bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human, multicenter phase Ⅰ study of TGRX-326 in patients with advanced ALK-positive non-small cell lung cancer.
Authors: Zhao Hongyun , Ma Yuxiang , Yang Nong , Wang Zhehai , Jin Wenjian , Li Xingya , Liu Yunpeng , Meng Rui , Zhou Jianying , Cheng Ying , Wang Yongsheng , Yu Zhuang , Zhang Li 
Published: June 2023

9113 Background: TGRX-326, a deuterated derivative of lorlatinib (LOR), is a potent 3rd generation ALK and ROS1 dual TKI with high potency against multiple ALK-resistant mutations. Deuteration of the key metabolic site of the molecule allows to achieve a higher exposure than with LOR and this may result in alleviated toxicities and better efficacy. Methods: The study comprised 3 phases: dose escalation (D-ESCAL), dose expansion (D-EXP) and cohort expansion (C-EXP). In D-ESCAL and D-EXP, ALK+ pts prior failed on 2nd gen ALK-TKIs or ROS1+ pts resistant to crizotinib (CRZ) were enrolled; in C-EXP, ALK+ pts progression after CRZ (C-EXP-A1),progression after ≥1 2nd gen TKIs (C-EXP A2), ROS1+ progression after CRZ (C-EXP-B) and pts with ALK TKI naïve (C-EXP-C) were enrolled. Results: Up to Jan 13, 2023, 185 pts (median age 53 years, 45.9% male) were enrolled; Median treatment and follow-up was 5.5 and 6.7 months, respectively. There were no DLT observed and no MTD identified in D-ESCAL (5-125mg QD, n=19). Based on the safety, efficacy and PK exposure data of 42 pts in D-ESCAL and D-EXP, 60 mg QD was selected as the RP2D for C-EXP,the average AUCtau of 60mg QD reached to 5443ng*hr/mL. Treatment-related adverse events (TRAEs) occurred in 87.5% patients (162/185), the most common TRAEs were hypercholesterolemia (74.1%), hypertriglyceridemia (68.1%), weight gain (36.2%), peripheral edema (15.7%), peripheral neuropathy (14.1%). As for R2PD, 132 of 155 (85.2%) experienced TRAEs, Grade ≥3 TRAEs occurred in 19.7%, most frequent were hypertriglyceridemia (11%) and hypercholesterolemia (8.4% ). Dose interruptions and dose reductions associated with TRAEs were reported in 10 (5.4%) and 5 (2.7%) pts respectively. Confirmed response were observed in 142 ALK+pts enrolled in C-EXP, results are shown in the Table (Efficacy of B-ROS1+ pts will be reported separately). Eleven ALK mutations were detected in 16 pts (either alone or in combination); 50.0% pts achieved PR. Out of 6 pts who were positive for G1202R, 50.0% experienced PR. Conclusions: TGRX-326 was well tolerated in pts with advanced ALK+ NSCLC and showed promising clinical antitumor activity irrespectively of ALK+ resistance to CRZ and 2nd gen TKIs, especially among those with brain metastases. Impressive activity was seen in ALK TKI naïve NSCLC. TGRX-326 demonstrated antitumor activity against multiple ALK mutations including G1202R. Clinical trial information: NCT05441956 . [Table: see text]
Characteristics of long-term survivors with EGFR mutant (EGFRm) metastatic non-small cell lung cancer (mNSCLC).
