Non-small Cell Lung Cancer Pts Research Articles

Abstract CT247: Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study

Abstract Background: TROP2 (trophoblast cell surface antigen 2) is commonly over-expressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we present the updated data from a Phase 2 expansion cohort for patients (pts) with advanced NSCLC. Methods: Pts with previously treated advanced NSCLC were enrolled to receive SKB264 at 5 mg/kg Q2W until disease progression or unacceptable toxicity (KL264-01, NCT04152499). Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: As of Nov 22, 2023, 43 NSCLC pts had been enrolled. Median follow-up was 17.2 months (mo). 21 pts with EGFR wild type had received median prior 3 regimens of therapy including anti-PD-1/L1 inhibitors. 22 pts with EGFR mutant had progressed on or after TKI therapy, 50% of whom also failed at least one line of chemotherapy. Updated efficacy results are shown in the Table. Overall, 30 pts (69.8%) experienced Grade ≥3 treatment-related adverse events (TRAEs). The most common Grade ≥3 TRAEs were neutrophil count decreased (34.9%), anemia (30.2%), WBC count decreased (25.6%), stomatitis (9.3%), and rash (7.0%). No TRAEs leading to treatment discontinuation or deaths occurred. No drug-related ILD/pneumonitis was reported. Conclusions: The updated data continues to demonstrate that SKB264 monotherapy delivers promising clinical efficacy with manageable toxicity in pretreated advanced NSCLC pts. A Phase 3 global study of SKB264 in pts with 3L+ EGFR mutant NSCLC (NCT06074588) and a Phase 3 study of SKB264 in China in pts with 2L EGFR mutant NSCLC (NCT05870319) are ongoing. TABLE 1: NAND Table Clinical outcomes by EGFR mutation status Overall (N=43) EGFR mutant (N=22) EGFR wild type Total (N=21) Non-squamous (N=9) Squamous (N=12) ORR*, % 43.6% 60.0% 26.3% 22.2% 30.0% Median DoR, mo (95%CI) 9.3 (3.7, 10.3) 8.7 (3.7, 10.3) 9.6 (3.5, NE) / / Median PFS, mo (95% CI) 7.2 (5.4, 11.3) 11.5 (5.7, 12.9) 5.3 (3.5, 6.2) 5.8 (1.5, 12.1) 5.1 (1.9, 9.3) Median OS, mo (95% CI) 22.6 (13.1, NE) 22.7 (19.7, NE) 14.1 (10.7, NE) 16.2 (5.8, NE) 12.8 (3.5, NE) 12-mo OS rate, % (95% CI) 69.0% (52.7, 80.7) 81.0% (56.9, 92.4) 57.1% (33.8, 74.9) 66.7% (28.2, 87.8) 50.0% (20.8, 73.6) 18-mo OS rate, % (95% CI) 56.5% (40.1, 70.0) 76.2% (51.9, 89.3) 35.9% (16.0, 56.4) 44.4% (13.6, 71.9) 30.0% (7.7, 56.9) *Including confirmed or unconfirmed response. Based on response evaluable pts (≥1 on-study scans) with 4 pts (2 EGFR mutant pts with non-squamous histology and 2 EGFR wild type pts with squamous histology) excluded. Citation Format: Wenfeng Fang, Ying Cheng, Zhendong Chen, Wei Wang, Yongsheng Li, Yongmei Yin, Xingya Li, Huiting Xu, Guohua Yu, Yanjun Mi, Zev A. Wainberg, Jordi Rodon, Xiang Wang, Xian Wang, Xiaoqing Zhang, Xiaoping Jin, Lian Lu, Junyou Ge, Jin Li, Li Zhang. Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT247.

Abstract 5037: Development of multiplexed Absolute Q digital PCR assays to rapidly quantify EGFR and KRAS genotype in advanced non-small cell lung cancer (NSCLC) patients’ plasma

Abstract Introduction: There are needs to identify and serially monitor driver and resistance mutations (muts) in therapy-treated cancer patients (pts). Quantitative liquid biopsy in cell-free (cf)DNA has been widely adopted. We have developed and clinically validated droplet digital PCR (ddPCR) assays to detect common driver/resistance muts such as EGFR del19, L858R, T790M and KRAS G12X in the cfDNA of advanced NSCLC pts. We have established ddPCR assays for 30+ driver/resistance muts in multiple genes (BRAF, MET, ESR1, etc.) relevant to melanoma, breast, and colorectal cancer. Our assays use tumor/cell line DNA as positive controls and serve as benchmarks to develop newer assays such as plasma NGS. In this study, we converted existing/validated EGFR and KRAS G12X ddPCR assays to the QuantStudio Absolute Q digital PCR (dPCR) system. The selected mutations maximize actionable clinical information and are designed to study oncogenic and resistance mutations in NSCLC efficiently. dPCR’s accuracy and efficiency enables target multiplexing, providing comprehensive information from limited materials and contributing to liquid biopsy research progress. Methods: Plasma from pts with tumors harboring EGFR and KRAS muts was collected at progression with advanced disease following consent to protocol DFCI #14-147. We designed a multiplex dPCR assay that identifies the most common and therapy-relevant KRAS muts in NSCLC, G12C/D/V, and detects other G12X using a drop-off probe. We also designed 2 EGFR kits, one identifying driver muts, the other resistance muts. Results: To validate assay performance, we used gDNA derived from cell lines with EGFR or KRAS muts. We serially diluted mut gDNA samples in background wt gDNA (16 ~ 1000 mut copies in 1000 wt copies) and performed KRAS and EGFR dPCR assays. We detected 16 mut copies with sensitivities similar to those of ddPCR assays. We then studied 48 cfDNA samples from plasma of NSCLC pts with tumor confirmed KRAS G12X or EGFR L858R, del19, T790M muts. No samples had both EGFR and KRAS muts detected, suggesting our assays are specific. We detected muts in samples with an allele frequency median of 0.9% for KRAS mut, 11.9% for EGFR driver mut, 2.9% for EGFR T790M. The concordance rate is 91.3% between dPCR and ddPCR results. Our findings suggest these assays are as sensitive and specific as our validated ddPCR assays. Multiplexed Absolute Q dPCR saves cfDNA and cuts turnaround time (TAT) to 90 min for KRAS assay and 3hr for EGFR assays. Conclusions: We developed rapid, sensitive and specific quantitative dPCR assays for KRAS and EGFR muts on the QuantStudio Absolute Q platform to quantify plasma genotyping in NSCLC. We will clinically pilot our validated rapid genotyping approach and quantify TAT advantage of multiplexed genotyping in NSCLC pts undergoing standard-of-care tumor genotyping. Citation Format: Benjamin Hanna, Shidong Xu, Cloud P. Paweletz, Yanan Kuang. Development of multiplexed Absolute Q digital PCR assays to rapidly quantify EGFR and KRAS genotype in advanced non-small cell lung cancer (NSCLC) patients’ plasma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5037.

