bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population.
Authors: Felip Enriqueta , Majem Margarita , Doger Bernard , Clay Timothy Dudley , Carcereny Enric , Bondarenko Igor , Peguero Julio Antonio , Cobo-Dols Manuel , Forster Martin , Ursol Grygorii , García Ledo Gema , Vilà Laia , Krebs Matthew , Iams Wade Thomas , Mueller Christian , Triebel Frederic 
Published: June 2022

9003 Background: Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC)/CD8 T-cell activation. Stimulation of the APCs and subsequent T cell recruitment with E may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We hereby report results of the extended first-line non-small cell lung carcinoma (NSCLC) cohort of the TACTI-002 (“Two ACTive Immunotherapies”) phase II trial. Methods: Pts with untreated metastatic NSCLC, unselected for PD-L1 expression were recruited. Objective response rate (ORR) by iRECIST was the primary endpoint (EP) and secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS) and exploratory biomarker. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) and then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks. PD-L1 was assessed centrally. This has been approved by relevant CAs, ECs, and IRBs. Results: From Mar 2019 to Nov 2021 114 pts were enrolled. Median age was 67 years (44-85) and 74% were male. ECOG PS was 0 and 1 in 37% and 63% of pts, respectively. Pts presented squamous (35%) or non-squamous (62%) NSCLC with 88% of pts at stage IV at the time of study entry. All PD-L1 subgroups were represented (Table). Pts received median 6.0 (range 1–35) P and 7.0 (1-22) E administrations. 19 (17%) pts discontinued treatment due to adverse events (AEs). The most common (≥15%) AEs were dyspnea (33%), asthenia (30%), decreased appetite (22%), cough (20%), anemia (20%), fatigue (19%), pruritus (18%), constipation (17%) and diarrhea (15%). At data cut-off (Jan 2022), 75 pts with a minimum follow-up of 6 months were evaluated for efficacy. ORR (iRECIST) was 37.3% in the ITT and 41.8%% in the evaluable pts assessed by local read. DCR 73.3% was reported. Response rate for squamous and non-squamous pathology were 33.3 % and 40.3 %, respectively. Results according to RECIST 1.1 were comparable. Responses were observed in all PD-L1 subgroups (Table). 24/28 (86%) responses were already confirmed while median duration of response was not yet reached (5 events). Conclusions: E + P is safe and shows encouraging antitumor activity in first-line metastatic NSCLC patients unselected for PD-L1, warranting further investigation. Clinical trial information: NCT03625323. [Table: see text]
Osimertinib plus necitumumab in EGFR-mutant NSCLC: Final results from an ETCTN California Cancer Consortium phase I study.
Authors: Riess Jonathan W. , Krailo Mark D. , Padda Sukhmani Kaur , Groshen Susan G. , Wakelee Heather A. , Reckamp Karen L. , Koczywas Marianna , Piotrowska Zofia , Steuer Conor Ernst , Kim Chul , Paweletz Cloud P. , Sholl Lynette M. , Heavey Grace , Kolesar Jill , Moscow Jeffrey , Janne Pasi A. , Lara Primo "Lucky" N. , Newman Edward M. , Gandara David R. 