Authors: Marmarelis Melina Elpi , Grady Connor B. , McCoach Caroline , Sun Fangdi , Liu Geoffrey , Patel Devalben , Nieva Jorge J. , Marrone Kristen A. , Velcheti Vamsidhar , Liu Stephen V. , Patil Tejas , Weiss Jared , Schwartzman William , Villaruz Liza C , Cass Amanda , Aisner Dara L. , Hwang Wei-Ting , Aggarwal Charu , Camidge D. Ross , Sun Lova 
Published: June 2023

9116 Background: Although osimertinib has become standard first-line (1L) therapy for patients (pts) with EGFRm mNSCLC, a subset treated with earlier-generation EGFR-targeted TKIs and chemotherapy have had long-term survival. We sought to characterize clinical features of long-term survival in pts with EGFRm mNSCLC treated prior to the osimertinib era. Methods: Data were abstracted from electronic medical records at 12 cancer centers participating in the Academic Thoracic Oncology Medical Investigator’s Consortium (ATOMIC). We included patients with mNSCLC with sensitizing mutations in EGFR who started 1L systemic therapy before 2015. Survival distributions and predictors were assessed using Kaplan-Meier estimates and a multivariable Cox proportional hazards model including time-dependent brain metastasis (met) development, age, 1L therapy (targeted vs. chemotherapy), sex, race, and smoking status. Multivariable logistic regression was used to evaluate baseline predictors associated with 5+ year survival vs. not for those with known survival status at 5 years after start of 1L. Results: We identified 304 patients (69% female, 56% White, 29% Asian, mean age 61.2). First-line targeted therapy was given in 70% of patients. With a median follow-up of 81.5 months, median overall survival was 63.5 months (95% CI 59.4-71.9). 135 (44%) pts survived 5+ years; among those with baseline next-generation sequencing (NGS), presence of a baseline pathogenic ERBB2 variant was higher in 5+ year survivors (4/51 [8%], 2x amplification, y772_A775dup, S310F) v others (1/65 [2%], amplification). Among 161 pts with baseline brain imaging, both baseline and on-treatment development of brain mets were associated with worse survival (HR 1.29, 95% CI 1.21-1.37; HR 1.59, 95% CI 1.47-1.72; both P < 0.001). Excluding 22 patients lost to follow-up before 5 years, a history of smoking (OR 2.99, 95% CI 1.35-6.90, P = 0.008) and baseline brain metastases (OR 3.57, 95% CI 1.64-8.13, P = 0.002) were associated with death before 5 years. Conclusions: Long-term survivors with EGFRm mNSCLC treated before the osimertinib era were more likely to be nonsmokers and have no baseline brain metastases. This highlights a subset of EGFRm patients who had excellent outcomes with older treatment strategies and may not benefit as much from intensification approaches. Additional baseline mutational data will be presented at the conference.
Stimulator of interferon gene (STING) expression as a biomarker for overall survival in PDL1-negative, TMB-low non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).
Authors: Hadfield Matthew James , Gandhi Nishant , Farrell Alex Patrick , Azzoli Christopher G. , Vanderwalde Ari M. , Halmos Balazs , Liu Stephen V. , El-Deiry Wafik S. , Naqash Abdul Rafeh 
Published: June 2023

9120 Background: cGAS-STING (CGS) is an intracellular DNA sensing pathway that when activated, stimulates interferon and other immune-related signaling pathways. While increased expression of CGS-related genes has been associated with better survival in NSCLC, studies investigating this phenomenon in tumors less likely to respond to ICIs such as PDL1-negative, TMB-Low NSCLC are lacking. Here we report the role of CGS pathway in NSCLC tumors that are both PDL1-negative and TMB-Low. Methods: DNA (592-gene or whole exome) and RNA sequencing (whole transcriptome) was performed for NSCLC specimens (n=7264) submitted to Caris Life Sciences (Phoenix, AZ). PDL1 negativity was defined as <1% TPS score (22C3) & TMB-Low as <10 mutations/Mb. Hierarchical Agglomerative Clustering (HAC) was performed on STING pathway genes (CXCL10, CCL5 and GZB) and tumors were grouped into STING-high (n=3070), STING-intermediate (n=1609) and STING-low (n=2585) groups. Microenvironmental cell populations (MCP)-counter analysis was used to estimate cellular composition of immune cells. Statistical significance was determined using chi-square/Fisher’s exact/Mann-Whitney U tests and adjusted for multiple comparisons (q<0.05). Kaplan Meier method was used to estimate the overall survival (OS) derived from insurance claims of IO treated pts with NSCLC (n=400). Pts were stratified into groups above or below the median expression of the STING gene ( TMEM173). Results: Compared to STING-low, tumors that were STING-high had enrichment in immune cell infiltrates including CD8+ T cells (4.4-fold) and B-cells (5.9-fold); Additionally, STING-high cohort had significantly higher expression of immune checkpoint (IC) genes including CD274(2.5-fold), CD80 (2.7-fold, all q<0.05). STING-high tumors also had a higher prevalence of TP53 mutations (mts) and a lower prevalence of STK11 and KEAP1 mts (Table). Median overall survival (OS) was 21.1 months in the STING-high cohort (n=200) vs 11.9 months in the STING-low cohort (n=199) in IO treated pts (HR = 0.62, p<0.000.1) Conclusions: To our knowledge this is the largest real-world dataset indicating that enrichment of both the STING gene, and gene signatures associated with the STING pathway represent valuable transcriptomic biomarkers to stratify pts with PDL1-negative and TMB-Low NSCLC who benefit more from IO therapies. Conversely, novel IO combination strategies need to be employed in STING-low tumors to enhance outcomes. [Table: see text]
Amplification of wild-type RET and clinical response to selpercatinib for non–small-cell lung cancer (NSCLC).
Authors: Gandhi Malini Marion , Ricciuti Biagio , Gildenberg Melissa , Singh Ankit , Li Yvonne Y. , Gagné Andréanne , Wang Xinan , Fitzgerald Kelly , Aizer Ayal , Nishino Mizuki , Alessi Joao Victor Machado , Pecci Federica , Di Federico Alessandro , Fisch Adam , Nardi Valentina , Sholl Lynette M. , Awad Mark M. , Rotow Julia K. 
Published: June 2023

9123 Background: RET rearrangements and RET kinase domain mutations represent targetable genomic alterations in various cancer types. However, the frequency and characteristics of RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. Methods: In a pan-cancer cohort of patients at the Dana-Farber Cancer Institute (DFCI) whose tumors underwent next-generation sequencing (NGS), we evaluated the frequency of wild-type (wt) RET amplification (defined as ≥6 copies) in the absence of RET rearrangements or activating mutations. We validated our findings using merged data from the TCGA, GENIE, and China Pan-Cancer datasets. Results: The frequency of wt RET amplification across all cancers was 0.08% (28/34,463) in the DFCI cohort and 0.16% (145/91,466) in the validation cohort. In NSCLC, the frequency of RET amplification was 0.10% (5/4773) in the DFCI cohort and 0.13% (15/11,622) in the validation cohort. Other cancer types with RET amplification included hepatobiliary cancer, prostate cancer, and breast cancer, among others. For 22 RET-amplified cases with available copy number data , the median RET gene copy number was 7 (range 6-36). Among 20 RET-amplified NSCLCs, 10 had no other known driver mutations, and 10 had concurrent driver mutations (including MET exon 14 skipping, MET amplification, KRAS G12C/S/D, EGFR L858R, EGFR exon 20 insertion, and EGFR exon 19 deletion). In cases with available smoking status, 5 out of 6 patients with RET-amplified NSCLC had a history of tobacco use. A 69-year-old man with unresectable stage III NSCLC had disease recurrence after chemoradiation and durvalumab. Both the initial and recurrent biopsy samples showed focal high-level RET amplification (22 and 28 copies, respectively); genomic and RNA sequencing showed no other driver mutations or RET rearrangements. He experienced partial response to the selective RET inhibitor selpercatinib with decrease of both intracranial and systemic tumor burden. Conclusions: Amplification of wt RET represents a novel, targetable, rare molecular subset of NSCLC and other cancers.
Results from a first-in-human phase 1B study of a complement factor H inhibitor (GT103) in patients with non-small cell lung cancer (NSCLC).
