bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of sequential dosing of sonidegib and pembrolizumab in advanced solid tumors (aST) and non–small-cell lung cancer (NSCLC).
Authors: Shanshal Mohamed , Foster Nathan R. , Lou Yanyan , Zhao Yujie , Seetharam Mahesh , Mansfield Aaron Scott , Leventakos Konstantinos , Zhu Mojun , Steinert Kimberly O. , Mikula Elizabeth , Shi Qian , Kizilbash Sani Haider , Dong Haidong , Adjei Alex A. , Ma Wen Wee 
Published: June 2023

9093 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance invariably emerges in the majority of patients. Potential mechanisms include activation of compensatory pathways. The inhibition of sonic hedgehog signaling (sHH) was previously shown to induce intra-tumoral (IT) infiltration by CD4+, CD8+ and HLA-DR class II cells. Our preclinical data showed sHH inhibitor enhanced IT penetration by monoclonal antibodies and induced PD-L1 expression. We conducted a phase I study using a novel sequential pulse dosing of sonedegib followed by pembrolizumab in aST with an expansion cohort to determine the maximum tolerated dose (MTD), tolerability and preliminary efficacy. Methods: The dose escalation utilized a 3+3 design to determine the MTD and proceeded to expansion cohort upon determination of the MTD. Patients enrolled to each dose level were observed for dose limiting toxicities (DLTs) during the 1st cycle. The expansion cohort consisted of NSCLC and head/neck squamous cell carcinoma (HNSCC) previously treated by anti-PD1/-L1. The recommended phase 2 dose (RP2D) was determined following the review of the toxicity profile of the combination from all cycles. The study treatment consisted of sonidegib oral daily from day 1 to 8 and pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle. The sonidegib dose levels explored were 400, 600 and 800 mg. Archival tumor and blood specimens were collected for correlative studies. Adverse events (AEs) were categorized and graded per CTCAE v5.0, and tumor response by RECIST v1.1. Results: The study enrolled a total of 33 patients and 29 received treatment (13 in escalation and 16 in expansion), including patients with NSCLC, HNSCC, skin cancer, gastric cancer and melanoma. The enrollment to the NSCLC cohort is complete and HNSCC continues. No DLT was encountered during dose escalation and the MTD was not reached. The highest planned dose level was selected to proceed to expansion (sonidegib 800mg days 1-8 in combination with pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle). The expansion cohort proceeded to enroll 15 patients evaluable for AEs (10 NSCLC and 5 HSNCC). Grade 3 and above treatment-related AEs across all patients were hyperglycemia, fatigue, dyspepsia, abdominal pain. The mature efficacy data will be reported at the meeting. Conclusions: The study successfully determined the RP2D of sonidegib when dosed sequentially with pembrolizumab in advanced solid tumors. The AE profile of the combination is similar to that for respective agents given individually. The efficacy data among anti-PD1/-PDL1-treated NSCLC will be reported at the meeting. Clinical trial information: NCT04007744 .
Retrospective clinical analysis of circulating tumor DNA (ctDNA)–based molecular response (MR) and baseline blood-based tumor mutational burden (bTMB) for monitoring response in phase 3 trial of bintrafusp alfa vs. pembrolizumab treatment of non-small cell lung cancer (NSCLC).
