yamaguchi Hiroyuki , Ikeda Satoshi , Hirano Katsuya , Visseren-Grul Carla M , Widau Ryan C , Zimmermann Annamaria H. , Homma Gosuke , Enatsu Sotaro , Nakagawa Kazuhiko 
Published: May 2020

9564 Background: The phase III randomized part of the RELAY study (Part B; RELAY; NCT02411448) showed a significant improvement in progression-free survival (PFS) for ramucirumab (RAM) plus erlotinib (ERL) vs placebo plus ERL in 449 untreated pts with EGFR-mutated metastatic NSCLC (median PFS: 19.4 vs 12.4 months; stratified hazard ratio: 0.59, 95% CI: 0.46–0.76, p<0.0001; 1-year PFS rate: 71.9% vs 50.7%). Here we report initial results from RELAY+ (additional cohort of RELAY; Part C), an open-label, single-arm, exploratory study evaluating RAM plus gefitinib (GEF) in East Asian pts. Methods: Previously untreated East Asian pts with metastatic NSCLC and EGFR exon 19 deletions (Ex19del) or exon 21 substitution mutation (Ex21.L858R) received RAM (10 mg/kg Q2W) plus GEF (250 mg/day) until disease progression or unacceptable toxicity. The 1-year PFS rate (primary endpoint, assuming a 1-year PFS rate of 55% for RAM+GEF), tumor response, biomarkers, and safety were assessed. EGFR T790M status (baseline/30-day follow-up) was assessed in liquid biopsy samples by Guardant360 NGS. Results: In total, 82 pts were enrolled (Japan: 68; Taiwan: 8; Korea: 6); 65.9% were female, 65.9% were never-smokers, and 43.9% had Ex19del. With median follow-up of 13.8 months (range: 2.6–20.2; censoring rate: 58.5%), the overall 1-year PFS rate (95% CI) was 65.0% (52.4–75.1), 67.2% (48.6–80.3) in pts with Ex19del (n=36), and 63.4% (45.0–77.1) in pts with Ex21.L858R (n=46). The objective response rate was 70.7% (95% CI: 59.6–80.3), disease control rate was 98.8% (95% CI: 93.4–100.0), and duration of response was immature at this point in time with a censoring rate of 56.9% where the median point estimate was 13.6 months (95% CI: 11.1–18.2). Post-progression EGFR T790M was seen in 7 of 9 (78%; 95% CI: 45.3–93.7) pts with 30-day follow-up NGS results in which EGFR activating mutation was detected. Grade ≥3 treatment-emergent adverse events reported in >5% of pts were ALT increased (23.2%), hypertension (22.0%), and AST increased (12.2%). Conclusions: With a 1-year PFS rate of 65.0%, the primary endpoint of RELAY+ was met. The efficacy of RAM+GEF in RELAY+ was similar to that of RAM+ERL in RELAY, and the safety profile of the combination was similar to that of the individual drugs. Clinical trial information: NCT02411448 .