8012 Background: Delta-like ligand 3 (DLL3) is a promising target for small cell lung cancer (SCLC) and other neuroendocrine tumors. We present results from an ongoing dose-escalation study of LB2102, an autologous CAR-T cell therapy engineered to target DLL3 and armored with a TGF-β receptor blockade to overcome the immunosuppressive tumor microenvironment. Methods: This open-label, multicenter, phase 1 study evaluates LB2102 in patients with SCLC or large cell neuroendocrine carcinoma (LCNEC), relapsed or refractory to ≥1 prior line of therapy (LOT). Dose escalation follows an i3+3 design, with dose levels (DL) of 0.3, 1.0, 2.0, 4.0, 8.0, 12.0, and 16.0x10 6 CAR+ T cells/kg. Subjects received a single infusion of LB2102 after standard lymphodepletion (LD). The primary objectives are to assess safety and tolerability, and to determine the recommended phase 2 dose. Results: As of 05-JAN-2026, 20 subjects received LB2102 (DL1–DL5, n = 3 each; DL6 was skipped based on data; DL7, n = 5). Seventeen subjects had SCLC and 3 LCNEC; 13 (65%) had a history of brain metastases. Median age was 56.5 yrs (range 20–73 yrs) with median 1 prior LOT (range 1–7); 95% received bridging therapy between apheresis and LB2102. The most-common grade ≥ 3 LB2102-related adverse events (TRAEs) were hematologic and co-attributed to LD. Four subjects (20%) had cytokine-release syndrome (CRS; 3 Grade 1 and 1 Grade 2); all resolved. Two subjects developed ICANS (1 Grade 1 and 1 Grade 3); both resolved. There were no dose-limiting toxicities (DLTs) or TEAE-related deaths. Other grade ≥ 3 non-hematologic LB2102-related TEAEs were dyspnea, prolonged QT, and hypoxia (all n = 1 at DL7). Of 17 response-evaluable subjects, best overall responses per RECIST1.1 criteria were 3 partial responses (PR, one each at DL3, DL4, and DL7) and 10 stable diseases (SD, at DLs 2–7), for an objective response rate (ORR) of 3/17 (18%) and a disease control rate (DCR) of 13/17 (76%). Median DOR among patients with a PR was 208 days. CAR-T expansion in peripheral blood (measured by qPCR) was observed at DL3 (N = 3), DL4 (N = 3), DL5 (N = 3), and DL7 (N = 5; 1 patient excluded due to incomplete PK profile): median C max was 694, 581, 527, and 2851 copies/µg gDNA; median T max was 15, 15, 6, and 6 days, respectively. Patients with partial responses had relatively higher PK exposure (median C max ) compared to the PK exposure of patients with stable diseases and progressive diseases. Median tumor expression of DLL3 at baseline was 97% (n = 16, range 45%–100%) and at Day 29 post-infusion was 90% (n = 8, range 55%–100%). Conclusions: LB2102 demonstrated consistent CAR-T expansion and encouraging anti-tumor activity at doses ≥ 2x10 6 CAR+T cells/kg (ORR 27% and DCR 91%). LB2102 was well tolerated with no DLTs and manageable CRS and ICANs. Clinical trial information: NCT05680922 .

