bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct genomic and immunophenotypic features of solid-predominant versus nonsolid-predominant stage I lung adenocarcinomas and association with disease recurrence after surgical resection.
Authors: Alessi Joao Victor Machado , Wei Zihan , Ricciuti Biagio , Vaz Victor R. , Barrichello Adriana Paula de Castro , Lamberti Giuseppe , Sharma Bijaya , Pfaff Kathleen L. , Felt Kristen , Turner Madison M. , Rodig Scott J. , Sholl Lynette M. , Awad Mark M. 
Published: June 2022

8514 Background: Compared to lung adenocarcinomas (LUAD) with nonsolid-predominant histology (lepidic, acinar, papillary, micropapillary), those with predominantly solid features have a higher risk of disease recurrence after surgical resection. However, little is known about the genomic landscape and immunophenotype of solid vs nonsolid stage I LUAD. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition), which underwent next-generation sequencing to identify genomic alterations and tumor mutational burden (TMB). A subset of these samples also had multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 to determine differences in tumor immune cells subsets according to histologic subtype. Disease free-survival (DFS) was compared in patients based on their predominant histologic subtype (solid vs nonsolid). Results: Among 658 LUADs, 11.4% (N = 75) had solid-predominant and 88.6% (N = 583) nonsolid-predominant histology. After a median follow-up of 50 months from the time of surgery, 145 patients (22.0%) experienced recurrence. Compared to nonsolid-predominant LUAD, those with solid predominance had a significantly lower prevalence of activating EGFR, BRAFV600E, and METex14 mutations as well as ALK/ RET/ ROS1 rearrangements (9.3% versus 31.6%, P < 0.001), no difference in KRASG12C frequency (24% versus 16.8%, P = 0.14), a higher TMB (median 12.2 versus 7.2 mutations/megabase; P < 0.001), and a shorter median DFS from the time of surgical resection (43.2 months versus not reached, HR: 3.3 [95% CI: 2.2-4.9], P < 0.001). The detrimental effect of solid-predominant LUAD in DFS remained significant after adjusting for other factors such as tumor stage, surgery type, smoking status, and TMB (HR: 2.66 [95% CI: 1.71-4.11], P < 0.001]. Among LUADs profiled by multiplex immunofluorescence, compared to tumors with nonsolid-predominant subtype (N = 197), those with solid predominance (N = 23) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally (P < 0.001) and at the tumor-stroma interface (P < 0.001). Solid-predominant subtype was also associated with a higher median PD-L1 expression level on tumor (5% versus 1%; P = 0.01) and immune cells (16% versus 7%, P = 0.02). Conclusions: Among patients with surgically-resected stage I LUAD, solid-predominant histology was associated with distinct genotypic and immunologic characteristics. These findings may aid in identifying patients at greater risk of recurrence after surgery.
Sintilimab plus anlotinib as second or further-line therapy for small cell lung cancer: An objective performance trial.
Authors: Ma Shuxiang , He Zhen , Wang Lili , Wu Yufeng , Yang Sen , Chen Haiyang , Wu Yingxi , Mo Yuqing , Liu Yang , Wang Qiming 
Published: June 2022

8516 Background: Small cell lung cancer (SCLC) tends to progress rapidly on first-line therapies, with limited subsequent-line treatment options. Methods: In this single-arm objective performance trial, adult patients with extensive-disease SCLC (ED-SCLC) received intravenous sintilimab 200 mg on day 1 and oral anlotinib 12 mg on days 1-14. Treatment lasted for 3 weeks per cycle and was continued until disease progression, unacceptable toxicities, or death. The primary endpoint was the superiority of progression-free survival (PFS) versus a PFS of 2.8 months with historical topotecan control. Results: Forty-two patients were enrolled, and 39 patients were evaluable for efficacy. Twenty-six patients (66.7%) had ED-SCLC, and 13 (33.3%) relapsed after concurrent chemoradiotherapy. The median follow-up was 11.9 months. The median PFS was 6.0 months (95%CI: 4.8-7.2). The 6- and 12-month PFS rate was 50.5% and 27.8%, respectively. Fourteen patients died by the data cut-off date, and overall survival (OS) was immature (16.1 months, 95%CI: 9.4-22.7). The 12- and 18-month OS rate was 56.7% and 42.5%, respectively. Three patients attained complete response and 16 achieved partial response, and 12 patients had stable disease; the objective response rate was 48.7% and the disease control rate was 79.5%. Forty patients (95.2%) had at least one treatment-related adverse event (TRAE). The most frequent TRAEs were hypothyroidism (45.2%), hypoproteinemia (40.5%) and elevated gamma-glutamyl transpeptidase (38.1%). Conclusions: Immunotherapy with sintilimab plus antiangiogenic drug anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further development of this combination regimen for ED-SCLC. Clinical trial information: NCT04055792.
Analysis of patients with relapsed small cell lung cancer (SCLC) receiving single-agent lurbinectedin in the phase 3 ATLANTIS trial.
Authors: Navarro Alejandro , Ponce Aix Santiago , Barneto - Aranda Isidoro C. , Smit Egbert F. , Lopez-Vilariño Jose Antonio , Nieto Antonio , Kahatt Carmen Maria , Zeaiter Ali Hassan , Cousin Sophie , Bischoff Helge , Roubec Jaromir , Syrigos Konstantinos , Paz-Ares Luis 
Published: June 2022

8524 Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, received accelerated approval from the US FDA in June 2020 as monotherapy (3.2 mg/m2 IV every 21 days) for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. This approval was based on the overall response rate (35.2%) and duration of response (DOR; 5.3 months) observed in 105 patients from a phase 2 trial. The ATLANTIS trial (NCT02566993) investigated the combination of lurbinectedin 2.0 mg/m2 IV + doxorubicin (DOX) 40.0 mg/m2 IV versus topotecan or CAV. This post hoc analysis explored the efficacy and safety of single-agent lurbinectedin in patients who completed 10 cycles of the combination and then switched to lurbinectedin monotherapy per protocol. Methods: Eligible patients were ≥18 years of age with limited-stage or extensive-stage SCLC, 1 prior line of platinum-based chemotherapy (PD-1/PD-L1 inhibitors were also permitted), ECOG PS ≤2, and chemotherapy-free interval ≥30 days. Tumor assessments were per an independent review committee (IRC). Results: Patients who completed 10 cycles of lurbinectedin + DOX and switched to lurbinectedin monotherapy (n = 50) had a median age of 61.5 years (range: 43, 77); 62% were male; and 100% had an ECOG PS < 2. The overall median number of cycles was 15 (range: 11, 47) and included a median of 5 (1, 37) cycles on monotherapy. The majority of patients who switched to lurbinectedin monotherapy maintained or improved their tumor response (Table). All 3 patients who achieved a complete response (CR) on combination therapy maintained their CR on monotherapy. Of the 26 patients with a partial response (PR) on combination therapy, 3 (12%) achieved a CR and 15 (58%) maintained their PR. Of the 19 patients with stable disease (SD) on combination therapy, 3 (16%) improved from SD to PR (n = 2) or CR (n = 1) and 8 (42%) maintained SD. The median DOR was 8.3 months (95% CI: 7.1, 11.0). The median overall survival (OS) was 20.7 months (95% CI: 15.7, 24.8). Grade 3/4 hematologic abnormalities based on laboratory assessment included lymphopenia (36%), anemia (16%), thrombocytopenia (12%), neutropenia (12%), and leukopenia (10%). Febrile neutropenia was reported in 4% of patients. Conclusions: Patients with relapsed SCLC in ATLANTIS who completed 10 cycles of lurbinectedin + DOX combination and switched to lurbinectedin monotherapy tended to maintain or improve their tumor response (including an increase in CRs), with favorable OS and DOR and acceptable tolerability with no new safety signals. Clinical trial information: NCT02566993. [Table: see text]
Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: Updated results from the CHRYSALIS study.
Authors: Krebs Matthew , Spira Alexander I. , Cho Byoung Chul , Besse Benjamin , Goldman Jonathan W. , Janne Pasi A. , Ma Zhiyong , Mansfield Aaron Scott , Minchom Anna Rachel , Ou Sai-Hong Ignatius , Salgia Ravi , Wang Zhijie , Llacer Perez Casilda , Gao Grace , Curtin Joshua C , Roshak Amy , Schnepp Robert W. , Thayu Meena , Knoblauch Roland , Lee Chee Khoon 
Published: June 2022