Abstract 2490: Quantification of tumor fraction and outcomes association in a real-world non-small cell lung cancer (NSCLC) cohort using a tissue agnostic epigenomic circulating tumor DNA (ctDNA) assay

Abstract Background: The validity of ctDNA assays for evaluating molecular response to therapy by measuring changes in variant allele fraction (VAF) while on treatment is well established, but they are prone to limitations such as low ctDNA levels and interference from copy number variation and clonal hematopoeisis (CH), which may be overcome by methylation-based quantification. ctDNA levels may be monitored throughout a patient's (pts) journey to indicate when relapse or progression is present, often sooner than current methods (RECIST). Here we describe the performance of a methylation-based ctDNA assay to quantify ctDNA levels and correlate changes with outcomes in a real-world NSCLC cohort. Methods: RADIOHEAD is a pan-tumor observational study of 1200 patients on standard of care ICI treatment regimens with plasma samples collected prospectively for retrospective analysis. We randomly selected 241 NSCLC pts that have a combined total of 761 samples (236 baseline, 191 C3D1, and 128 at 6 months post first dose). Samples were analyzed using a commercial NGS assay, which quantifies circulating tumor fraction (cTF) via interrogating thousands of methylation sites from ctDNA, validated with LoB, LoD, LoQ, and linearity studies. Cox proportional hazards (CPH) were used for comparison of real-world progression free survival (rwPFS). Gender, age, disease stage, and blood-assessed tumor mutational burden (bTMB) were included as covariates. Median rwPFS was calculated using Kaplan Meier analysis. rwPFS ordinal groups were defined as PFS event within 3mo, 3-6mo, 6-12mo, and greater than 12mo, and association with early ctDNA changes was assessed with a chi-squared test. Results: In this cohort, 4, 11, 83 and 142 pts were stage I to IV, respectively (1 unknown). Methylation based detection of ctDNA at baseline or C3D1 was associated with shorter rwPFS (baseline: mPFS 12.7 mo [9.3-19.5] vs NR [16.4-NR]; HR=2.2 [1.3-3.7] p<0.005, C3D1: mPFS 12.4 mo [9.3-16.1] vs NR [19.5-NR] HR= 2.2 [1.3-3.5], p<0.005) independent of stage, gender, or age. Longer rwPFS was associated with >95% reduction in cTF from baseline to C3D1 or low ctDNA at both timepoints (rwPFS <3mo = 12.5%, 3-6 mo = 30.8%, 6-12 = 37.1%, ≥12 mo = 55.3%; N=153, p=0.015). For pts with ctDNA not detected at C3D1, ctDNA detection at 6 months post first dose was strongly associated with shorter rwPFS (mPFS 13.5 mo [9.5-NR] vs. NR [19.5-NR]; HR= 6.2 [1.9-20.1], p<0.005). Conclusions: These data demonstrate a significant association of ctDNA detection via methylation-based cTF and on-treatment changes in cTF with rwPFS. Furthermore, subsequent cTF detection 6-months on-treatment, without cTF detected early on-treatment was associated with worse outcomes, suggesting the value of serial monitoring to improve identification of patients likely to progress. Citation Format: Sara Wienke, Sean Gordon, Samantha Liang, Jing Wang, Reagan Barnett, Kyle Chang, Shile Zhang, Carin R. Espenschied, Katie Quinn, Kimberly Banks. Quantification of tumor fraction and outcomes association in a real-world non-small cell lung cancer (NSCLC) cohort using a tissue agnostic epigenomic circulating tumor DNA (ctDNA) assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2490.

Comparison of molecular testing rates and biomarker positivity by histology among patients (pts) with stage IV non-small cell lung cancer (NSCLC): A quality initiative by Integra Connect PrecisionQ.

582 Background: National Comprehensive Cancer Network guidelines for NSCLC recommend biomarker testing for EGFR, ALK, ROS1, BRAF, NTRK1/2/3, METex14 skipping, KRAS, RET, and ERBB2 (HER2) in advanced or metastatic NSCLC regardless of histology. We sought to understand the testing rates for these markers among pts with a squamous (S) histology compared to pts with a non-squamous (NS) histology, while also assessing positivity rates among pts based on histology by the respective biomarkers for pts with stage IV NSCLC. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 2 million cancer pts across 500 sites of care to assess testing rates and biomarker positivity rates based on histology among adult NSCLC patients. We included 3,889 Stage IV NSCLC pts, where we conducted chart reviews, investigating testing rates across each of the biomarkers based on patient histology (group 1). In addition, we evaluated 6,303 stage IV NSCLC pts, regardless of whether we conducted chart reviews, to assess rates of positivity among the respective biomarkers (group 2). Pts included in the analysis were diagnosed on or after 1/1/2019. We assessed rates of biomarker testing in group 1 and biomarker positivity (irrespective of the type of mutation) in group 2 stratified by histology. Descriptive analyses were used and proportions were compared using a two-tailed two-sample z-test. Results: Among the Group 1 stage IV pts in the comparison of tested vs. not-testedbased on histology (N= 3889), the average age was 72.9 (median = 75), 49% were female, 81.6% were NS. We found the testing rates among S pts (N=714) vs. NS (N=3175) as follows: EGFR-S 76% vs. EGFR-NS 92%, ALK-S 77% vs. ALK-NS 92%, BRAF-S 75% vs. BRAF-NS 87%, KRAS-S 71% vs. KRAS-NS 81%, MET-S 72% vs. MET-NS 80%, RET-S 72% vs. RET-NS 79%, ROS1-S 72% vs. ROS1-NS 79%, ERBB2-S 69% vs. ERBB2-NS 76%, and NTRK-S 62% vs. NTRK-NS 68%. All comparisons were statistically significant at P < .01. Among the Group 2 stage IV pts who were tested(N = 6303), the average age was 72.6 (median = 73), 50.8% were female, 86.0% were NS. We found the positivity rates among S pts vs. NS pts as follows: EGFR-S 7.5% (N = 827) vs. EGFR-NS 19.5% (N = 4650), ALK -S 1.3% (N =837) vs. ALK-NS 3.6% (N = 5099), BRAF-S 2.8% (N = 742) vs. BRAF-NS 6.0% (N = 4399), KRAS-S 10.4% (N = 694) vs. KRAS-NS 31.1% (N=3763), MET-S 4.3 (N=645) vs. MET-NS 7.5% (N = 3537), RET-S 0.5% (N = 635) vs. RET-NS 1.4% (N= 3397), ROS1-S 0.6% (N = 629) vs. ROS1-NS 1.4% (N = 3346), ERBB2-S 2.2% (N = 504) vs. ERBB2-NS 3.8% (N = 2510), and NTRK-S 1.0% (N = 486) vs. NTRK-NS 1.5% (N = 2444). Conclusions: Our results indicate a need to increase biomarker testing among pts with S histology to be equivalent to those who were tested with a NS histology, as biomarker positivity rates present in pts with S histology warrant a molecular evaluation regardless of histology.