Published: June 2022

9014 Background: Osimertinib (Osi) is standard of care in 1st line (1L) EGFR mut NSCLC and TKI resistant T790Mpos NSCLC but acquired resistance emerges; outcomes are less robust in T790Mneg, C797Xpos and EGFR exon 20 insertion (ex20ins) disease. We examined Osi with the EGFR monoclonal antibody Necitumumab (Neci) in select settings of EGFR TKI resistance. Methods: Pts were accrued to 5 expansion cohorts (ExC) at recommended phase 2 dose (RP2D) of Osi 80 mg daily and Neci 800 mg D1 + D8 of q21d cycle. ExC (18 pts/cohort): A) T790Mneg progressive disease (PD) on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 1st/2nd gen TKI and PD on 3rd gen TKI, C) T790Mpos PD on 1st/2nd gen TKI and PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy, E) PD on 1L osi. In ExC A-C, T790M was confirmed centrally (tissue) by ddPCR. Additional correlative studies include: tissue NGS (> 400 gene panel), EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR. Adverse events were graded (Gr) by CTCAEv5; ORR, PFS by RECIST 1.1. Primary pre-specified efficacy endpoint ≥3/18 pts responding per cohort. Results: 101 patients accrued (100 evaluable). Efficacy is summarized in the Table. Drug related Gr 3 AEs were seen in 38% of pts, mainly rash (21%). ORR among all pts was 19% (95% CI 12-28%) that varied across cohorts (Table). In ExC A-C, 69% pts had detectable EGFR activating mutations in ctDNA, with decline in mutant allele frequency (AF) on treatment in 80% and ctDNA clearance in 33%. Conclusions: Osi/Neci is feasible and tolerable at the RP2D. EGFR ctDNA was detectable at baseline in the majority of pts with decrease in AF on treatment. Osi/Neci was active in select settings of EGFR-TKI resistance, meeting its prespecified efficacy endpoint in T790Mneg PD on 1st/2nd gen TKI as last therapy (ExC A), EGFR ex20ins post-chemo (ExC D) and PD on 1L osimertinib (ExC E). mPFS in the EGFR ex20ins cohort was within the range of current EGFR Exon 20 ins agents in development. EGFR monoclonal antibodies with osimertinib warrant further study in settings of de novo and acquired EGFR dependent resistance to EGFR-TKI. Clinical trial information: NCT02496663. [Table: see text]
A randomized phase II/ III trial of nivolumab versus nivolumab plus docetaxel for previously treated advanced or recurrent non–small cell lung cancer: TORG1630.
Authors: Kawashima Yosuke , Taniguchi Yuri , Shimokawa Tsuneo , Takiguchi Yuichi , Misumi Toshihiro , Nakamura Atsushi , Furuya Naoki , Tanaka Kentaro , Harada Toshiyuki , Tanaka Hisashi , Miura Satoru , Sata Masafumi , Kato Terufumi , Tokito Takaaki , Naoki Katsuhiko , Bessho Akihiro , Goto Yasuhiro , Nakamichi Shinji , Okamoto Hiroaki 
Published: June 2022

9030 Background: Immuno-checkpoint inhibitor (ICI) monotherapy is a standard second-line treatment for non-small-cell lung cancer (NSCLC). Addition of a cytotoxic agent to ICI may enhance the benefits. Methods: This multi-institutional open-label randomized phase II/III study compared the arm A consisting of nivolumab (NIV) monotherapy and arm B consisting of NIV + docetaxel (DTX) for patients with previously treated ICI-naïve NSCLC, prestratified by PS/histological types/sex/driver-mutations. The primary endpoint was superiority of arm B in OS in the phase III part. Assuming a HR of 0.75 for OS with the estimated mOS of arm A/B as 10.5/14.0 mo, a total 350 patients would be required to provide 80% power at a one-sided α of significance being 0.05. It was started at Nov. 2017, however, the patients’ accrual was discontinued due to the approval of ICI in the first-line setting in late 2018. Eventually, a total of 131 patients were enrolled for analysis. Results: 128 patients (64 in each arm) were eligible and included in full analysis set (FAS), and the patients’ demographics were well-balanced in each arm. The mOS was 14.7 mo (95%CI, 11.4-18.7) in arm A, and 23.1 mo (95%CI, 16.7-NR) in arm B. The HR of OS was 0.63 (90%CI, 0.42-0.95; p = 0.0310). The mPFS was 3.1 mo (95%CI, 2.0-3.9) and 6.7 mo (95%CI, 3.8-9.4) in arm A and B, respectively. The HR for PFS was 0.58 (95%CI, 0.39-0.88; p = 0.0095). The ORR was 14.0% (95%CI, 6.3-25.8) in arm A, and 41.8% (95%CI, 28.7-55.9) in arm B, with a statistical significance (p = 0.0014). Subgroup analyses for OS disclosed that the HRs favored arm B over arm A across all prespecified subgroups. The mOS of EGFR-mutant subgroup also showed better tendency in arm B than A (11.0 mo in arm A; 95%CI, 3.5-14.0; vs 20.6 mo in B; 95%CI, 5.8-NR; HR 0.45; 95%CI, 0.17-1.17). The hematological toxicity and gastrointestinal adverse events were more common in arm B than in A. Six (9.4%) in arm A and 25 patients (39.1%) in arm B discontinued protocol treatment due to adverse events. Overall, two treatment-related deaths were observed; one from pneumonitis in arm A, and one from myocarditis in arm B. Conclusions: Although the resulting statistical power was limited because of reduced sample size, the addition of DTX to NIV in the second-line NSCLC therapy significantly improved OS, PFS, and ORR, despite slightly elevated risk of toxicity. This is the first randomized clinical trial that confirmed significant survival benefit of ICI + chemotherapy over ICI alone in any cancer type. Clinical trial information: UMIN000021813.