Authors: Feng Zheng , Machl Andreas , Wang Danyi , Overstreet Brooke , Yablonovitch Arielle , Scheuenpflug Juergen 
Published: June 2023

9098 Background: The clinical utility of ctDNA-based approaches, such as bTMB and MR, to monitor and predict response during chemo-immunotherapy was evaluated using longitudinal cohort samples from a Phase 3 study of bintrafusp alfa versus pembrolizumab as a first-line treatment in patients with PD-L1 expressing advanced NSCLC. Methods: ctDNA was collected at baseline and day 42 after treatment with bintrafusp alfa (Q2W, 1200mg) or pembrolizumab (Q3W, 200mg). The GuardantOMNI liquid biopsy (LBx) assay was used to detect somatic alterations in 497 genes and generate bTMB from baseline, and MR scores from baseline and day 42 (n = 424 samples). bTMB and somatic alterations influencing response were explored. MR scores were calculated using the validated Guardant Response algorithm. Associations between ctDNA metrics and PFS were assessed. Results: 418/424 samples passed sequencing QC; of these, somatic mutations were detected in 236/237 baseline samples and 177/181 day 42 samples. Of 212 NSCLC patients with eligible bTMB results at baseline, 104 (49.1%) patients received bintrafusp alpha and 108 (50.9%) received pembrolizumab. bTMB high (bTMB-H) is defined as >20mut/MB. In the bintrafusp alpha arm, PFS was significantly longer in patients with bTMB-H (median 8.3 months vs 2.7 months, p = 0.00086). In the pembrolizumab arm, PFS was also longer in patients with bTMB-H (median 5.65 months vs 5.5 months, p = 0.0898). Of 132 NSCLC patients with eligible MR results, 67 (50.8%) patients received bintrafusp alpha and 65 (49.2%) patients received pembrolizumab. In the bintrafusp alpha arm, molecular responders had significantly longer PFS (median 7.9 months vs 4.2 months, p = 0.00042). In the pembrolizumab arm, molecular responders also had significantly longer PFS (median 8.95 months vs 4.1 months, p = 0.00054). Conclusions: ctDNA analysis from plasma samples supported MR assessment in patients treated with ICI, indicating its utility as an adjunct to RECIST in monitoring of tumor response. Blood-based TMB-high was associated with immunotherapy treatment benefit. Analysis of b-TMB and MR allowed identification of patients with improved PFS in both treatment arms. Investigation of treatment specific TMB cut off selection and potential clinical utility of defined somatic mutations is ongoing. Clinical trial information: NCT03631706 .
Association between duration of immunotherapy and overall survival in advanced non–small-cell lung cancer.
Authors: Sun Lova , Bleiberg Benjamin Aaron , Hwang Wei-Ting , Marmarelis Melina Elpi , Langer Corey J. , Singh Aditi Puri , Cohen Roger B. , Mamtani Ronac , Aggarwal Charu 
Published: June 2023

9101 Background: For patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with front line immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown. We aimed to assess practice patterns surrounding ICI treatment discontinuation at two years, and to evaluate association of duration of therapy with overall survival by comparing pts who received fixed duration ICI therapy for 2 years vs those who continued therapy beyond two years. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, and included adult pts diagnosed with advanced NSCLC from 2016-2020, who received frontline immunotherapy-based treatment. Pts who were still on treatment without progression at 2 years were classified as “fixed duration” (treatment discontinuation at 2 years, between 700-760 days) vs “indefinite duration” (continued treatment beyond two years, > 760 days). Overall survival from 760 days was analyzed using Kaplan-Meier methodology. Multivariable Cox regression adjusted for patient and cancer-specific factors was used to compare survival between fixed and indefinite-duration groups. Results: Our analytic cohort consisted of 113 pts in the fixed duration group and 593 in the indefinite duration group; median age was 69, 49% were female, and 71% were White. Pts in the fixed duration group were more likely to have a history of smoking and be treated at an academic center. There was no significant difference in overall survival between pts in the fixed duration and indefinite duration groups, either on univariable (HR 1.26, 95% CI 0.77-2.08) or multivariable Cox regression (HR 1.33, 95% CI 0.78-2.25). Conclusions: In a real world cohort of advanced NSCLC pts treated with front line ICI, only about 1 in 5 stopped treatment at two years rather than continuing treatment beyond two years. The lack of significant overall survival advantage for the indefinite duration cohort on adjusted analysis provides reassurance to pts and providers who wish to stop therapy at 2 years.
The final analysis of a phase I/II study of nivolumab, ipilimumab combined with nintedanib in advanced non-small cell lung cancer.