Sintilimab, SBRT and GM-CSF for Metastatic NSCLC: A Prospective, Multicenter, Phase II Trial

PD-1/PD-L1 inhibitors have transformed the therapeutic landscape in metastatic non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Incorporating SBRT to PD-1/PD-L1 inhibitors may improve treatment efficacy and the anti-tumor immunity induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. The current trial (NCT04106180) is the first prospective, multicenter, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), SBRT and GM-CSF in metastatic NSCLC patients without sensitizing driver mutations. Metastatic EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy were eligible. Pts received SBRT (8 Gy*3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. Sintilimab would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). The trial was designed to enroll 56 patients and if ≥17 pts evaluated had an objective response, it was regarded as positive. By the time of 2022/10/30, the trial was early closed after 18 of the 51pts enrolled from 6 academic centers documented PR. The majority of pts were male, ECOG 1 and non-squamous NSCLC, having more than 5 lesions at baseline, with a median age of 62 (range, 32-74). The sites of SBRT included lung (n = 20), regional lymph node (n = 16), pleural nodule (n = 5), vertebra (n = 3), distant lymph node (n = 3), liver (n = 2) and others (n = 2). Treatment-related adverse event (TRAE) occurred in most pts and grade 3 TRAE occurred in 6 (11.8%) pts. No grade 4-5 TRAE occurred and the most common grade 3 TRAEs were ALT/AST elevation (n = 2), transient acute heart failure (recovered within 7 days) (n = 1), leucopenia/neutropenia (n = 2), pneumonitis (n = 1) and creatinine elevation (n = 1). With a median follow-up of 19.2 (range, 4.6-35.4) months, 49 pts had evaluable efficacy, with 18 PR, 15 SD and 16 PD. Median PFS and OS were 5.9 (95% CI, 3.9-9.2) and 16.2 (95% CI, 12.6-34.1) months, respectively. The results of biomarker testing will also be presented. Triple combination of Sintilimab, SBRT and GM-CSF is safe and shows promising efficacy in metastatic EGFR/ALK negative NSCLC.

Friendly-user score assessing gut dysbiosis and resistance to immune checkpoint inhibitors (ICI).

103 Background: Accumulating evidence pointed to the impact of the intestinal microbiota on ICI outcomes across various cancers. Although specific gut microbial species have been associated with beneficial responses ( i.e. Akkermansia muciniphila (Akk)), no consensus exists on a gut fingerprint predicting immunoresistance to clinical routine use. Methods: NCT04567446 provided whole genome sequencing (WGS) of longitudinal fecal samples from patients (pts) with advanced non-small cell lung cancer (NSCLC) during ICI (alone or with chemotherapy) in France and Canada. Topological Pearson networks clustered into species interacting groups (SIG) correlating with overall survival (OS; OS<12=NR; OS>12=R). Forty harmful (SIG1) and thirty-four beneficial (SIG2) WGS species were associated with NR and R to ICI. A monodimensional score (TOPOSCORE) based on SIG1/SIG2 ratio combined with Akk relative abundance was calculated and compared to machine-learning (ML) algorithms. Multivariate Cox analysis (MVA) adjusted for established risk factors (ATB, gender, age, ECOG, PD-L1, LIPI score). Intraindividual dynamics of the TOPOSCORE was evaluated in pts with at least two fecal samples. Three independent cohorts of NSCLC and genitourinary (GU) cancers pts validated the data. Results: In n=245 and n=148 NSCLC pts, we could classify pts into dysbiotic (SIG1+,33%) and eubiotic (SIG2+, 67%), using the TOPOSCORE. Pts falling within the SIG2+ exhibited a significantly prolonged OS than pts falling into SIG1+ (HR: (95% CI), 0.50 (0.36-0.71), p<0.0001). TOPOSCORE also predicted OS in 277 ICI-treated NSCLC and GU pts and compared to the state-of-the-art ML algorithms, held the highest percentage of correct predictions (63%). At MVA, TOPOSCORE was independently associated with OS (HR: 0.56 (0.39-0.81), p=0.002). Analyzing the intraindividual dynamics of the TOPOSCORE (n=67), we found that 74% of SIG2+ and 68% of SIG1+ individuals remained in their initial classification during ICI treatment. We finally scaled the calculation of the TOPOSCORE down to 24WGS (instead 75WGS) and set up a qPCR-based friendly-user test capable of accurately identifying the fecal presence of the bacteria of interest within 48 hrs. We confirmed (n=323) that OS was superior in those pts harboring a 24-bacteria-qPCR-based TOPOSCORE falling within the SIG2+ category (HR: 0.65 (0.48 to 0.87), p=0.0005). Conclusions: TOPOSCORE represents a robust biomarker predicting and following the dynamic of the immunoresistance to ICI across cancers on an individual basis. By converting the WGS TOPOSCORE to a qPCR-based test with a rapid turnaround time, it will be possible to adopt this score in routine clinical practice to improve pts stratification and ICI success rates guiding the selection of dysbiotic pts amenable to microbiota-centered interventions and eubiotic fecal microbiota transplantation donors. Clinical trial information: NCT04567446 .

Explore ALK: Alectinib activity in patients with ALK+ metastatic non-small cell lung cancer—A national real world analysis (GFPC 03-2019).

9092 Background: Alectinib is a standard of care option in advanced ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients (pts), with efficacy established by phase 3 trials, in first-line and beyond. There are few efficacy data in unselected populations. Methods: The objective of this study was to evaluate the efficacy of alectinib in real-world setting. All ALK+ advanced NSCLC pts initiating alectinib, between December 13, 2017 (date of access in France) and June 27, 2020, whatever the line, were included in explore ALK study. Patient characteristics, alectinib duration of treatment (DOT), progression-free survival assessed locally (rwPFS), overall survival (OS) according to the prescription line of alectinib, the presence of brain metastases at alectinib initiation, response rate and tolerance were collected from the medical files. Results: The analysis included 223 pts: 46.2% were men, 84.7% had no smoking history or were former smokers, median age was 59 (22-101) years and 95% were adenocarcinomas. Alectinib was initiated as first-line treatment in 119 pts, with a PS of 0/1/>1 in 42%/31%/27% of cases, a median number of metastatic sites of 2 (cerebral, hepatic, bone in 33%, 24% and 32% of cases). In first-line setting, after a median follow-up of 33.7 months (95%CI, 32.2-37.5), the median of rwPFS and DOT were 28.1 (95%CI, 20.7-40.4) and 26.9 (95%CI, 20.2-31.3) months, respectively. The median OS was not reach (NR), the 3-year OS rate was 72.1%. The rwPFS was not significantly different depending on whether or not the patient has brain metastases, 28.1 (95% CI, 14.5-NR) and 30.5 (85% CI, 18.9-40.4) months, respectively. The best response was complete (CR), partial (PR) and stable (SD) in 21%, 58% and 17%. The cerebral response, evaluable in 30/39 of the pts, was CR, PR and SD in 26%, 46% and 23% respectively; 33% of pts had a grade 3 adverse event, resulting in a temporary interruption of treatment in 7.6% of cases and a permanent discontinuation in 5.9% of cases. At the time of progression, 48.1% of pts had a new biopsy (66% of tissue biopsy). Efficacy data for alectinib prescribed as second line and above are summarized in the table. Conclusions: In this large real-world, cohort of unselected advanced ALK+ NSCLC pts, alectinib initiated in 1st-line or beyond provides similar efficacy and safety results as obtained in phase III clinical trials. [Table: see text]