Association of depth of target lesion response to brigatinib with outcomes in patients with ALK inhibitor-naive ALK+ NSCLC in ALTA-1L.
Authors: Camidge D. Ross , Kim Hye Ryun , Ahn Myung-Ju , Yang James Chih-Hsin , Han Ji-Youn , Hochmair Maximilian , Lee Ki Hyeong , Delmonte Angelo , Campelo Rosario Garcia , Kim Dong-Wan , Griesinger Frank , Felip Enriqueta , Califano Raffaele , Spira Alexander I. , Thomas Michael , Gettinger Scott N. , Tiseo Marcello , Liu Yuyin , Zhang Pingkuan , Popat Sanjay 
Published: June 2022

9072 Background: In patients (pts) with crizotinib (CRZ)-refractory advanced ALK+ NSCLC in the phase 2 ALTA trial (NCT02094573), the depth of target lesion response to brigatinib (BRG) correlated with PFS and OS. Here, we examine the association of maximum decrease in target lesions with PFS and OS in ALTA-1L (NCT02737501), a randomized phase 3 trial of BRG vs CRZ in pts with ALK inhibitor-naive advanced ALK+ NSCLC. Methods: Pts were randomized 1:1 to receive BRG 180 mg qd (7-day lead-in at 90 mg; n=137) or CRZ 250 mg bid (n=138). Pts with target lesion assessment by blinded independent review committee (BIRC) were grouped based on greatest decrease from baseline per RECIST v1.1: none–50%, 51%–75%, and 76%–100% shrinkage. Outcomes in the ≤50% target lesion shrinkage group served as the comparator for outcomes in the 51%–75% and 76%–100% groups. Results: At study end (last pt contact: Jan 29, 2021), 124/137 pts in the BRG arm and 125/138 pts in the CRZ arm had ≥1 evaluable target lesion assessment; female (BRG/CRZ), 51%/59%; median age, 57.5/60.0 years. Median follow-up was 40.8/15.7 months. In BRG/CRZ arms, 76%-100% shrinkage was observed in 56%/34% of pts, 51%-75% shrinkage in 27%/30%, and ≤50% shrinkage in 16%/35%, respectively. BRG was associated with significantly more pts with target lesion shrinkage >75% vs CRZ ( P=0.0005), and a Cochran-Armitage trend analysis demonstrated significantly deeper response across all shrinkage groups for BRG compared with CRZ ( P<0.0001). A majority of pts in the BRG arm experienced 76%–100% target lesion shrinkage in all subgroups analyzed. Pts treated with BRG or CRZ with target lesion shrinkage >50% had lower risk of a PFS event (BRG HR [95% CI]: 51%–75% shrinkage, 0.58 [0.29–1.18]; 76%–100%, 0.23 [0.12–0.46]; CRZ: 51%–75% shrinkage, 0.68 [0.41–1.12]; 76%–100%, 0.26 [0.15–0.45]) or an OS event (BRG: 51%–75% shrinkage, 0.39 [0.17–0.89]; 76%–100%, 0.15 [0.07–0.35]; CRZ: 51%–75% shrinkage, 0.43 [0.21–0.85]; 76%–100%, 0.23 [0.10–0.50]) than pts with ≤50% shrinkage. Longer median time to PFS and OS and higher 4-year estimated OS rates were associated with depth of response in both arms (Table). Conclusions: In this exploratory post hoc analysis, BRG demonstrated significantly deeper target lesion response vs CRZ. Pts with >75% shrinkage had significantly reduced risk of a PFS or OS event vs pts with ≤50% target lesion shrinkage. Clinical trial information: NCT02737501. [Table: see text]