Authors: Clarke Jeffrey Melson , Stinchcombe Tom , Gu Lin , Mamdani Hirva , Antonia Scott Joseph , Simon George R. , Sonpavde Guru P. , Ready Neal E. , Crawford Jeffrey , Campa Michael , Gottlin Elizabeth , Bushey Ryan , Herndon James Emmett , Patz Edward 
Published: June 2023

9128 Background: GT103 is a first-in-class IgG3 monoclonal antibody that was derived from a single human B cell and inhibits complement factor H (CFH). CFH is implicated in cancer immune evasion and overexpression portends a poor prognosis in multiple malignancies. CFH regulates C3 convertase in the alternative pathway of the complement cascade, limiting downstream opsonization and membrane attack complex formation. Monoclonal antibody inhibition of CFH facilitates complement-dependent tumor cell lysis, modulates the adaptive immune response, and inhibits tumor growth. Methods: GT103 is being evaluated in a multi-institutional, first-in-human, phase Ib study in patients with advanced stage, refractory NSCLC. A standard ‘3+3’ dose escalation schema was used across four dose levels, with treatment given until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) observation period included cycle 1 and radiographic disease assessment was performed every 6 weeks. We have previously reported that no DLT was seen at the highest two dose levels of 3 mg /kg or 10 mg/kg administered IV every 3 weeks. Two expansion cohorts have now been opened at 10 mg/kg IV every 2 week and 15 mg/kg every 3 weeks dose levels allowing up to 6 patients at each dose level. We herein present updated clinical outcomes and analysis of correlative biomarkers. Results: As of February 3, 2023, twenty-five patients have been treated, with a median follow up of 230 days. Five of the 21 patients in the dose escalation cohort demonstrated stable disease by RECIST criteria. In the 10 mg/kg dose level, one patient has experienced prolonged disease stabilization and has received 12 cycles to date with tumor reduction on CT. The DLT period is ongoing for two patients enrolled in the 10 mg/kg IV every 2 weeks and two patients in the 15 mg/kg every 3 weeks expansion cohorts. Soluble C5b-9 (s C5b-9) is a candidate pharmacodynamic biomarker for GT103 and was measured at baseline and at day 15 from patients in all four dose escalation levels (0.3, 1, 3, 10 mg/kg). An increase in sC5b-9 was found in 13 of 21 patients at day 15. A marked doubling of the baseline sC5b-9 level was demonstrated in a subset of patients by day 15 indicative of biologic activity. Conclusions: GT103 is well tolerated in heavily pretreated advanced NSCLC population. Early clinical activity has been demonstrated to date with stable disease seen in 24% of patients. Updated clinical results and correlative data will be presented. A separate phase 2 study of combination GT103 with pembrolizumab is planned for patients with refractory NSCLC. Trial Registration: The study was approved by Duke University IRB with approval number Pro00104564. Clinical trial information: NCT04314089 .
Evaluating generalizability of practice-changing randomized clinical trials in non-small cell lung cancer using machine learning-based in-silico trials.