Mass cytometry immune profiling to detect signatures of clinical activity of bintrafusp alfa (BA) in patients with advanced non-small cell lung cancer (NSCLC).

e21016 Background: BA, a bifunctional fusion protein targeting programed death-ligand 1 and transforming growth factor-β, is clinically active in a subset of patients (pts) with advanced NSCLC. In this study, mass cytometry was used to identify immune features associated with response and survival in pts with NSCLC treated with BA. Methods: Peripheral blood mononuclear cells were collected at baseline and after 1 and 3 doses of BA from 12 NSCLC pts treated every 2 weeks in a dose expansion biomarker cohort of a phase I clinical trial (NCT02517398). Samples were analyzed using a 44-marker mass cytometry panel designed to detect immune cell subsets and functional states of the innate and adaptive immune system. Manually gated immune cell subpopulations and unsupervised clusters were analyzed with Kruskal Wallis and Wilcoxon Rank Sum testing for multigroup comparison; and with linear correlation, univariate Cox regression and Kaplan Meier methods for progression free survival (PFS) analysis. Results: Among 12 pts, 3 had an objective response (OR), 6 had stable disease (SD) and 3 developed progressive disease (PD). Immune cell subsets associated with clinical activity by multigroup analyses included memory B cells, CD16+ natural killer (NK) cells, and double negative T cells (DNT). Pts with OR had a 2-fold higher frequency of memory B cells at baseline compared to pts who developed SD or PD. After 1 dose of BA, pts who subsequently developed an OR or SD had a 5-fold increase of CD16+ NK cells compared to pts with PD. After 3 doses of BA, pts who subsequently developed an OR had 4-fold more memory B cells and 3-fold more T-bet+ DNTs compared to pts with PD or SD. Immune cell subpopulations associated with survival included 3 unsupervised clusters annotated by the clustering algorithm as CD16+ NK cells, DNTs and classical monocytes. Fewer CD16+ NK cells at baseline were associated with longer PFS (p = 0.0053). Longer PFS was also associated with higher CD161+ CD127+ DNT cells after 1 dose of BA relative to baseline (p = 0.029), while an expansion of IgG4+ PD-1+ classical monocytes after 3 doses of BA was associated with shorter PFS (p = 0.015). Linear correlation analysis did not find strong associations between any one immune state and survival. Conclusions: Our study demonstrates the ability of mass cytometry immune profiling to detect potential immunological markers of response and survival in NSCLC pts treated with BA. The association between CD16+ NK cell frequencies and clinical benefit could reflect the ability of BA to facilitate antibody-dependent cellular cytotoxicity by NK cells in NSCLC. A high fraction of memory B cells at baseline and after 3 doses identifies pts likely to respond to BA. If validated in larger studies, these novel immune signatures can be used to improve clinical outcomes in pts with NSCLC considering immunotherapy.

Large-scale transcriptomic profiling of the tumor immune microenvironment in ALK+ lung cancer.

9020 Background: Patients (pts) with ALK+ Non-Small Cell Lung Cancer (NSCLC) do not derive significant clinical benefit from immune checkpoint inhibitors. To better understand this lack of immunotherapy sensitivity, we aimed to characterize major immune components of the tumor microenvironment (TME) by comprehensive transcriptomic and immunohistochemistry (IHC) analyses. Methods: We analyzed NGS data from 5490 NSCLC pts that underwent DNA (592 Gene Panel, NextSeq, or WES, NovaSeq) and RNA (NovaSeq, WTS) sequencing at Caris Life Sciences (Phoenix, AZ). 374 ALK-rearranged cases were evaluated, along with 3169 KRAS-mut ( STK11/ KEAP1-wt) and 1947 EGFR-mut cases serving as comparators with known heterogenous and inert immune TMEs, respectively. PD-L1 (22C3) was evaluated by IHC. Immune cell fractions were inferred using quanTIseq. Gene expression profiles were analyzed for a T cell-inflamed signature (TIS) predictive of response to immunotherapy and for other immune modulatory genes such as IFNG, GZMB, TGFB1, and those of the adenosine pathway ( CD73/NT5E, CD39/ENTPD1, ADORA1, ADORA2A/B). A significant difference between genomic subgroups was defined as fold-change > 1.2. In an independent cohort of 14 ALK+ NSCLC pts, density and spatial organization of CD4+ and CD8+ T cells, Tregs, major myeloid lineage cells, PDL1, and CD73 were assessed by quantitative IHC. Results: ALK+ tumors were associated with high PD-L1 (≥50%) expression (40% vs 47% for KRAS-mut vs 18% for EGFR-mut, p < 0.001) and low TMB (median 3 mut/MB vs 9 for KRAS-mut vs 4 for EGFR-mut, p < 0.001). The abundance of CD8+ T cells (fold-change -1.3, p < 0.001), Tregs (fold-change -1.2, p < 0.001), M2 macrophages (fold-change 1.2, p < 0.001), and CD4+ T cells (fold-change 1.9, p < 0.001) differed from KRAS-mut; notably, similar to EGFR-mut. In ALK+ tumors, IFNG (fold-change -1.5, p < 0.001), GZMB (fold-change -1.6, p < 0.001), TGFB (fold-change -1.3, p < 0.001), LAG-3 (fold-change -1.4 p < 0.001), CD73/NT53 (fold-change -1.7 p < 0.001) , and ADORA2A (fold-change -1.4, p < 0.001) were decreased while ADORA1 (fold-change 1.3, p < 0.001) was increased compared to KRAS-mut. EML4-ALK comprised 94.7% of the ALK+ tumors and distribution of EML4-ALK variants was consistent with prior reports (e.g. v1 35.6%, v3 35.1%). Immune cell fractions and immune-related gene expression did not vary significantly between major variant subgroups (v1 vs non-v1, and v3 vs non-v3, p > 0.05). Conclusions: To our knowledge this is the largest transcriptomic analysis of the ALK+ NSCLC TME. Despite high levels of PD-L1, ALK+ tumors exhibit multiple features of an inert immune TME, primarily characterized by low TMB and decreased CD8+ T cells and immune activation markers. Our findings suggest that, while immunosuppressive factors such as M2 macrophages and adenosine signaling may also be targeted, strategies to enhance immunogenicity are critical for an effective immune response in ALK+ NSCLC.