Use of RET inhibitors among patients with advanced NSCLC: A real-world evidence analysis.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen 
Published: June 2022

9079 Background: RET rearrangements are found in approximately 1% to 2% of patients with NSCLC. Two selective RET inhibitors have been FDA approved based on phase 1/2 data showing significant activity among patients with advanced NSCLC that have RETrearrangements. The objective of this retrospective analysis was to look at the prognostic outcome associated with the use of selective RET inhibitors (sRETi) and multikinase inhibitors (MKIs) that have been used to target RET fusions among pts with NSCLC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 84 million pt lives available through the TriNetX Research Network. We identified 1,215 pts with metastatic NSCLC treated with selpercatinib, praseltinib, cabozantanib or vandetanib. Overall survival (OS) was evaluated with Kaplan Meier statistics and compared between patients treated with either sRETi (selpercatinib or pralsetinib) vs either MKI (cabozantanib or vandetanib). Results: Mean age among all anti-RET treated patients was 67.6 years. 518 pts (43%) were female and 697 (57%) were male. 531 (39.6%), 205 (15.3%) and 605 (45.1%) pts had received selpercatinib, pralsetinib, and either cabozantinib or vandetinib, respectively. 56.6% of pts receiving pralsetinib received prior selpercatinib. Among pts receiving sRETi, 39.7%, 6.4%, 11.2%, and 32.4% received sRETi in the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis, respectively. Among pts receiving MKIs, 17.0%, 8.4%, 13.3%, and 44.9% received MKIs in the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis. Median OS after treatment with MKIs and sRETi during any time frame was 16.3m and 25.0m, respectively (p < 0.01). Among pts treated with MKIs vs sRETi during the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis, 1-year survival probability after treatment was 59.7% vs 55.9% (p = 0.39), 45.0% vs 83.1% (p < 0.01), 53.9% vs 82.2% (p < 0.01), and 57.7% vs 87.1% (p < 0.01), respectively. 30% of pts of all anti-RET treated patients had brain metastases, and median OS from index metastasis among pts with and without brain metastases was 31.4m and 63.1m respectively (p < 0.01). Conclusions: To our knowledge this is the first real world data set to show a > 8m improvement in OS with the use of sRETi compared to MKIs among pts with metastatic NSCLC. OS improvements may be more significant in pts treated in later lines of therapy with sRETi.
Evaluation of weight gain and overall survival of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy.
Authors: Roeland Eric , Fintelmann Florian J. , Hilton Fiona , Tarasenko Lisa , Calle Roberto A , Bonomi Philip D. 