Immune checkpoint blockade (ICB) combined with chemotherapy as a first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC) has shown modest survival benefits. While a subset of patients with immune-inflamed tumors respond to ICB, the mechanisms underlying these responses and the lack of predictive biomarkers in clinical practice remain challenges. In this work, we identify high NOTCH1 expression as a key predictor of overall survival (OS) in patients treated with atezolizumab (atezo) plus chemotherapy in both ASCL1-enriched (HR 0.39, P=0.0012) and NEUROD1-enriched (HR 0.44, P=0.024) subsets. Expression of other major NOTCH signaling genes, including NOTCH2, REST, and HES1 showed no association with OS. Using in vitro models, we demonstrate that NOTCH1 upregulates MHC Class I expression and antigen presentation machinery (APM) genes, while REST is not required for these effects. Mechanistically, NOTCH1 promotes epithelial-mesenchymal transition (EMT) and epigenetically enhances STING1 expression by modulating H3K27ac occupancy at the 5’ end of the STING1 locus. Knockout of STING1 in NOTCH1-active cells partially diminishes APM gene expression and HLA-B levels, indicating that STING is critical for NOTCH1-driven immune activation. Concordantly, STING1, AXL expression, and APM signature are enriched in NOTCH1 high compared to low NOTCH1 expressing tumors in IMpower133, validating our proposed mechanisms. Furthermore, using syngeneic mouse models, we show that NOTCH1 activation converts SCLC tumors from immune-excluded to highly inflamed enabling CD8+ T cell-mediated complete tumor regression. Notch1 knockout cells exhibit reduced tumor-intrinsic surface MHC Class I expression, diminished EMT features, and decreased STING expression accompanied by tumor-extrinsic depletion of both total and activated CD8+ T cells, highlighting NOTCH1 as a key driver of tumor immunogenicity. Combining a STING agonist (MSA-2) with ICB results in complete and durable tumor regression specifically in NOTCH1-active tumors. Immunohistochemical analyses demonstrate active NOTCH1 signaling in approximately 30% of SCLC tumors, underscoring its relevance for patient stratification. In conclusion, our results suggest NOTCH1 as a predictive biomarker for ICB and a therapeutic target to enhance anti-tumor immune responses in SCLC and related neuroendocrine cancers in which NOTCH1 is typically suppressed. Yoo Sun Kim, Barzin Y. Nabet, Briana N. Cortez, Nai-Yun Sun, Robin Sebastian, Christophe E. Redon, Anagh Ray, Sivasish Sindiri, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Jane Trepel, Noemi Kedei, Thorkell Andresson, Sudipto Das, Suresh Kumar, Alan E. Bers, Hongliang Zhang, Alberto Chiappori, Priyanka Gopal, Mohamed E. Abazeed, Haobin Chen, Mirit I. Aladjem, Yves Pommier, Moises J. Velez, David S. Shames, Nitin Roper. NOTCH1 drives immunogenicity through STING and improves survival with immune checkpoint blockade in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6404.

8104 Background : Delta-like- ligand 3 (DLL3) is a promising therapeutic target for SCLC and other neuroendocrine tumors. Here, we present preliminary results from the ongoing dose-escalation study of LB2102, an autologous CAR-T cell therapy engineered to target DLL3 and armored with a TGF-β receptor blockade to overcome the immunosuppressive tumor microenvironment. Methods : This ongoing, open-label, multicenter, phase 1 study evaluates LB2102 in patients with SCLC/LCNEC who are relapsed/refractory to ≥1 prior line of therapy. Dose escalation follows a modified 3+3 design, with planned dose levels of 0.3, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 x 10 6 CAR+ T cells/kg. All subjects undergo 3-day lymphodepletion (LD) with fludarabine (30 mg/m 2 ), and cyclophosphamide (300 mg/m 2 ). The primary objective is to assess safety, tolerability and determine the recommended phase 2 dose (RP2D). Results : As of December 13, 2024, 9 patients were treated with LB2102 across dose-level (DL) 1 at 0.3x10 6 (n=3), DL2 at 1x10 6 (n=3), and DL3 at 2x10 6 CAR+ T cells/kg (n=3). Eight subjects had SCLC and one subject on DL2 had LCNEC. The median age was 54 (range 20-61), and the median prior lines of therapy was 2 (range 1-7). Bridging therapy was administered in all patients. No Dose-limiting toxicities (DLT) and no neurotoxicity was observed. One subject in DL3 experienced grade 1 CRS. Grade >3 treatment-emergent adverse events (TEAEs) attributed to LB2102 included anemia (n=2), leukopenia (n=2) and neutropenia (n=2); none were classified as serious, and all were deemed related to lymphodepletion. At DL3, best observed response per RECIST1.1 was 1 partial response (with deepening of response over time) and 2 stable disease (SD). The best overall response for subjects at DL1 was progressive disease (n=3) and at DL2 was SD (n=3) (with increased tumor shrinkage in 1 subject). Significant CAR-T expansion in peripheral blood was observed as measured by qPCR at DL3 (n=3) with a median C max of 694.4 copies/µg genomic DNA (range, 45.6-2256.7) and a median T max of 15 days (range, 10-29). Conclusions : LB2102 has been well tolerated with no DLT observed up to DL3 (2 x 10 6 CAR+ T cells/kg). There appears to be a dose-dependent efficacy signal observed at higher doses with responses correlating to CAR-T expansion, although the data is limited. Given no DLTs and preliminary efficacy signal up to DL3, further exploration of higher dose levels is warranted. Clinical trial information: NCT05680922 . Dose levels (CAR+ T cells/kg) Subject No. Best Overall Change in Sum of Tumor Size (%) DL1: 0.3 x 10 6 1 +22.8% 2 Non-evaluable* 3 +57.1% DL2: 1 x 10 6 4 -31.6% 5 -22.6% 6 -4.8% DL3: 2 x 10 6 7 -14.3% 8 -69.8% 9 -20.6% *Subject had non-measurable disease at baseline and progressed during study period.

Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC), limiting response to immune checkpoint blockade (ICB). While a high-MHC class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the IMpower133 clinical trial, high, but not low, NOTCH1 expression was significantly associated with longer survival with the addition of ICB to chemotherapy among approximately 80% of SCLC patients with NE-enriched tumors (ASCL1-enriched, HR 0.39, P = 0.0012; NEUROD1-enriched, HR 0.44, P = 0.024). Overexpression or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically upregulated MHC class I through epigenetic reactivation of STING. In syngeneic mouse models, Notch1 activation reprogrammed SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression was significantly enriched in high- compared with low-NOTCH1-expressing tumors in IMpower133, validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash antitumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.

PURPOSE:Tarlatamab, a DLL3-targeted bispecific T-cell engager, has emerged as a second-line therapy for extensive-stage small cell lung cancer (ES-SCLC) following progression on platinum-based chemoimmunotherapy. While clinical trials have demonstrated promising efficacy, real-world data on safety remain limited. METHODS:This retrospective study included 40 patients with SCLC or high-grade neuroendocrine carcinoma treated with tarlatamab at Moffitt Cancer Center between May 2024 and February 2025. Clinical, laboratory, and treatment-related variables including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reviewed. Predictive models for these toxicities were developed using Firth logistic regression based on data from 30 patients who did not receive prophylactic tocilizumab. RESULTS:The median age was 66.5 years; 55% were male, and 87.5% had an ECOG performance status of 0 to 1. Among patients who did not receive prophylactic tocilizumab (N = 30), 53.3% developed CRS and 23.3% developed ICANS after Cycle 1 Day 1, with 10% experiencing grade ≥ 3 severity for each. Three patients discontinued treatment due to severe CRS/ICANS, with 2 deaths and 1 transition to hospice. Among those who received prophylactic tocilizumab (N = 10), 1 patient developed grade 2 CRS and none developed ICANS. Elevated LDH and liver metastasis were independent predictors of CRS; LDH was also predictive of grade ≥ 2 CRS. Diabetes and cardiovascular disease were independently associated with ICANS. CONCLUSION:Tarlatamab is associated with higher CRS and ICANS rates in real-world settings than observed in trials. Prophylactic tocilizumab may mitigate these toxicities in high-risk patients and should be considered for incorporation into treatment protocols.

Abstract Recent studies have identified distinct molecular subtypes of small cell lung cancer (SCLC) (SCLC-A, SCLC-N, SCLC-P, and SCLC-Y) based on ASCL1, NEUROD1, POU2F3, and YAP1 expression. In this study, we investigated the correlation between immunohistochemistry (IHC), multiplex immunofluorescence (mIF), and RNA Salah Targeted Expression Panel (RNA STEP) for ASCL1, NEUROD1, POU2F3, and YAP1 in formalin-fixed-paraffin-embedded (FFPE) samples from 14 SCLC samples collected under an IRB-approved protocol (MCC19163). For the mIF evaluation, FFPE samples were immunostained using the AKOYA Biosciences OPAL TM 7-Color Automation IHC kit on the BOND RX autostainer. For RNA STEP, nanoString nCounter TagSet chemistry was used to measure gene expression levels of test FFPE samples relative to a reference pooled human normal mRNA control. All three methods demonstrated significant correlation for ASCL1 levels (Table 1). IHC and RNA STEP NEUROD1 results exhibited significant correlation. However, mIF NEUROD1 results did not correlate with the results of other methods likely due to non-specific positivity of the NEUROD1 mIF antibody. No strong correlation was observed between any of the methods for POU2F3 and YAP1. Only 2 of the 14 samples displayed positive POU2F3 protein expression by IHC; one of these also had elevated POU2F3 expression by RNA STEP. Importantly, the sample with the highest POU2F3 protein expression by IHC also had the highest values by mIF and RNA STEP. All samples were negative for YAP1 by IHC and RNA STEP. Notably, ASCL1 staining was primarily observed in CD56+ POU2F3- cells by mIF. These findings highlight the reliability and utility of IHC and RNA STEP in assessing transcriptional factors in SCLC. Also, mIF presents an innovative method for the simultaneous analysis of multiple markers using a single tissue section, enabling the concurrent detection of multiple markers within individual cells. Table 1. Statistical Significance (p-values) and Correlation Analysis (Spearman's Coefficients) IHC vs RNA STEP IHC vs mIF RNA STEP vs mIF p r P r p r ASCL1 0.021 0.62 <0.0001 0.91 0.010 0.67 NEUROD1 0.002 0.78 0.517 -0.14 0.671 0.12 POU2F3 0.201 0.36 0.422 0.18 0.045 0.55 YAP1 0.299 0.30 0.364 0.20 0.295 0.30 Citation Format: Hilal Ozakinci, Aileen Alontaga, Jonathan V Nguyen, Carlos M Moran Segura, Daryoush Saeed-Vafa, Jhanelle Gray, Eric Haura, Alberto A Chiappori, Theresa Boyle. Comparison of small cell lung cancer transcriptional factor expression by immunohistochemistry, multiplex immunofluorescence, and a targeted RNA expression panel [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 2529.

BACKGROUND:Plinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC. METHODS:In Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS). RESULTS:Between 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m2. Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively. CONCLUSIONS:Plinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.

Introduction: The translation of gene expression profiles of SCLC to clinical testing remains relatively unexplored. In this study, gene expression variations in SCLC were evaluated to identify potential biomarkers. Methods: RNA expression profiling was performed on 44 tumor samples from 35 patients diagnosed with SCLC using the clinically validated RNA Salah Targeted Expression Panel (RNA STEP). RNA sequencing (RNA-Seq) and immunohistochemistry were performed on two different SCLC cohorts, and correlation analyses were performed for the ASCL1, , NEUROD1, , POU2F3, , and YAP1 genes and their corresponding proteins. RNA STEP and RNA-Seq results were evaluated for gene expression profiles and heterogeneity between SCLC primary and metastatic sites. RNA STEP gene expression profiles of independent SCLC samples (n = 35) were compared with lung adenocarcinoma (n = 160) and squamous cell carcinoma results (n = 25). Results: The RNA STEP results were highly correlated with RNA-Seq and immunohistochemistry results. The dominant transcription regulator by RNA STEP was ASCL1 in 74.2% of the samples, NEUROD1 in 20%, and POU2F3 in 2.9%. The ASCL1, , NEUROD1, , and POU2F3 gene expression profiles were heterogeneous between primary and metastatic sites. SCLCs displayed markedly high expression for targetable genes DLL3, , EZH2, , TERT, , and RET. . SCLCs were found to have relatively colder immune profiles than lung adenocarcinomas and squamous cell carcinomas, characterized by lower expression of HLA genes, immune cell, and immune checkpoint genes, except the LAG3 gene. Conclusions: Clinical-grade SCLC RNA expression profiling has value for SCLC subtyping, design of clinical trials, and identification of patients for trials and potential targeted therapy. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