Authors: Orcutt Xavier , Mamtani Ronac , Sondhi Arjun , Cohen Aaron B. , Parikh Ravi Bharat 
Published: June 2023

9130 Background: Results of randomized clinical trials (RCTs) of anticancer agents are not generalizable to many real-world patients. Advances in machine learning (ML) and increasing availability of curated real-world data offer opportunities to assess generalizability by simulating trials “in-silico”. Our objective was to assess the generalizability of survival outcomes reported in 2 practice-changing phase III trials in first-line (1L) advanced non-small cell lung cancer (aNSCLC). Methods: Our cohort included patients from the nationwide Flatiron Health EHR-derived de-identified database diagnosed with stage IIIB-IV or recurrent aNSCLC between 2011 and 2020. First, we trained and validated supervised ML models (gradient boosted, random forest, support vector machine and penalized Cox) to predict 1-year survival for patients with aNSCLC; the Lung Cancer Prognostic Index (LCPI), a published disease-specific prognostic index, was used as a comparator model. We used 130 demographic, vital sign, laboratory, and biomarker features at aNSCLC diagnosis to build models. Second, we used the best-performing ML model to create 4 prognostic risk groups. Third, we simulated 2 seminal trials for 1L treatment of aNSCLC, using inverse probability of treatment-weighted survival analyses, coarsely reproducing inclusion/exclusion criteria across ML-derived risk groups. We compared median overall survival (mOS) using Kaplan-Meier curves from the start of 1L treatment to death in in-silico trials (ISTs) vs. RCTs. Results: Our cohort included 61,339 patients with aNSCLC. The best-performing gradient boosted model outperformed the LCPI (AUC 0.784 vs 0.688). In ISTs, survival benefits of novel treatments varied across risk groups and were generally lower in ISTs compared to RCTs (Table). IST results in high- and very high-risk patients were inconsistent with RCT survival results. For example, for KEYNOTE-024, mOS in the pembrolizumab arm was 30.0 months, whereas in the IST, mOS among patients receiving pembrolizumab varied from 1.3 months in very high-risk patients to 41.5 months in low-risk patients. RCT results overestimated treatment effects for high-risk aNSCLC patients. Conclusions: ML-based ISTs can reveal heterogeneity in real-world survival outcomes associated with novel oncology treatments and elucidate populations for whom RCT results generalize poorly. [Table: see text]
Real-world outcomes of first-line immune checkpoint inhibitors with or without chemotherapy in KRAS G12C altered NSCLC according to PD-L1 status.
Authors: Aggarwal Charu , Parkar Lamisa , Huerga Iker , Sasser Kate , Nimeiri Halla , Korytowsky Beata , Patel Jyoti D. 
Published: June 2023

9136 Background: There is a considerable debate whether treatment approaches should be tailored in advanced KRAS G12C-mutated NSCLC. Increasing evidence suggests that KRAS G12C-mutated NSCLC is associated with genomic heterogeneity that may impact clinical outcomes. Herein, we report a multimodal, real world outcomes analysis of 1L patients with advanced KRAS G12C-mutated NSCLC stratified by treatment type and PD-L1 status. Methods: Deidentified multimodal real-world data (RWD) of 1576 advanced, 1L NSCLC patients across the US were retrospectively analyzed from the Tempus database. Selection criteria included: Tempus xT targeted NGS, known PD-L1 status, absence of EGFR, ALK and ROS1 mutations, and treatment with chemotherapy (CT) + pembrolizumab (P), or P only. Patients were stratified by the presence or absence (wt) of KRAS G12C alterations. Median OS (mOS) was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS G12C status, PD-L1 status, and pathogenic alterations of STK11 and KEAP1. Results: In this study, two cohorts were assessed, KRAS G12C (n = 201) and KRAS G12C wt (n = 1375). Characteristics and demographics were balanced between both cohorts. Among TPS < 50 patients treated with CT + P, KRAS G12C (n = 109, 54%) had a mOS of 11.64 months (m) versus 16.81m (HR = 1.32, p = 0.06) for KRAS G12C wt (n = 864, 62.8%). Among TPS < 1 patients treated with CT + P, KRAS G12C (n = 46, 22%) had a mOS of 11.18 m versus 16.44 m (HR = 1.67, p = 0.01) for KRAS G12C wt (n = 489, 35%). Among TPS ≥50 patients treated with P only, KRAS G12C (n = 45, 22.3%) had a mOS of 30.03m compared to 25.03m (HR = 0.94, p = 0.83) in KRAS G12Cwt (n = 236,17.1%). TPS < 50 subgroup was enriched for select co-mutations with KRAS G12C ( STK11, 24.5%; KEAP1, 10.7%) vs. TPS ≥50 ( STK11, 3.8%; KEAP1, 5.1%). When evaluating the impact of co-mutations in the KRAS G12C with TPS < 50, STK11 (n = 30) mOS was 10.59m (HR = 1.01, p = 0.81) and KEAP1 (n = 13) mOS was 7.63m (HR = 2.14, p = 0.03). Conclusions: This largest RWD analysis to date demonstrates that 1L KRAS G12C NSCLC patients with TPS < 1% and < 50% receiving standard CT + P have the shortest survival among all evaluated sub-groups. Novel KRAS G12C targeted combination therapies in development for this patient population may offer the promise of better outcomes. [Table: see text]
Non-comparative, open-label, international, multicenter phase I/II study of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic merkel cell carcinoma (MCC) (CheckMate 358).