Prognostic value of baseline immune suppressive biomarkers to select non-small cell lung cancer (NSCLC) patients (pts) likely to benefit from the plinabulin/docetaxel (Plin/Doc) combination.

e21018 Background: Baseline Neutrophil-to-Lymphocyte (L) ratio (NLR), Platelet-to-L ratio (PLR), and L-to-Monocyte ratio (LMR) are biomarkers that can predict anticancer outcomes. Plin, a novel small molecule immune-enhancing agent, exerts anticancer activity by GEF-H1-dependent activation of dendritic cells, and hence T-cells. We evaluated the correlation of Plin’s anticancer effects with NLR, PLR, LMR immune suppressive (IS) signature. We correlated baseline NLR, PLR, and LMR (broken down in quartiles [Q]) with overall survival (OS) in NSCLC pts from the DUBLIN-3 trial, which had met the primary OS endpoint in favor of Plin/Doc vs Doc alone (Han ESMO 2021). Methods: DUBLIN-3 (NCT02504489) was a global Phase 3 study in 2nd/3rd line EGFR-wild type, stage IIIB/IV NSCLC pts (N = 559) randomized 1:1 to Plin/Doc or Doc alone. Doc (75 mg/m2 on D1) and Plin (30 mg/m2 on D1/D8) were given by IV infusions. Baseline (i.e., prior to dexamethasone premedication, Doc and Plin) blood draws were taken from each pt within 28 days prior to any study medication given to obtain baseline NLR, PLR, and LMR. The survival duration of each pt was obtained. NLR, PLR, and LMR values for Plin/Doc and Doc were divided into Qs, and the corresponding median OS for each Q was calculated. Only 2nd line pts were included in this analysis to avoid confounding with multiple lines. Results: Increasing Qs of baseline NLR and PLR (thus with increasing IS signature) were associated with decreasing median OS for both Plin/Doc and Doc. Increasing Qs for LMR (thus with decreasing IS signature) were associated with increasing median OS in both Plin/Doc and Doc. Median OS in each Q was consistently higher with Plin/Doc vs Doc alone, except for Qs with an IS signature. With baseline NLR ≤3.6, PLR≤194, or LMR≥5.9, thus avoiding an IS signature, median OS was on average 2.5 Mo (range 0.6-4.5 Mo) longer with Plin/Doc vs Doc alone. For each of the Qs in the table, the n = 52 ± 2 pts. Conclusions: Baseline IS biomarkers were predictive of median OS with both Plin/Doc and Doc alone. Baseline NLR, PLR, and LMR, at cut-off levels to avoid IS levels, could serve as prognostic markers to identify likely responders to the immune-enhancing agent Plin in combination with Doc in NSCLC. Clinical trial information: NCT02504489 . [Table: see text]

Safety, tolerability, and quality of life (QoL) of single-agent plinabulin (Plin) for the prevention of docetaxel (Doc) chemotherapy (chemo)-induced neutropenia (CIN) in non-small cell lung cancer (NSCLC) patients (pts) from two randomized trials.

e21168 Background: Plin, is a novel, non-G-CSF, small molecule agent with comparable CIN-preventive effects vs pegfilgrastim. In contrast to pegfilgrastim, Plin is given on the same day of chemo (30 mins after chemo), and does not cause bone pain, nor thrombopenia. In the two randomized controlled (placebo (Plac)/no treatment) cancer trials, Phase (Ph) 2 Study 101 and Ph3 Study 103, single-agent (SA) Plin reduced estimated Doc-induced mean duration of severe neutropenia by > 1 Day vs Plac. We conducted a post hoc analysis of safety, tolerability, and QoL in NSCLC pts from these trials. Methods: NSCLC pts in 2nd/3rd line, with at least 1 NCCN FN risk factor, were randomized to Doc (75 mg/m2) + Plin (n = 116; at the CIN dose of 20 mg/m2 or its pharmacokinetic equivalent), or Doc + Plac (n = 296) in trials 101 (NCT00630110) and 103 (NCT02504489). Doc was given on day (D) 1, and Plin was given twice per cycle, on D1 and D8 (Plin D1 and D8 dosing is supratherapeutic for CIN but facilitated a more robust safety/tolerability evaluation [the CIN Plin dose is D1 only]). Safety blood draws and AE collection on D1 and D8; tolerability; and QoL (pre-dose and D8) were evaluated over 4 cycles. All pts received dexamethasone premedication. QoL scores were obtained in study 103 only, with Plin (n = 80) and Plac (n = 234), by validated questionnaires (EORTC QLQ C30, to evaluate global health status/QoL; the combined symptom scales/items, and the lung cancer-specific QoL questionnaire QLQ-LC13). Results: QoL scores over 4 cycles between Plin and Plac were similar, indicating Plin was well-tolerated. Grade (Gr) 3/4 AEs of interest for Plin (+Doc) and Plac (+Doc) are summarized in the table. With Plin, AE frequency of diarrhea was slightly higher (5.2% vs 1%; 1 Gr4 case with Plin), but was manageable, and so was hypertension (11.2% vs 1.7%; all Gr3 cases) vs Plac. Hypertension occurred around the time of infusion and was short-lasting (~2-4 hours) and typically self-limiting. Plin had less AEs of neutropenia (16.4% vs 50.3%) and leukopenia (15.5% vs 38.5%) vs Plac. Conclusions: Plin is an effective agent for CIN, has a favorable safety, tolerability, and QoL profile, and has the advantage of dosing on the same day of chemo. Clinical trial information: NCT02504489 . [Table: see text]

Clinical characteristics and treatment outcome of patients with advanced non-small-cell lung cancer (NSCLC) and FGFR fusions.

e21139 Background: Activating FGFR fusions are targetable genetic alterations in several solid tumours and hematologic malignancies, but little is known about their frequency in advanced NSCLC patients (pts). Furthermore, clinical characteristics and treatment outcome in NSCLC have not been sufficiently identified yet. Methods: Within Network Genomic Medicine (NGM), we screened advanced NSCLC pts without targetable mutations for genetic fusions using RNA-NGS (ArcherDx FusionPlex) and analysed fusion frequencies, patient characteristics and clinical courses. Results: From 01/2019 to 09/2022, we screened a total of 3309 NSCLC pts. We found 37 pts (1.1%) with FGFR activating fusions. Of these patients, 26 cases had squamous cell carcinoma (70.3%), 10 cases adenocarcinoma (27%), one patient had sarcomatoid differentiation (2.7%). The most common FGFR fusion was FGFR3-TACC3 with 21 cases (56.8%). All patients had UICC stage IIIB or IV at time of diagnosis: 13 were females (35.1%), 24 were males (64.9%); median age at first diagnosis was 69 years (range 36-91), 27 pts were former smokers (72.9%), 8 pts were current smokers (21.6%) and only one patient was a never smoker (2.7%). Co-occurring mutations were identified in 30 pts (81.1%): TP53 co-mutations were the most frequent co-mutation with 27 cases (72.9%), two cases had KEAP1 (5.4%), one case harboured either PTEN (2.7%), PIK3CA (2.7%) or MAP2K1 (2.7%). One patient harboured FGFR2 S587C co-mutation (2.7%). From 37 identified patients, 34 were available for follow-up. The median overall survival (mOS) was 24.87 months (95% confidence interval [CI]: 11.57–38.17). We counted 26 pts who received immunotherapy (either as monotherapy or chemoimmunotherapy) with a mOS of 26.44 months (95% CI: 20.23–32.66) comparing to the median OS of 9.5 months for patients (n = 8) with no immunotherapy (95% CI: 0.0–22.58) (p = 0.037). For three patients there was no information regarding therapy regimen obtainable. Six pts (16.21%) received targeted therapy (Erdafitinib/Rogaratinib) with no improved mOS compared to standard therapy (p = 0.026). Patients with TP53 mutation had longer mOS than pts with TP53 wild type (WT) (mOS 26.45 months [95% CI: 20.06–32.83] vs 9.24 months [95% CI: 1.43–17.06] [p = 0.031]). Conclusions: Activating FGFR fusions in NSCLC are rare events. The majority of patients are elder males with smoking history and predominantly squamous histology. The most frequent co-mutation is TP53 with prolonged OS comparing to TP53 WT patients. In contrast to other NSCLC with targebatle driver mutations, patients with FGFR fusion seem to benefit from immunotherapy, if added to their treatment. Targeted therapy is beneficial, but sufficient long-term data are currently missing.