Authors: Puri Sonam , Tanvetyanon Tawee , Creelan Ben C. , Shafique Michael Rahman , Saltos Andreas Nicholas , Chiappori Alberto , Haura Eric B. , Thapa Ram , Chen Dung-Tsa , Boyle Theresa A. , Antonia Scott Joseph , Gray Jhanelle Elaine 
Published: June 2023

9102 Background: Nintedanib (NT) is an oral triple kinase inhibitor that is active against NSCLC and inhibits the activity of the immunosuppressive cancer associated fibroblasts in the tumor microenvironment (TME). Targeting the TME with NT may represent an important synergistic approach in improving immunotherapy (IO) outcomes for NSCLC. We initiated a phase Ib/II trial to evaluate the combination of NT, nivolumab (N) and ipilimumab (I) in advanced (a)NSCLC. Based on the phase IB (dose escalation) results, the combination of N (3mg/kg/2w), I (1mg/kg/6w) and NT (150mg once daily) was declared as the recommended phase 2 dose (RP2D). Here we present the final analysis of the regimen in treatment naïve (TN), and IO pretreated (IP) aNSCLC. Methods: This is a single institution, non- randomized, parallel assignment phase I/II clinical trial of aNSCLC pts. Eligible pts were TN (Arm A) or with disease progression following IO (Arm B) with planned sample size of 40/arm. Enrollment into phase II was by the Bayesian two-stage design method with the primary objective of determining the overall response rate (ORR) in the intent to treat population. Key secondary objectives were overall survival (OS) and progression-free survival (PFS). Descriptive statistics were used to summarize demographic and safety data. The Kaplan- Meier method with log-rank test (5% level of significance, 95% CI and 2-sided test) was used for survival analysis. Results: 22 and 29 pts received the N+I+NT at the RP2D in Arm A and B, respectively. The median age was 67 [42;92] with 53% (27/51) females, 84% (42/51) Caucasian, ECOG 1 in 88% (45/51), and a current/prior history of tobacco use in 88% (45/51) pts. Adenocarcinoma histology was common (64%, 33/51) with PD-L1 ≥1% in 52% (22/42) pts. As of Oct 24, 2022, 18 and 26 pts were evaluable for response in Arm A and B, respectively. Clinical efficacy was observed in the TN and IP cohorts (Table). The most common treatment-related adverse events (TRAEs) were similar in both cohorts. TRAE of any grade in Arm A were nausea (8, 36%), diarrhea (8, 36%), fatigue (7, 32%), and in Arm B were nausea (10, 34%), fatigue (9, 31%), anorexia (8,27%). Conclusions: The combination of nivolumab, ipilimumab and nintedanib had a manageable toxicity profile and demonstrated promising antitumor activity in both TN and IP aNSCLC patients. Clinical trial information: NCT03377023 . [Table: see text]
Association of alterations in multiple tumor suppressor genes with poor outcomes in patients with EGFR-mutant lung cancer.
Authors: Stockhammer Paul , Grant Michael J , Wurtz Anna , Foggetti Giorgia , Expósito Francisco , Gu Jianlei , Chung Sangyun , Li Fangyong , Walther Zenta , Gettinger Scott N. , Politi Katerina A. , Goldberg Sarah B. 
Published: June 2023

9104 Background: Co-occurring alterations in tumor suppressor genes (TSG) have been described as determinants of disease heterogeneity in EGFR-mutant non-small cell lung cancer (NSCLC), however, detailed analyses of their impact on patient outcomes are limited. Methods: Patients with EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) at the Yale Cancer Center who had tumor genomic profiling either before EGFR-TKI therapy (pre-TKI) or at disease progression (post-TKI) were included. Whole exome sequencing (WES) of paired pre- and post-TKI tumor specimens were performed for a subset of patients. The cohort was divided into three subgroups based on alterations in TP53 and five additional TSGs ( RB1, NF1, ARID1A, BRCA1 and PTEN): patients with tumors harboring a TP53 mutation plus a mutation in at least 1 additional TSG ( TP53mut/TSGmut), patients with tumors harboring a TP53 mutation without an additional TSG mutation ( TP53mut/TSGwt), and patients with TP53wt tumors. Clinical characteristics including progression-free (PFS) and overall survival (OS) were assessed. Results: One-hundred-one patients were included in this retrospective study. TP53 mutations were identified in 65 (64%) tumors, of which 23 (35%) and 42 (65%) were classified as TP53mut/TSGmut and TP53mut/TSGwt, respectively. Among those cases with paired WES available (n = 34), frequencies of alterations in the