9008 Background: Amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, is approved for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion after prior platinum-based chemotherapy. Given its bispecific nature, amivantamab is being explored in patients (pts) with primary MET exon 14 skipping mutation (METex14) in the MET-2 cohort of the CHRYSALIS study. Methods: CHRYSALIS (NCT02609776) is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in pts with advanced NSCLC. Pts with primary METex14 whose disease progressed on or who declined current standard of care therapy were treated with amivantamab 1050 mg (pts <80 kg) or 1400 mg (pts ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by investigators using RECIST v1.1. Results: As of 2 Dec 2021, 43 pts with METex14 had received amivantamab. Median age was 70 y (range, 43-88), 58% were women, median prior lines of therapy was 2 (range, 0-10) [eg, crizotinib (n=13), capmatinib (n=11), tepotinib (n=5), anti-MET antibody (n=1)], and 23% had history of brain metastases at baseline. In 36 pts with ≥1 postbaseline disease assessment, median duration of follow-up was 5.8 months (range, 0.3-15.8); 6 pts had no prior treatment, 11 had no prior MET inhibitor, and 19 had a prior MET inhibitor. Overall response rate was 33% (50% [3/6] in treatment-naïve pts, 46% [5/11] in pts with no prior MET inhibitor, and 21% [4/19] in pts with prior MET inhibitor therapy). Clinical benefit rate was >54% regardless of prior treatment (Table). Median duration of response (DOR) was not reached (range, 2.1-12.2 months); 67% (8/13) had DOR ≥6 months. Ten of the 12 responders remain on treatment (6.0-14.4 months) with ongoing responses; 2 discontinued after 2 and 12 months, respectively. Safety profile was consistent with previously reported experience of amivantamab (Sabari 2021 JTO 16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 3 pts, each. Conclusions: Amivantamab demonstrates anti-tumor activity in primary METex14 NSCLC including after prior MET inhibitor treatment. Enrollment is ongoing and updated data will be shown. Clinical trial information: NCT02609776. [Table: see text]
Sintilimab versus pembrolizumab in monotherapy or combination with chemotherapy as first-line therapy for advanced non–small cell lung cancer: Results from phase 2, randomized clinical trial (CTONG1901).
Authors: Liu Si-Yang Maggie , Zhou Qing , Yan Hong-Hong , Bin Gan , Yang Ming-Yi , Deng Jia-Yi , Tu Hai-Yan , Zhang Xuchao , Su Jian , Yang Jinji , Wu Yi-Long 
Published: June 2022

9032 Background: Immunotherapy has become standard therapy for untreated advanced NSCLC. However, no direct comparison between anti-PD-1 inhibitors has been reported. Methods: CTONG1901 is an open label, randomized, phase II clinical trial to compare sintilimab and pembrolizumab in monotherapy or combination with chemotherapy for advanced NSCLC at first-line setting. The primary endpoint was objective response rate (ORR). Patient without EGFR and ALK alteration were enrolled. Patients with PD-L1 tumor proportion score (TPS) ≥50% were randomly to receive sintilimab (A) or pembrolizumab (B) ; and with TPS<50% were randomly to receive sintilimab (C) or pembrolizumab (D) combined with chemotherapy. Sample size was calculated by Optimal Two-Stage Designs. 20 patients were enrolled in 1st stage. When ≥4 patients achieve partial response (PR) in sintilimab arms, the study will enter into 2nd stage and the sample size will be calculated based on the ORR results of the 1st stage. Results: The ORR was 57.1% in sintilimab and 33.3% in pembrolizumab arms at the 1st stage. The study successfully entered into the 2nd stage. 48 additional patients should be enrolled after calculation. When 15 PR in sintilimab arms achieved, the primary endpoint will be reached. From Mar. 2020 to Jan. 2022, 71 patients were screened and 68 patients were enrolled in two stages. Histologic subtypes and brain metastasis were well balanced between arms. As of Dec. 31st 2021, the median follow-up was 5.6 months. The confirmed ORR was 45.5% (15/33) in sintilimab vs. 28.6% (10/35) in pembrolizumab arms (A vs. B: 30.8% [4/13] vs. 28.6% [4/14]; C vs. D: 55.0% [11/20] vs. 28.6% [6/21]). Unconfirmed ORR was 57.6% vs. 42.9% and disease control rate (DCR) was 87.9% vs. 91.4% in sintilimab and pembrolizumab arms. The primary endpoint was reached. Survival data was immature. Any grade and 3-4 grade treatment-related adverse events (TRAEs) were comparable in sintilimab and pembrolizumab arms (Table). Conclusions: This is the first head-to-head phase II study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. The result suggested comparable tumor response and similar safety profile between sintilimab and pembrolizumab. Clinical trial information: NCT04252365. [Table: see text]
Outcomes of single-agent PD-(L)-1 versus combination with chemotherapy in patients with PD-L1-high (≥ 50%) lung cancer.
Authors: Elkrief Arielle , Alessi Joao Victor Machado , Ricciuti Biagio , Rizvi Hira , Preeshagul Isabel Ruth , Egger Jacklynn V. , Chaft Jamie E. , Rudin Charles M. , Riely Gregory J. , Kris Mark G. , Ladanyi Marc , Hellmann Matthew D. , Awad Mark M. , Schoenfeld Adam Jacob 
Published: June 2022