Co-mutational status and PD-L1 expression in KRAS mutant non-small cell lung cancer (NSCLC): Role in treatment selection and association with clinical outcomes.

9038 Background: In NSCLC, different KRAS mutations (mt) define unique subgroups and certain co-mutations (co-mt) could have prognostic and therapeutic implications. Retrospective studies associate poor prognosis with co-mts in STK11 and KEAP1 with KRAS. It is unclear if PD-L1 expression and co-mt in KRAS mt NSCLC impacts outcomes. Methods: Molecular profiles of 27748 NSCLC tumors were tested with next-generation sequencing (Caris Life Sciences, Phoenix, AZ) and classified by KRAS mt. PD-L1 IHC (22C3) was reported as TPS. Real-world post-immunotherapy (IO) overall survival (OS) was obtained from insurance claims and calculated from start of an immune check-point inhibitor (with or without chemotherapy) to the last day of follow-up. Results: In all, 7634 (28%) samples had a KRAS mt; most common being G12C (11%), G12V (5.3%), G12D (3.9%) and G13X (2.0%). The most frequent co-mt was KRAS-TP53 (KP) (46%), similar in all KRAS subtypes. KRAS-STK11(KL) was in 23% of KRAS mt, enriched in G13X (33%) and lowest in G12D (16%). KRAS-KEAP1(KK) was co-mt in 10% of KRAS mt, highest in G13X (16%) and lowest in G12D (8%). KRASmt/ STK11wt/ KEAP1wt/ TP53wt (K only) was 27% of KRAS mt, highest in G12D (36%) and lowest in G13X (16%). A small subgroup, 5.6% was KRAS-STK11-KEAP1 co-mt (KKL). The majority of pts in the KL (61%), KK (52%) and KKL (62%) cohorts had TPS <1%. In 1723 KRAS mt NSCLC pts treated with IO, KL, KK and KKL had significantly worse post-IO OS than KP and K only (table); KKL had the lowest OS. In the TPS≥1% KRAS mt group, KL, KK and KKL had worse post-IO OS than KP and K-only. In TPS<1% group, KL and KK had poor post-IO OS and K-only had favorable outcomes. However, KP had worse post-IO OS compared to K-only in TPS<1%. In G12C and G12V, similar trend with worse post-IO OS in KL, KK and KKL, compared to KP and K only was noted. Conclusions: We report a large real-world dataset evaluating outcomes with check-point inhibitors in NSCLCs with KRAS and specific co-mts. KL, KK and KKL subgroups demonstrate universally poor outcomes in all KRAS subtypes irrespective of PD-L1. Pts with KP co-mts have adverse post-IO outcomes in TPS<1% but favorable in TPS≥1%. TPS score remains a predictive marker of IO outcomes in KP, but not in KL, KK and KKL. These observations emphasize that both PD-L1 and co-mts have a clear association with clinical outcomes in KRAS-mt NSCLC, and must be used in predictive models for individualized therapy. [Table: see text]

Reporting of patient reported outcomes in randomized clinical trials (RCTs) in non-small cell lung cancer (NSCLC) patients (pts).

6573 Background: A patient-centric approach to clinical trials has become necessary, with regulators emphasizing the importance of pts' experience. PRO is of utmost relevance for pts with cancers such as NSCLC, that are likely to be highly symptomatic and/or with an unfavorable prognosis. Methods: To evaluate the rate at which PRO included in clinical trials are made publicly available when trial results are published, we searched Citeline Trialtrove, a registry of clinical trials, for NSCLC phase 3 RCTs, recruiting during 2017-2022, with PRO listed - regardless of publication type. We excluded supportive care, radiotherapy, and unpublished trials. We identified publications associated with the trial, and extracted various parameters, including if PRO outcome was published. Results: Of 122 NSCLC RCTs identified, 66 listed at least 1 PRO. Trials were reported as full-text (43), abstract (9), 1 only in a trials registry; 13 not published. Fifty-three trials were included, all had PRO as a secondary endpoint. The sponsor was industry in the majority of the trials. Most included stage III/IV NSCLC pts, and 1st/2nd line or maintenance. 24 PRO tools were used, mainly EORTC QLQ LC13 (35 trials), EORTC QLQ C30 (34), EQ-5D-5L (14), LCSS (8), EQ-5D-3L (6). Seven trials listed 1 tool, 26 listed 2, 18 listed >3. PRO was reported in 36 (68%) of the published trials. In the subgroup of trials with disease control (DC) benefit and no overall survival (OS) benefit, PRO was reported in 15/21 (71%) trials. PRO benefit was shown in 9 of them. Of 43/53 trials published as full-text, 31 (72%) had PRO reported. A benefit in at least 1 PRO tool was reported in 21 studies, 9 did not show a PRO benefit; in 5 trials, only descriptive and no comparative analysis of PRO was reported. Of the 21 trials with PRO benefit, 19 had a DC benefit and 10 had also OS benefit. PRO was reported together with the first reporting of other outcomes in 18 (50%) trials, and after 7-32 months after the initial one in 18 trials. Conclusions: Of 122 RCTs only 66 had at least 1 planned PRO, and only 35 had it published. Even where full-text was available or no OS benefit shown, about 1/3 of the trials did not report PRO. Characteristics as disease stage, therapy line, sponsor, and primary endpoint did not differ between all included trials and those reporting PRO. The reporting rate increased compared to our previous report yet it is not satisfactory. The importance of quality of life and pts centric outcomes, and the great efforts needed from pts and operators to collect the data, should translate into routine, timely and appropriate reporting of PRO to allow a thorough assessment of treatment effect. [Table: see text]

Sintilimab, SBRT and GM-CSF for metastatic NSCLC: A prospective, multicenter, phase II trial.