Published: June 2022

9088 Background: Cachexia is a multifactorial syndrome frequently associated with cancer characterized by anorexia and unintentional weight loss, including skeletal muscle loss, fatigue, functional impairment, poor quality of life, and worse survival. The objective of this post-hoc analysis was to examine the relationship between weight gain and overall survival (OS) in patients with NSCLC treated with first-line platinum-based regimens. Methods: Data were pooled from three phase 3 clinical trials (NCT00254891, NCT00254904, and NCT00596830) conducted between Nov 2005 and Mar 2011 in patients with advanced NSCLC (stage IIIB or stage IV) treated with first-line standard-of-care (SOC) chemotherapy (control arm). Weight was recorded at baseline, prior to dosing on day 1 of each 3-week treatment cycle (up to 6 cycles), and post-treatment according to each study’s schedule. Weight gain was categorized as > 0%, > 2.5%, and > 5% increase from baseline up to 4.5 months. Cox Proportional Hazards modeling of OS including time to weight gain and time to confirmed objective response (RECIST v1.0) and baseline covariates were used to estimate hazard ratios (HR) for each category. Results: The total 1,030 patients from the SOC control arms were predominantly male (70.5%) with Stage IV NSCLC (88.5%) and a mean age (SD) of 60.9 (9.4) years and BMI 24.6 (4.4) kg/m2. Overall, 486 (47.2%), 299 (29.0%), and 164 (15.9%) patients experienced weight gain from baseline of > 0%, > 2.5%, and > 5%, respectively. Median time to > 0%, > 2.5%, and > 5% weight gain was 24, 43, and 64 days, respectively. After adjusting for statistically significant time-dependent confirmed objective response, the risk of death was significantly less for patients with weight gain. For patients with > 0% vs. ≤0% weight gain, HR was 0.70 (95%CI 0.61, 0.82) with median OS of 13.6 vs. 8.3 months. For patients with > 2.5% vs. ≤2.5% weight gain, HR was 0.70 (95%CI 0.59, 0.83) with median OS of 15.3 vs. 9.1 months. For patients with > 5% vs. ≤5% weight gain, HR was 0.76 (95%CI 0.61, 0.94) with a median OS of 14.4 vs. 9.8 months. Conclusions: In this pooled analysis, weight gain during treatment with first-line platinum-based chemotherapy was associated with a significantly reduced risk of death in patients with advanced NSCLC, independent of tumor response defined by RECIST criteria. The survival benefit was comparable for > 2.5% vs. > 5% weight gain. Weight gain of 2.5% may be an earlier predictor of survival outcomes and may have implications for the design of cancer cachexia trials. Clinical trial information: NCT00254891, NCT00254904, and NCT00596830.
Molecular analysis of circulating tumor DNA (ctDNA) in patients (pts) with EGFR exon 20 insertion-positive (ex20ins+) advanced NSCLC treated with mobocertinib.
Authors: Vincent Sylvie , Su Zhenqiang , Bunn Veronica , Joshi Adarsh , Yu Ziji , Chatterjee Sampurna , Guha Minakshi , Zhang Pingkuan 
Published: June 2022

9108 Background: ctDNA is an important tool to diagnose and monitor mutations in pts with non–small cell lung cancer (NSCLC). We evaluated epidermal growth factor receptor gene ( EGFR) ex20ins mutations in tumor vs plasma samples, assessed changes in EGFR ex20ins variant allele frequency (VAF) with mobocertinib treatment and correlation with response, and identified potential emerging variants of acquired resistance. Methods: Tumor tissue samples were collected at baseline (BL) from pts with EGFR ex20ins+ advanced NSCLC receiving mobocertinib 160 mg QD in a phase 1/2 study (NCT02716116); plasma samples were collected at BL, after 2 treatment cycles (Cycle 3, Day 1 [C3D1]) and at disease progression/end of treatment (DP/EOT). ctDNA samples were analyzed by next-generation sequencing for EGFR ex20ins to determine concordance rate detection between tissue and plasma ctDNA at BL. Changes in VAF for EGFR ex20ins from BL were analyzed at C3D1 and DP/EOT by confirmed response (RECIST v1.1) to mobocertinib per independent review committee. Emerging variants at DP/EOT were evaluated by elimination of germline variants seen in healthy populations (gnomAD databases and 1000 Genomes) and nonharmful variants predicted by PolyPhen and SIFT tools or annotated as benign in ClinVar database. Results: BL EGFR ex20ins mutations were detected by ctDNA sequencing in 29 of 38 pts (76%) with tissue-confirmed EGFR ex20ins+ NSCLC. VAFs for EGFR ex20ins significantly decreased at C3D1 in mobocertinib-treated pts with confirmed partial response (PR; P=0.0057) or stable disease (SD; P=0.0016), but not in pts with progressive disease (PD; P=0.14) (Table). ctDNA at EOT/DP analysis identified numerous genetic variants; EGFR, TP53, and DNMT3A were the most common genes with emerging variants. Twelve emerging missense mutations were identified in EGFR in 9 pts, including mutations located in the exon 20 loop following the C-helix (6), T790M (5), and D379E (1). Conclusions: Concordance between tissue and plasma ctDNA for EGFR ex20ins mutations at BL was 76%. EGFR ex20ins VAF decreased significantly after 2 treatment cycles in mobocertinib-treated patients with PR and SD. Plasma ctDNA longitudinal monitoring may be useful to assess mutation status and disease progression in pts with NSCLC treated with mobocertinib. Clinical trial information: NCT02716116. [Table: see text]
Uncommon EGFR mutations on osimertinib, real-life data (UNICORN study): Updated results, brain efficacy, and resistance mechanisms.