Authors: Bhatia Shailender , Topalian Suzanne Louise , Sharfman William Howard , Meyer Tim , Lao Christopher D. , Fariñas-Madrid Lorena , Devriese Lot A. , Aljumaily Raid , Ferris Robert L. , Honma Yoshitaka , Khan Tariq Aziz , Srirangam Anjaiah , Garnett-Benson Charlie , Lee Michelle , Nghiem Paul 
Published: June 2023

9506 Background: MCC is a rare and aggressive skin cancer. Programmed death-ligand 1 (PD-L1) is often upregulated in MCC and blockade of PD-L1 or its receptor, PD-1, has improved survival for patients with metastatic MCC. Anti–PD-1 combined with anti–CTLA-4 has been reported to improve outcomes over anti–PD-1 monotherapy (NCT03071406; Kim S et al., Lancet 2022), however further investigation is needed. CheckMate 358 (NCT02488759) assessed NIVO ± IPI in 2 non-randomized MCC cohorts. Methods: Eligible pts had recurrent or metastatic MCC, ≤ 2 prior therapies, ECOG performance status (PS) 0–1, and no prior immune checkpoint inhibitor (ICI) therapy. Pts were eligible regardless of PD-(L)1 status. Pts received NIVO 240 mg Q2W or NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W for ≤ 24 months (m) or until disease progression, unacceptable toxicity, or consent withdrawal. Imaging was conducted Q8W in year 1 and Q12W thereafter. Planned sample sizes were 23 pts for NIVO and 40 pts for NIVO + IPI. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DOR), investigator-assessed progression-free survival (PFS), and overall survival (OS). Results: 68 pts received NIVO (n = 25) or NIVO + IPI (n = 43) with ≥ 24 m follow-up (median: NIVO, 62.5 m; NIVO + IPI, 24.4 m). In the NIVO arm, median age was 66 yrs (range, 27–88), 10 (40.0%) pts had ECOG PS of 1, and 15 (60.0%) were treatment-naive. In the NIVO + IPI arm, median age was 70 yrs (range, 48–85), 27 (62.8%) pts had ECOG PS of 1, and 33 (76.7%) were treatment-naive. Treatment duration was 15.8 m in the NIVO arm, and 7.9 m for NIVO and 6.0 m for IPI in the NIVO + IPI arm. Efficacy and safety outcomes are summarized in the table. ORR was 60.0% (95% CI, 38.7–78.9) in the NIVO arm and 58.1% (95% CI, 42.1–73.0) in the NIVO + IPI arm. The most common reasons for treatment discontinuation were disease progression (NIVO, 28.0%; NIVO + IPI, 32.6%) or study-drug toxicity (NIVO, 20.0%; NIVO + IPI, 25.6%). There was 1 study drug-related death in each arm (NIVO, pneumonitis; NIVO + IPI, gastrointestinal motility disorder). Conclusions: Both NIVO and NIVO + IPI show durable clinical efficacy in advanced MCC. While the non-randomized trial design limits comparisons between the arms, results do not suggest additional efficacy benefit with IPI added to NIVO. Higher incidence of grade 3/4 TRAEs observed in the combination arm could have resulted in shorter treatment duration. Clinical trial information: NCT02488759 . [Table: see text]