e21172 Background: PD-1/PD-L1 inhibitors have transformed the therapeutic landscape in metastatic non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Incorporating SBRT to PD-1/PD-L1 inhibitors may improve treatment efficacy and the anti-tumor immunity induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. The current trial (NCT04106180) is the first prospective, multicenter, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), SBRT and GM-CSF in metastatic NSCLC patients without sensitizing driver mutations. Methods: Metastatic EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy were eligible. Pts received SBRT (8 Gy*3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. Sintilimab would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). The trial was designed to enroll 56 patients and if ≥17 pts evaluated had an objective response, it was regarded as positive. Results: By the time of 2022/10/30, the trial was early closed after 18 of the 51pts enrolled from 6 academic centers documented PR. The majority of pts were male, ECOG 1 and non-squamous NSCLC, having more than 5 lesions at baseline, with a median age of 62 (range, 32-74). The sites of SBRT included lung (n = 20), regional lymph node (n = 16), pleural nodule (n = 5), vertebra (n = 3), distant lymph node (n = 3), liver (n = 2) and others (n = 2). Treatment-related adverse event (TRAE) occurred in most pts and grade 3 TRAE occurred in 6 (11.8%) pts. No grade 4-5 TRAE occurred and the most common grade 3 TRAEs were ALT/AST elevation (n = 2), transient acute heart failure (recovered within 7 days) (n = 1), leucopenia/neutropenia (n = 2), pneumonitis (n = 1) and creatinine elevation (n = 1). With a median follow-up of 19.2 (range, 4.6-35.4) months, 49 pts had evaluable efficacy, with 18 PR, 15 SD and 16 PD. Median PFS and OS were 5.9 (95% CI, 3.9-9.2) and 16.2 (95% CI, 12.6-34.1) months, respectively. The results of biomarker testing will also be presented. Conclusions: Triple combination of Sintilimab, SBRT and GM-CSF is safe and shows promising efficacy in metastatic EGFR/ALK negative NSCLC. Clinical trial information: NCT04106180 .

Preliminary efficacy and safety of camrelizumab plus metronomic oral vinorelbine as first-line therapy for people aged 70 and above with advanced non-small cell lung cancer (NSCLC) from a phase II trial.

e14677 Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .

Phase II trial of lazertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive (M+), metastatic non-small cell lung cancer (NSCLC) with asymptomatic or mild symptomatic brain metastases after failure of EGFR tyrosine kinase inhibitor (TKI) (KCSG LU20-15).

9054 Background: Central nervous system (CNS) metastases occur not infrequently, ultimately devastating consequences in advanced EGFR M+ NSCLC. Lazertinib, a 3rd-generation (G) EGFR-TKI, has shown potent antitumor activity in EGFR-mutant NSCLC. We conducted a phase II single-arm study of lazertinib in EGFR M+ NSCLC patients (pts) having CNS metastases to evaluate its CNS activity. Methods: The patients exhibiting CNS progression upon 1st or 2nd-G EGFR-TKIs with least one measurable CNS lesion were enrolled. The primary endpoint was intracranial objective response rate (iORR) in evaluable for response set (ERS). Secondary endpoints included iORR without T790M mutation, overall ORR (oORR), disease control rate (DCR), intracranial progression-free survival (iPFS) in ERS. Overall survival (OS) and safety analyses were performed in pts who received at least one dose of lazertinib. Cerebrospinal fluid (CSF) penetration was measured as exploratory biomarker study. Results: Of 40 pts enrolled, 38 were evaluable for tumor response. Nineteen pts harbored exon 19 deletion and 21 pts for exon 21 L858R and 30% of pts had radiologic evidence of leptomeningeal carcinomatosis (LM) with 2 cytological confirmed cases. Forty-five percent of pts received afatinib as first line treatment, followed by 42.5% of gefitinib and 12.5% of erlotinib. Baseline plasma samples of all the 40 patients obtained for liquid-based next-generation sequencing (Guardant360) and T790M was found in 5 pts prior to lazertinib treatment. iORR was 57.9% (22/38). iORR with T790M-negative, oORR, and DCR were 54.5%, 39.5%, and 97.4%, respectively. With median follow-up of 13.6 months, median iPFS and OS were not reached. Treatment-related adverse events (TRAEs) emerged in 85.0% of pts with most common TRAEs being skin rash (50.0%) and paresthesia (42.5%). Grade 3 or 4 TRAEs were reported in 10.0%. The CSF penetration rates of lazertinib and its metabolite (YH26334) were 46.2% and 33.1%, respectively in paired CSF and plasma samples, suggesting high CNS penetration efficacy. Conclusions: Lazertinib has substantial CNS activity regardless of T790M status against the progression of intracranial metastases ± LM during the treatment of 1st or 2nd-G EGFR-TKIs in metastatic EGFR M+ NSCLC pts. These results suggest that using lazertinib instead of brain local treatment would be a potential strategy in EGFR M+ NSCLC, who progressed on CNS metastases after prior EGFR-TKI. Clinical trial information: NCT05326425 . [Table: see text]

Final results from a phase II trial of CIMAvax-EGF and nivolumab as second-line (2L) therapy after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC).

9135 Background: CIMAvax-EGF (C-E) is a recombinant anti-human epidermal growth factor (EGF) depleting immunotherapy which has previously shown increased survival as maintenance after platinum-based chemotherapy in patients (pts) with advanced NSCLC. The primary objective of this single-arm phase II trial was to evaluate the 12-month overall survival (OS) in pts receiving C-E in combination with Nivolumab(N) as 2L therapy for advanced NSCLC. Methods: Pts with previously treated, immunotherapy-naive advanced NSCLC received 2.4 mg C-E IM every 2 weeks(w) for 4 doses (loading phase) in combination with N 240mg IV every 2 w, then continued monthly maintenance C-E combined with N 240mg IV every 2 w. Enrollment to this arm was terminated before estimated sample size was met due to poor accrual as immunotherapy became incorporated into 1st line therapy. We present OS and progression-free survival (PFS) data [determined using a Kaplan-Meier test with 90% confidence intervals (CI)] of pts who were able to complete the loading phase per protocol (PP). Results: 21 out of 23 enrolled pts were included in the PP analysis. Among the 21 pts, 17 (81.0%) had non-squamous(nsq) histology, 12 (57.1%) were KRAS wildtype (9.5% unknown status), 13 (61.9%) had PD-L1 tumor proportion score 0%. 43% pts (n=3) with known KRAS mutation (n=7) had co-mutated STK11. Disease control rate was 47.6% (n=10) defined as pts who had stable disease or partial response as best response per RECIST v1.1. The 21 PP pts had a 29% 3-year(yr) OS rate (90% CI 14, 45; intention-to-treat [ITT] population in 23 pts with 26% 3-yr OS rate, 90% CI 13, 42). Median(m) OS for PP pts was 11.9 months, 90% CI 8.0 – 23.9 months (ITT mOS 10.4 months, 90% CI 6.8-13.6). Pts with squamous histology had a better 3-yr OS rate compared to those with nsq histology [50% (90% CI 10, 81) vs 24% (90% CI 9, 41), respectively]. Pts with PD-L1 expression ≥1% had higher 3-yr OS [38% (90% CI 12, 63)] and 3-year PFS [38% (90% CI 12, 63)] compared to pts with no PD-L1 expression (3-yr OS 23% [90% CI 8, 44] and 3-yr PFS 8% [90% CI 1, 25]). mOS, 1-yr and 3-yr OS for EGFR/ALK/KRAS wildtype pts was higher [31.7 months (90% CI 5.9, NR), 67% (90% CI 4, 84), 50% (90% CI 24,71), respectively) compared to KRAS mutated NSCLC [10.1 months (90% CI 6.5, 12.1), 29% (90% CI 6, 56), 0% (90% CI 1, 41), respectively]. Conclusions: NSCLC pts who were able to complete the PP combination of C-E plus N at the minimum had numerically better OS compared to historical study cohorts with N as 2L monotherapy. Among pts who completed PP treatment, pts with KRAS wildtype NSCLC had the longest mOS observed. C-E is currently being investigated in combination with pembrolizumab as maintenance therapy after completing 1L chemoimmunotherapy for NSCLC with PD-L1 < 50% and as 1L therapy in combination with pembrolizumab for EGFR/ALK wildtype NSCLC and PD-L1 ≥ 50%. Clinical trial information: NCT02955290 .