TPS8128 Background: Treatment options are limited for patients (pts) with small-cell lung cancer (SCLC) whose disease has progressed on or after platinum-based chemotherapy. Therefore, there is an urgent need for evaluation of novel agents in this setting. Aurora kinase A (AURKA) is a key regulator of mitosis and AURKA expression is associated with worse prognosis in multiple solid tumor types. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor under investigation for treating SCLC. Phase 1/2 clinical trials of alisertib as either monotherapy or in combination with paclitaxel for relapsed/refractory solid tumors (including SCLC) reported response rates of 21–22%. The most common treatment-related grade ≥3 AEs were neutropenia, febrile neutropenia, and leukopenia. Preclinically, greater alisertib sensitivity has been reported in models with high c-Myc expression and/or loss of RB1 function. In a clinical study of alisertib + paclitaxel vs placebo + paclitaxel in SCLC, either c-Myc expression or mutation in RB1, RBL1, RBL2, or CDK6 showed strong correlation with an improvement in both PFS and OS in the alisertib arm. Methods: ALISCA-Lung1(NCT06095505) is a phase 2 study to determine whether there is a biomarker-defined population of pts with extensive-stage SCLC that derives increased benefit from alisertib monotherapy. Key inclusion criteria: ≥18 years of age; progression on or after first-line treatment with platinum-based chemotherapy + anti-PD-L1 immunotherapy; ≥1 measurable lesion per RECIST v1.1; availability of tissue sample for retrospective biomarker evaluation. Key exclusion criteria: prior treatment with AURKA-specific or pan-Aurora-targeted agents; active infection; immunocompromise; unstable brain metastases; inability/unwillingness to swallow tablets. Primary objective: to determine whether any biomarker(s) correlate with increased benefit to alisertib monotherapy. Biomarkers will be assessed by next-generation sequencing, mRNA expression analysis, and immunohistochemistry. Candidate biomarkers include, but are not limited to, RB1 loss of function, c-Myc expression, TP53mutation, AURKA expression, and SCLC molecular subtype. Secondary objectives: to determine investigator-assessed efficacy, survival, safety, and population pharmacokinetics. Eligible pts will receive alisertib 50 mg orally BID d1−7 q21d (including primary prophylaxis with G-CSF) until disease progression, unacceptable toxicity, or withdrawal of consent. All pts will undergo sparse pharmacokinetic sampling. Recruitment is underway and up to 60 pts will be enrolled at ~20 centers in the USA. Findings are anticipated to identify a biomarker-defined pt population that derives the greatest clinical benefit from alisertib. Future development of alisertib in SCLC is anticipated to focus on this biomarker-defined population. Clinical trial information: NCT06095505 .

TPS8118 Background: Each year, approximately 35,000 patients are diagnosed with stage I lung cancer in the United States. Despite early detection, the 5-year overall survival for this population remains disappointing, ranging between 73-86% with recurrence rates from 18-38%. The current standard of care for stage I NSCLC is surgery alone followed by observation as prior trials of adjuvant chemotherapy in this subgroup have failed to show benefit. More modern therapies such as programmed death-1 (PD-1) inhibitors have not been evaluated in the stage I setting but have demonstrated significant improvements in pathologic complete response, event free survival, and overall survival when added to chemotherapy for patients with fully resected stage II and III disease. The use of PD-(L)1 inhibition has also demonstrated clinically and statistically significant improvements in OS in both unresectable stage III NSCLC following chemoradiation and in the metastatic setting. Given the activity of PD-(L)1 inhibition in nearly every other subset of NSCLC patients, we aimed to evaluate this therapy following resection in stage I NSCLC patients. Methods: This study is a randomized phase II multicenter trial of adjuvant Pembrolizumab versus observation alone following complete resection of stage I NSCLC with tumors between 1-4cm. The trial randomizes patients 1:1 to either Pembrolizumab 400mg IV every 6 weeks for up to 9 cycles or observation alone. Patients are stratified by PD-L1 score (PD-L1 ≥50% vs. < 50%) and tumor size (1-2cm vs. > 2-4cm), and they undergo repeat CT imaging every 12 weeks. The study is being conducted through the Big Ten Cancer Research Consortium, and there are currently 11 sites open to accrual with one additional site pending activation. The primary endpoint is disease free survival with secondary endpoints including OS, DFS at multiple timepoints (1-, 2-, and 3-years), and safety. The trial initially opened to accrual at the lead site, Indiana University, in May 2020, and enrollment is currently at 95 patients with a planned enrollment of 244. (NCT04317534) Clinical trial information: NCT04317534 .

Abstract Background Glutathione S-transferase Pi (GSTP) has a role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways may lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-human dose escalation and expansion study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously. The dose escalation phase enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Final results from the dose escalation and expansion of NBF-006-001 are reported here. Results Thirty-eight NSCLC patients, with or without KRAS mutation, received treatment at 0.3 mg/kg [n=1], 0.6 mg/kg [n=12], 1.2 mg/kg [n=14], or 1.6 mg/kg [n=11]. NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia and bilateral pleural effusions (both at 0.6 mg/kg). The most common NBF-006-related AEs were Grade 1 or 2 infusion related reactions (IRRs) (18 %) and nausea (11 %). IRRs (n=8 in seven patients), occurred in the first cycle and were well-managed. One patient discontinued due to recurring IRR. Cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. Linear PK (t1/2 ~41 hrs) was observed with dose proportional increases up to 1.6 mg/kg without exposure accumulation or reduction after repeat doses. GSTP mRNA knock-down in PBMCs was statistically significant at 1.2 and 1.6 mg/kg dose levels. Patients had received 1-7 prior lines of therapy (1 line [n=10], 2 lines [n=10], and ≥ 3 lines [n=16] respectively). Two patients (1.2 and 1.6 mg/kg) experienced a durable PR, 17 patients experienced SD. The disease control rate is 19/38 (59%). Patient enrichment strategies were evaluated with interesting trends observed. Conclusion NBF-006 is well tolerated up to 1.6 mg/kg dose level for over a year with early signs of efficacy in heavily pre-treated pan-KRAS mutant NSCLC patients. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted. Citation Format: Lyudmila Bazhenova, Hirva Mamdani, Alberto Chiappori, Alexander Spira, Wade Iams, Anthony Tolcher, Minal Barve, Afshin Gabayan, Andrae Vandross, Cima Cina, Yael Cohen-Arazi, Zachary Albaugh, Annie Huynh, Joachim Gullbo, Sonya Zabludoff. First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer [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 CT040.