Authors: Bar Jair , Peled Nir , Schokrpur Shiruyeh , Dudnik Elizabeth , Wollner Mira , Girard Nicolas , Aboubakar Nana Frank , Derijcke Sofie , Kian Waleed , Patel Sandip P. , Gantz Sorotsky Hadas Yocheved , Zer Alona , Moskovitz Mor , Metro Giulio , Rottenberg Yakir , Calles Antonio , Hochmair Maximilian , Cuppens Kristof , Decoster Lynn , Addeo Alfredo ,   UNICORN Study Investigators
Published: June 2022

9109 Background: About 10% of EGFR mutations (EGFRm) are ‘uncommon mutations’ (ucEGFRm). osimertinib is a 3rd generation EGFRi, active against common EGFRm. We aimed to collect real-world data about systemic and brain response and resistance mechanisms to osimertinib for ucEGFRm patients. Methods: This is a multi-center, retrospective study of ucEGFRm mNSCLC treated with osimertinib as first EGFRi. RECIST and RANO-BM response was evaluated by investigators. Progression free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated from initiation of osimertinib. Mutations found at resistance were collected. Results: 62 patients (pts) were identified in 22 centers from 9 countries. Median age was 64 (35-91) years, 74% females, 84% Caucasian, never/former/current smokers were 48%/39%/11% respectively, ECOG PS was 0-1/2/3-4 in 84%/10%/5%. Histology was adenocarcinoma in 97%. The largest subgroups were G719X, de novo T790M and L861Q (Table). Compound EGFR mutations were found in 27 pts (44%), TP53 mutations in 21 pts (34%). In 17 cases (27%), compound mutations included the common L858R/deletion19 and/or de novo T790M. Most frequent metastatic sites were lung/bone/brain in 45%/44%/39%. Most frequent toxicities were gastrointestinal (32 pts, 52%) and skin (24 pts, 39%); 8 pts had grade 3-4 AEs. No grade 5 AE occurred. 3 pts had AEs leading to discontinuation. RECIST response (RR) was available for 53 pts, CR - 4 (8%), PR - 27 (51%), SD - 17 (32%), and PD - 5 (9%). Median DOR (mDOR) was 17.4 months (95% CI 9.1-NA). mPFS was 9.5 months (95% CI 8.5–17.4). mOS was 24.5 months (95% CI 17.4-35.1). See Table for efficacy in the major subgroups. 24 pts (39%) had brain metastasis at presentation, for 12 pts a brain response by RANO-BM was available with 25%/25%/33%/17% CR/PR/SD/PD. For 14 pts, rebiopsy mutation analysis at progression on osimertinib was available: 3 pts with an additional EGFR mutation (C797S,D585Y, E709K), 3 pts with a new TP53 mutation, 1 with c-Met amplification and 1 pt with transformation to neuroendocrine carcinoma. Conclusions: Osimertinib demonstrated activity in ucEGFRm with 91% disease control rate and encouraging PFS and DOR. Brain response was seen in 50% of cases. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRm presented so far. [Table: see text]