Safety, efficacy and biomarker data in patients with non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab in combination with platinum doublet.

9089 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP), expressed in various tumors, is essential for IL-1α and IL-1β signaling. IL-1α/IL-1β are implicated in tumor progression and therapy resistance, and chemotherapy can upregulate IL-1α in e.g. non-small cell lung cancer (NSCLC). Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α/IL-1β signaling. Here, data are reported from clinical phase 1/2 trials in NSCLC pts given nadunolimab and platinum doublet. Methods: Pts with advanced NSCLC, 1st line or progressed on pembrolizumab, received nadunolimab at 1 (n=16), 2.5 (n=3) or 5 mg/kg (n=11) with cisplatin/gemcitabine (NCG), or at 2.5 mg/kg with carboplatin/pemetrexed (NCP) (n=5). Four additional pts, 3rd line or beyond, received NCG at 1 or 1.75 mg/kg nadunolimab. Primary objective was safety; efficacy was evaluated as a secondary objective and effects on serum and tumor tissue biomarkers explored. Results: The 30 1st or 2nd line pts given NCG had a median PFS of 7.2 months (95% CI 5.5-8.2), ORR of 53% (34-72) and DoR of 5.8 months (3.7-7.5). A dose-response trend was observed for PFS and DoR (Table). Twenty non-progressing pts continued nadunolimab as monotherapy post chemo; 8 of these remained in disease control for a further 12-131 wks. Nadunolimab monotherapy was well tolerated with ≥grade 3 adverse events reported less frequently. Two pts (non-squamous, 2nd line post pembrolizumab) showed complete responses, one observed after >40 wks of nadunolimab monotherapy. Furthermore, confirmed partial responses were observed in 3 of 5 pts given NCP, and 2 of 4 3rd line or beyond pts given NCG. NCG reduced several serum markers, e.g. CRP and tumor-promoting HGF, effects which were maintained by nadunolimab monotherapy. Additionally, a decrease of MCP-3 and 4 was observed during monotherapy. NCG also reduced IL-1- and tumor microenvironment (TME)-related markers in serum (angiopoietin 1, CXCL5, IL-8, TWEAK and VEGFA). Spatial analyses of protein and RNA markers in tumor biopsies are ongoing to verify potential effects in the TME. Conclusions: NCG shows promising efficacy in NSCLC with a trend for dose response, and long-term disease control by nadunolimab monotherapy post chemo with good safety. These observations are supported by changes in TME-related serum biomarkers. Preliminary data suggest similar efficacy with NCP, and in more heavily pretreated pts. Clinical trial information: NCT03267316 , NCT05116891 . [Table: see text]

SKB264 (TROP2-ADC) for the treatment of patients with advanced NSCLC: Efficacy and safety data from a phase 2 study.

9114 Background: TROP2 (trophoblast cell surface antigen 2) is commonly overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. SKB264 is a novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4. The design was to achieve a more effective balance between stability in circulation and release of the ADC payload in tumor cells. Here we report clinical efficacy and safety results of SKB264 in the treatment of patients (pts) with NSCLC from a Phase 2 expansion cohort. TROP2 expression level by immunohistochemistry was assessed retrospectively. Correlation analyses between response and TROP2 level will be provided. Methods: This is a Phase 1/2, multicenter dose-escalation/expansion study in pts with relapsed or refractory locally advanced/metastatic NSCLC and other tumor types (NCT04152499). All NSCLC pts received SKB264 at 5 mg/kg IV Q2W. Tumor assessments based on RECIST 1.1 were performed every 8 weeks by investigators. Results: As of February 9th, 2023, 43 pts (63% male, 88% ECOG PS 1, median age 58 yrs [44-74]) were enrolled. Median follow-up was 11.5 months (mo; 95% CI, 10.4-12.2). Median treatment duration was 5.7 mo (range, 0.5-14.1). Among 39 response-evaluable pts, the ORR was 44% (17/39, 15 confirmed and 2 pending confirmation), median DoR was 9.3 mo (range, 1.3+ to 11.2+), 6-month DoR rate was 77%. For EGFR wild type subgroup (previously received median 2 lines of therapy including anti-PD-1/L1), the ORR was 26% (5/19), DCR was 89% (17/19), median PFS was 5.3 mo, and 9-month OS rate was 80.4%. For subgroup with TKI resistant EGFR mutant NSCLC (50% also failed at least one line of chemotherapy), the ORR was 60% (12/20), DCR was 100% (20/20), median PFS was 11.1 mo, and 9-month PFS rate was 66.7%. 67.4% (29/43) of pts had Grade ≥ 3 treatment-related adverse events (TRAEs). The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were neutrophil count decreased (32.6%), anemia (30.2%), white blood cell count (WBC) decreased (23.3%), stomatitis (9.3%), rash (7.0%), and lymphocyte count decreased (7.0%). Grade 4 TRAEs occurred only for neutropenia and WBC decreased. Most of the hematology toxicity occurred within the first two months of treatment and resolved after treatment with granulocyte colony stimulating factor or erythropoietin without blood transfusions. 23.3% (10/43) of the pts experienced dose reduction due to TRAEs. No neuropathy or drug-related ILD/pneumonitis was reported. No TRAEs led to treatment discontinuation or death. Conclusions: SKB264 at 5 mg/kg Q2W demonstrated encouraging anti-tumor activity and manageable safety profile in pts with relapsed or refractory locally advanced/metastatic NSCLC. TRAEs were mainly hematologic. Phase 3 studies of SKB264 in pts with advanced NSCLC have been planned. Clinical trial information: NCT04152499 .