8545 Background: In pre-clinical studies, WEE1 inhibitors have displayed synergy with cisplatin in lung cancer cell lines. Adavosertib (AZD1775) is an orally available inhibitor of the WEE1 kinase with platinum-doublet combination RP2D of 225 mg twice daily (BID) on days 1-3 (5 doses) of a 21-day cycle with the most common adverse events being bone marrow toxicity, diarrhea, vomiting, and fatigue. This phase II, single-arm, single-institution trial of carboplatin, paclitaxel, and AZD1775 was conducted at Moffitt Cancer Center ( NCT02513563 ). Methods: Patients with advanced/metastatic SqCLC who had not previously received platinum or paclitaxel for metastatic disease were enrolled. Previous use of immune checkpoint inhibitors or vaccines was allowed. Patients were treated with carboplatin AUC5 and paclitaxel 175 mg/m2 plus AZD1775 PO 225 mg once daily for one day and BID for two days for a total of 5 doses over days 1-3 of a 21-day cycle for up to 6 cycles, followed by AZD1775 maintenance until disease progression, intolerance or withdrawal. The primary endpoint was PFS. Secondary endpoints included overall survival (OS), duration of response (DoR), duration of stable disease (DSD), and disease control rate (DCR). Outcomes were measure using 80% CI obtained from Kaplan-Meier estimator, with the lower bound corresponding to a one-sided 90% CI, to test whether the median PFS exceeds 4.0 months at α = 0.10. Results: Between 10/2015 and 09/2021, 42 patients were enrolled, and 41 received at least one of the planned treatments. Baseline characteristics included : median age 66 (range, 38-82), 66% male, 93% White, 90.2% Non-Hispanic, 90% ever smoker, 85% ECOG PS 1, and 44% with negative tumoral PD-L1 expression. Among the 41 patients, 32 were evaluable for response assessment. The median PFS was 4.8 months (80%CI, 4.1 to 5.7), and the median OS was 7.3 months (80%CI, 6.4 to 8.5). The DCR was 60.9 % (14 partial responses, 11 with stable disease), with a median DoR of 4.44 months (80%CI, 3.25 to 6.94), and a median DSD of 3.5 months (80%CI, 3.0 to 4.9). Adverse events (AEs) occurred in 36 of 41 patients (88%), including grade 3 AEs in 39% patients. The three most common AEs with the combination therapy were fatigue (61%), diarrhea (51%), and nausea (49%). Drug interruptions or delays occurred in 17 patients (41%). Conclusions: The study met its primary endpoint with a median PFS of 4.8 months with the combination of Adavosertib with carboplatin and paclitaxel. However, the study regimen achieved similar response rates and median PFS of platinum-doublet combination when comparing to historical data from phase II/III trials. Although the combination was safe, over a third of patients experienced grade 3 AEs, and 10% required dose reductions or delays due to AEs. Clinical trial information: NCT02513563 .

PURPOSE:We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial. METHODS AND MATERIALS:Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mg/kg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests. RESULTS:The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3+) possible treatment-related toxicity, most commonly pulmonary AEs (n = 8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n = 12, 63%) or patient choice (n = 2, 11%). Eleven patients (58%) experienced G2+ pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached [NR]), and 12-month freedom from G2+ pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumonia/chronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method. CONCLUSIONS:Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk.

Rationale: Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes. Methods. We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC. Results: An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab’s immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A. Conclusions: The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine.

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.