six included TSGs did not significantly differ between pre- and post-TKI tumor specimens. In the full study cohort, the presence of a TP53 mutation was associated with numerically worse PFS (HR 1.46, CI 0.97 – 2.21, p = 0.09) and OS (HR 1.68, CI 1.05 – 2.70, p = 0.04) on first-line EGFR-TKI. Strikingly, after dividing the TP53mut cohort into TP53mut /TSGmut and TP53mut /TSGwt cases, alterations in additional TSG were found to drive the poor outcomes: TP53mut /TSGmut cases had significantly worse PFS and OS on first-line EGFR TKI than TP53mut /TSGwt(mPFS 8.0 vs 10.6 months, p = 0.006; mOS 30.0 vs 33.3 months, p = 0.12) or TP53wt cases (mPFS 8.0 vs 12.6 months, p < 0.0001; mOS 30.0 vs 48.8 months, p = 0.001). There was no significant difference in PFS or OS between patients with TP53mut /TSGwt and TP53wt tumors. Similar outcome differences between the three groups were found in patients who received osimertinib in the second-line setting. Conclusions: The inferior outcomes associated with EGFR/TP53-mutant NSCLC tumors may be due to additional TSG alterations rather than TP53 mutational status alone. Alterations in the investigated TSGs did not appear to emerge under EGFR-TKI therapy, which suggests that they are truncal. Our findings may have implications for understanding the biologic underpinnings of differential outcomes to EGFR TKIs.
Tissue and plasma-based mechanisms of resistance to first-line osimertinib in EGFR-mutant NSCLC: A multi-institutional cohort.
Authors: Piotrowska Zofia , Chen Lanyi Nora , Shum Elaine , Park Cathleen , Guo Matthew , Liu Ying , Tran Misha , Marks Jennifer Aline , Banwait Mandeep , Liu Stephen V. , Scott Susan Combs , Bestvina Christine M. , Riess Jonathan W. , Marrone Kristen A. , Hall Richard Delmar , Gentzler Ryan D. , Shu Catherine A. 
Published: June 2023

9108 Background: Osimertinib (osi) is the preferred 1st line (1L) therapy for patients (pts) with EGFR+ NSCLC, but acquired resistance is universal. Identification of mechanisms of resistance (MoR) to 1L osi can inform subsequent therapies. We report a retrospective, multi-institutional cohort of pts with tissue biopsy (TBx) and/or liquid biopsy (LBx) upon 1L osi progression (PD). Methods: Pts with advanced EGFR+ NSCLC who had TBx and/or LBx (for ctDNA analysis) obtained at PD on 1L osi at 8 participating institutions were included. Molecular testing was performed using next-generation sequencing (NGS) and, in a subset, FISH per local standards. We retrospectively collected clinical characteristics, tissue histology, NGS/FISH results and subsequent therapies. Results: 193 pts (128 female; median age 64 yrs) had TBx (n = 129) and/or LBx (n = 122) upon PD on 1L osi, 58/193 had both tissue and ctDNA. Primary EGFR mutations included del19 (102), L858R (76), and other (15). Median time from osi start to first bx was 14 mos (range, 1-55). MoRs are summarized in the table. In all, 86/193 (45%) pts had a known MoR identified on TBx and/or LBx. Among 129 pts with TBx, histologic transformation (trans) and MET amplification (amp) were the most common MoR, each seen in 16% pts. Among 122 pts with LBx, secondary EGFR mutations were the most common MoR, seen in 15%. Among the 58 pts with both TBx + LBx, discordance between major MoRs was seen in 21/58 pts (36%), most commonly due to histologic trans detected on TBx only (n = 7) and discordant MET amp status (n = 8; 6 TBx+/LBx-, 2 TBx-/LBx+). No MoR was identified in 53% TBx and 75% LBx (including 14% Lbx where the original EGFR mutation was not detected in ctDNA). Results of TBx led to MoR-directed 2L therapy in 41/129 (32%) pts, while LBx results led to MoR-directed 2L therapy in 16/122 (13%). Conclusions: In this large, multi-institutional cohort, histologic trans (16%) and MET amp (16%) were the most common MoR to 1L osimertinib on tissue bx. In ctDNA, secondary EGFR mutations (15%) were the most frequent MoR. The results of TBx were more likely to impact second-line therapy than LBx. Our results underscore the importance of tissue biopsy (and limitations of liquid biopsy) after osimertinib PD, where tissue testing remains the gold standard. In addition, with more than half of patients having no identifiable MoR despite comprehensive testing, our results highlight the need for MoR-agnostic treatment strategies. [Table: see text]
Contemporary biomarker testing rates in both early and advanced NSCLC: Results from the MYLUNG pragmatic study.