9052 Background: Single agent PD-(L)-1 blockade (IO) and PD-(L)-1 blockade combined with chemotherapy (ChemoIO) are both standard first-line treatments for patients with PD-L1-high (≥ 50%) metastatic non-small cell lung cancer (NSCLC). These regimens have not been compared prospectively, so comparative effectiveness is unclear. It is also unknown if clinical and molecular tumor characteristics differentially associate with benefit to IO vs ChemoIO in patients with NSCLC with high PD-L1 tumor expression. Methods: All patients with metastatic NSCLC treated with IO or ChemoIO at two institutions (Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute) were reviewed. Patients with EGFR or ALK alterations, PD-L1 expression < 50%, treated with IO or ChemoIO in > 1st line setting were excluded. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the IO vs ChemoIO groups and association with clinical, pathologic, and molecular features was examined. To account for NGS panel differences, tumor mutational burden (TMB) values were harmonized using a z-score conversion as previously described (Vokes et al, 2019). Results: Of 639 patients with stage IV EGFR/ ALK wild-type NSCLC and PD-L1 ≥50% treated in the 1st line setting, 504 received IO and 135 received ChemoIO. Baseline ECOG performance status (p = 0.3), median PD-L1 % (p > 0.9) and TMB (p = 0.2) were similar between the IO and ChemoIO groups. For patients receiving IO vs ChemoIO, there was no significant difference in OS (HR 0.8, 95% CI 0.6 to 1.08; p = 0.2). Median PFS was shorter (HR 0.7, 95% CI 0.6 to 0.9; p = 0.004) and ORR was lower (40% IO vs 55% ChemoIO, p = 0.002) in the IO group. Among patients with durable responses (> 6 months), never smokers were less common in the IO group (6% vs 18%, p < 0.001), but there was no difference in PD-L1 expression, TMB, or mutational ( KRAS, STK11, or KEAP1) profile to suggest differential predictors of benefit to IO or ChemoIO. Conclusions: In patients with PD-L1 high NSCLC, there was no survival benefit associated with the addition of chemotherapy to IO. There were also no clear differences in PD-L1 expression or molecular features associated with durable response to IO vs ChemoIO. These findings have implications for treatment selection in this population.
SAF-189s in advanced, ALK-positive, non–small cell lung cancer: Results from a first-in-human phase 1/2, multicenter study.
Authors: Yang Jin-Ji , Zhou Jianying , Cheng Ying , Li Mingjun , Zhao Qiong , Zhang Zhiye , Zang Aimin , Fan Yun , Hui Ai-Min , Zhou Yongchu , Wu Zhuli , Sun Juan , Pan Zhaoyang , Qiu Jingjun , Wu Yi-Long 
Published: June 2022

9076 Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]
BRAF mutation classes and co-occurring mutations in NSCLC.
Authors: Niu Jiaxin , Flannery Cynthia A. , Hall David W. , Hoag Jess W. , Therala Nishitha , Kemkes Ariane C. , Routh Josh , De La O Jean-Paul , Macera Lisa , Thakkar Snehal Govind 
Published: June 2022

9083 Background: Targeted therapy against unique molecular drivers has revolutionized non-small cell lung cancer (NSCLC) treatment. BRAF mutations, present in 2%-5%, have emerged as therapeutic targets, and can be divided into three classes: kinase-activating monomers (class I, V600) or dimers (class II), or kinase-inactivating dimers (class III). Most studies have focused on BRAF V600E NSCLC. Limited clinical data suggest classes II and III may not respond well to chemo- or targeted therapy and tend to have a poorer prognosis. Little is known about co-occurring mutations. This study examines BRAF classes and co-occurring mutations in NSCLC. Methods: Between October 2018 and October 2021, data from 3009 NSCLC Oncotype MAP test results were analyzed. This test utilizes tumor DNA to identify single nucleotide variants, indels, copy number alterations, and select structural variants/fusions by next generation sequencing with a 257 gene panel. Tumor mutational burden and microsatellite instability are also assessed. Pathogenic/likely pathogenic mutations were identified, BRAF mutations assigned to 3 different classes based on current understanding, and associations of other mutated genes with BRAF class examined. Results: Among samples, 133 (4.4%) had BRAF mutations: 30 class I (1%); 42 class II (1.4%); 36 class III (1.2%); and 25 unclassified (0.8%) (Table). Two genes showed associations with BRAF class: STK11 was significantly overrepresented in class II and III, and SETD2 in class I (p<0.05 for both). BRAF class II mutations were further divided into subclasses, IIa (n= 5) and IIb (n= 35); two could not be assigned. The lack of a positive association between KRAS (and NF1) and BRAF class III was unexpected since class III is RAS-dependent while class I and II are RAS-independent. The overrepresentation of STK11 in classes II (with 11/12 events in IIb) and III might explain, at least in part, the poor prognosis relative to class I. By contrast, SETD2 is overrepresented in class I, which might help explain its better response to immunotherapy. Conclusions: For the first time we report the incidence of BRAF mutation classes and associated co-mutations in NSCLC. These associations may help to explain therapeutic outcomes. The impact of coexisting STK11 mutations in class II subclasses warrants further investigation.[Table: see text]