Background Extensive Stage Small Cell Lung Cancer (ES-SCLC) and Large Cell Neuroendocrine of the lung (LCNEC) are aggressive neuroendocrine carcinomas with an exceptionally poor prognosis.1 2 Although the majority of patients experience response to first line of therapy, the durability of response is often limited. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the cell surface in SCLC (~85% of the patients having positive staining in >25% tumor cells) and LCNEC (74% having positive staining in at least 1% of tumor cells).3 4 Preclinical studies of LB2102, an autologous DLL3-directed CAR-T cell, have demonstrated DLL3-specific antitumor effects with a low risk of on-target/off-tumor toxicities and off-target/off-tumor toxicities. Methods This phase 1, open-label, multicenter, dose-escalation and cohort expansion study of LB2102 will treat up to 41 subjects with ES-SCLC or LCNEC (NCT05680922). Part A will enroll and treat 12–24 subjects, and Part B will treat 11–17 subjects (figure 1). Subjects will be pooled from Part A and Part B to a total of 23 subjects treated at the recommended dose for expansion. The patient population is adult subjects with histologically/cytologically confirmed unresectable small cell lung carcinoma (SCLC), large cell neuroendocrine lung carcinoma (LCNEC), combined SCLC, or combined LCNEC as per WHO 2021 criteria. Patients enrolled have received at least one prior line of standard treatment with progression or insufficient response, and for whom standard treatment is intolerable, unlikely to confer significant clinical benefit, is no longer effective, or the subject declines further standard treatment. Other key criteria include ECOG PS 0 or 1; life expectancy > 4 months per investigator judgment; available archival or fresh biopsy tissue, presence of ≥ 1 radiologically measurable lesion per RECIST 1.1, and adequate organ function per protocol. No prior DLL3 targeted therapy is allowed. LB2102 will be manufactured from autologous T cells collected from peripheral mononuclear blood cell apheresis. Subjects may receive optional bridging therapy followed by lymphodepletion chemotherapy with fludarabine and cyclophosphamide for 3 days. The subject will then receive one infusion of LB2102 and will be followed post-infusion for safety and disease assessments. The objectives of the study include characterization of safety and tolerability, evaluation of the recommended phase 2 dose, and assessment of preliminary antitumor activity. US sites will begin enrollment in fall 2023. Acknowledgements This study is funded by Legend Biotech USA Inc. Trial Registration Registered on Clinicaltrial.gov (NCT05680922). References Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. Atieh T, Huang CH. Treatment of advanced-stage large cell neuroendocrine cancer (LCNEC) of the lung: A tale of two diseases. Front Oncol. 2021;11:667468. Rojo F, Corassa M, Mavroudis D, Oz AB, Biesma B, Brcic L, et al. International real-world study of DLL3 expression in patients with small cell lung cancer. Lung Cancer. 2020;147:237–43. Hermans BCM, Derks JL, Thunnissen E, van Suylen RJ, den Bakker MA, Groen HJM, et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer. 2019;138:102–8.

Purpose: Adverse event (AE) is a critical element in clinical trial to evaluate patient safety profile of the drug for benefit-risk assessment. AE is also shown to have clinical association. However, due to its complexity, utilization of AE data has been suboptimal. This study takes a unique approach to utilize AE parameters and to derive a set of innovative AE metrics which could have the potential as a predictive biomarker of treatment response and survival outcomes. Methods: The AE-derived biomarkers integrated toxicity severity level (grade) and treatment relatedness, with further tune-up by AE occurrence, frequency, and duration. Implementation of AE-derived biomarkers was performed in a comprehensive strategy starting from overall AE, toxicity category, down to individual AE. Landmark analysis at day 30 from initial treatment date was used to define early AE biomarkers. Two study cohorts (Cohort A and B) from two immunotherapy trials in late-stage non-small cell lung cancer were used to evaluate the potential of AE-derived biomarkers. Clinical outcomes for statistical analysis included progression-free survival, overall survival, disease control, and duration of treatment. Results: Both cohorts showed that early AEs were associated with clinical outcomes. Patients experienced with low-grade AEs (including treatment related AEs) at early time point had improved PFS, OS, and were associated with disease control. The significant early AEs included treatment related low-grade AE in overall AE, endocrine disorders, hypothyroidism (immune-related adverse event (irAE)), and platelet count decreased for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of higher-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included treatment related high-grade AE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, 3 toxicity categories, and 5 related individual AEs for Cohort B. One treatment related low-grade AE, alanine aminotransferase increased, was irAE and correlated with worse OS in Cohort A. Conclusions: The study demonstrated evidence of AE utility in predicting positive and negative clinical outcomes. It could be treatment related AEs or combination of treatment related and not related AEs. Grade level played a key role in determining direction of clinical outcomes with low-grade leaning to positive effect and high-grade to negative impact. Significant AEs covering overall AEs, toxicity category AEs, to individual AEs provided relatively comprehensive view of AE results for clinical relevance. Citation Format: Dung-Tsa Chen, Jhanelle Gray, Andreas Saltos, Trevor A Rose, Alberto Chiappori, Zachary Thompson, Ram Thapa. Seamless statistical analysis of adverse event data for clinical association [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 987.