Authors: Evangelist Makenzi Colleen , Butrynski James Edward , Paschold John C. , Ward Patrick J. , Spira Alexander I. , Ali Kashif , Espirito Janet L. , Hakimian David , Jotte Robert M. , Koselke Beth , Larson Timothy , Meshad Michael W. , Neubauer Marcus A. , Ogden Katie , Owera Rami , Richards Donald A. , Robert Nicholas J. , Walberg Jennifer M. , Wang Yunfei , Coleman Robert L. 
Published: June 2023

9109 Background: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study aims to identify and overcome barriers to timely and appropriate biomarker testing in patients (pts) with NSCLC. We previously reported retrospective real-world testing rates for 5 biomarkers from 2018-2020 in metastatic pts. We now report results from the prospective observational phase, including additional biomarkers in pts with both early and advanced NSCLC. Methods: This was a prospective, non-interventional cohort study of newly diagnosed pts with early stage (ES), locally advanced (LA), or metastatic NSCLC (mNSCLC) between 12/2020 and 9/2022 and enrolled from 12 community practices (69 sites) across The US Oncology Network. The proportion of pts with test results for 9 biomarkers at time of protocol initiation were examined: ALK, BRAF, EGFR, ROS1, PD-L1, KRAS, MET, NTRK, and RET. Timing of tests, use of single vs multigene NGS testing, clinical and socioeconomic factors, and reasons for not testing were collected in real time. Results: Of 1002 pts screened, 987 were enrolled and analyzed. There were 405 stage IB-IIIC pts [n = 284 stage IB-IIIA (ES cohort); n = 121 stage IIIB-IIIC (LA cohort)] and 582 stage IV pts (mNSCLC cohort). Descriptions for ES and LA vs mNSCLC pts respectively include median age 68 vs 69 yrs, 49% vs 52% female, 83% vs 77% white, 58% vs 79% adenocarcinoma histology, 71% vs 68% ECOG 0-1, and 33% vs 30% high school education level. Testing rates for ES vs mNSCLC cohorts are shown in the table below: prior to treatment initiation, 64% of ES and 83% of mNSCLC pts had at least one biomarker result; and 37% of mNSCLC pts had results for all 9 biomarkers. NGS testing occurred in 37% and 57% of the ES and mNSCLC cohorts respectively. Reasons for not testing included: barriers to ordering (42%, 25%), insufficient tissue (18%, 18%), clinical deterioration/crisis (5%, 12%), and other reasons (37%, 49%), respectively. Conclusions: As more genomic alterations are identified in NSCLC, we observed that many pts do not get full genotyping prior to treatment, and biomarker testing remains of utmost importance. Further analyses by distinct stages (e.g. LA), histology, social determinants, utilization of targeted therapies, and other reasons for not testing will be performed. These data will be used to evaluate future prospective interventions for MYLUNG, to help improve comprehensive biomarker testing for NSCLC. [Table: see text]
Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.
Authors: Shi Yuankai , Hu Xingsheng , Li Xingya , Li Yongsheng , Wang Ke , Wang Pingli , Jiang Liyan , Zhang Shucai , Meng Xiangjiao , Wang Huijuan , Dong Xiaorong , Yang Runxiang , Luo Yongzhong , Mei Qi , Sun Yinghui 
Published: June 2023

9110 Background: SY-3505 is a potent, brain-penetrant, 3rd-generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1st and 2nd-gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2nd-gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2nd-gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .