AbstractGT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a “3 + 3” schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103. Secondary objectives included describing objective response rate, progression-free survival and overall survival. Dose escalation cohorts included GT103 given intravenously at 0.3, 1, 3, 10, and 15 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. Thirty one patients were enrolled across 3 institutions. Two dose-limiting adverse events were reported: grade 3 acute kidney injury (0.3 mg/kg) and grade 2 colitis (1 mg/kg). No dose-limiting toxicities were noted at the highest dose levels and the MTD was not reached. No objective responses were seen. Stable disease occurred in 9 patients (29%) and the median overall survival was 25.7 weeks (95% confidence interval [CI], 19.1–30.6). Pharmacokinetic analysis confirmed an estimated half life of 6.5 days. The recommended phase 2 dose of GT103 was 10 mg/kg every 3 weeks, however further dose optimization is needed given the absence of an MTD. The study achieved its primary objective of demonstrating safety and tolerability of GT103 in refractory NSCLC.

TPS8118 Background: The addition of immune checkpoint blockade to neoadjuvant and adjuvant therapy is now standard of care in early-stage surgically resectable non-small cell lung cancer (NSCLC). However, resistance to immunotherapy limit their benefit for most patients. The pathological complete response (pCR) rate, a surrogate for long term survival, remains close to 20%, leaving many patients at a high risk of recurrence and death. Thus, there is a need to apply strategies to overcome immunotherapy resistance in earlier stages of NSCLC to improve cure. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major cholesterol regulator, has emerged as an inhibitory modulator of anti-tumor immunity. Preclinical evidence showed that PCSK9 downregulated MHC class I antigen expression on tumor cells. This effect was reversed by genetic or pharmacologic inhibition of PCSK9. PCSK9 inhibitor synergized with immune checkpoint blockade to increase cytotoxic T-cell mediated tumor death. Retrospective clinical analyses of NSCLC patients treated with immune checkpoint inhibitors also showed a correlation between higher PCSK9 levels and poorer survival. Methods: TOP 2301 is a multi-center, open label, two-arm, randomized, phase 2 trial of chemotherapy and cemiplimab (350mg IV every 3 weeks) with or without the PCSK-9 inhibitor, alirocumab (150 mg SC every 4 weeks), prior to surgery. Eligible patients will have stage IB-3A NSCLC, deemed surgical candidates, and have no EGFR or ALK mutations. One hundred and twenty-six patients will be randomized 1:1 to receive neoadjuvant SOC chemotherapy and cemiplimab versus SOC chemotherapy, cemiplimab and alirocumab. Approximately 64 participants are required in each arm to have 90% power to reject the null hypothesis. The primary objective is to compare the pCR rates for neoadjuvant chemotherapy plus cemiplimab versus chemotherapy, cemiplimab, and alirocumab. Secondary efficacy objectives for the experimental arm include: the objective response rate (ORR), disease free survival (DFS), and overall survival (OS). A secondary safety objective is to determine the safety and tolerability of neoadjuvant chemotherapy and cemiplimab with alirocumab in early-stage NSCLC. The correlative science objective will evaluate the difference in tumor infiltrating lymphocytes and dendritic cells through IHC, FACs analysis, and bulk RNA-seq with CIBERSORT from postsurgical specimens of patients treated with neoadjuvant chemotherapy and cemiplimab with or without alirocumab. The trial was open to enrollment on 12/15/2024. Clinical trial information: NCT06385262 .

TPS8124 Background: Standard treatment for limited-stage small-cell lung cancer (LS-SCLC) has recently changed to add durvalumab consolidation after concurrent chemoradiotherapy. Although durvalumab consolidation increases overall survival (OS; Cheng et al. 2024), other therapeutic agents may be able to provide further improvement. BMS-986489 is a potential first-in-class fixed-dose combination of atigotatug (BMS-986012) and nivolumab. Atigotatug binds to fucosyl-monosialoganglioside-1 (fuc-GM1), which is highly expressed on SCLC cells and is largely absent in normal tissues. This binding results in tumor cell death by antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity. The immune effects initiated by atigotatug may further enhance T cell activation by nivolumab, thereby improving outcomes after chemoradiotherapy. In a randomized phase II study in extensive-stage SCLC, atigotatug improved median OS when added to carboplatin, etoposide, and nivolumab (CE/NIVO): 15.6 months (95% confidence interval [CI]: 11.3-NE) vs 11.4 months (95% CI: 9.3-16.5) with CE/NIVO alone (Kalinka et al. 2024). Methods: TIGOS-LS is an open-label, randomized study to evaluate the safety and efficacy of BMS-986489 as consolidation therapy vs the new standard durvalumab following chemoradiotherapy in LS-SCLC. Approximately 250 participants will be enrolled at 80 sites within the US. Eligible participants will be adults (≥18 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and histologically or cytologically confirmed LS-SCLC. All participants must have completed concurrent chemoradiotherapy for LS-SCLC without progression; prophylactic cranial irradiation (PCI) will be permitted before initiation of study treatment. Confirmation of fuc-GM1 expression will not be required. Participants will be stratified based on disease stage (I/II vs III) and receipt of PCI and will be randomly allocated in a 1:1 ratio to either the BMS-986489 or durvalumab arms. BMS-986489 or durvalumab will be administered intravenously at a fixed dose once every 4 weeks for up to 2 years or until other discontinuation criteria are met. Response will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Survival follow-up will occur every 12 weeks for up to 3 years. The primary endpoint is OS. Key secondary endpoints include progression-free survival, objective response rate, clinical benefit rate, disease control rate, duration of response, and safety parameters. Enrollment is projected to start in April 2025. Clinical trial information: NCT06773910 .

PURPOSE:Low-density lipoprotein receptor-related protein 1b (LRP1b) is a cell surface receptor, commonly altered in many cancers and associated with improved responses, progression-free survival (PFS), and overall survival with immune checkpoint inhibition. EXPERIMENTAL DESIGN:LRP1b alterations were determined by whole-exome sequencing and associated with PFS and objective response rates in patients with non-small cell lung cancer (NSCLC) in a post hoc analysis of the randomized controlled phase III CheckMate-026 (CM026) trial (NCT02041533) examining chemotherapy compared with nivolumab, adjusting for tumor mutational burden (TMB) and clinical features. We separately evaluated a deidentified nationwide (US-based) NSCLC clinico-genomic database for associations of LRP1b alterations and PFS with anti-PD-1 immunotherapy. RESULTS:In the clinico-genomic database cohort of patients with NSCLC (N = 18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n = 1,569; adjusted HR, 0.86; P = 0.014). In CheckMate-026, patients with LRP1b alterations had a statistically significant improvement in objective response rate to nivolumab versus LRP1b wild-type patients (OR 3.5; 95% confidence interval, 1.71-7.13; P = 0.0006) but not with chemotherapy (OR 0.63; 95% confidence interval, 0.32-1.26; P = 0.19), adjusting for TMB, age, gender, histology, smoking, and performance status. LRP1b mutations were associated with improved PFS with nivolumab (HR, 0.66; P = 0.04) but not chemotherapy (HR, 1.26; P = 0.25), also maintained in multivariate and TMB-adjusted analyses. CONCLUSIONS:LRP1b mutations are a candidate predictive biomarker for immune checkpoint inhibition versus chemotherapy in NSCLC. Further mechanistic characterization of LRP1b and prospective validation are warranted and might enable future clinical use.

TPS8127 Background: Atigotatug is an innate immune inducer monoclonal antibody that binds fucosyl-monosialoganglioside-1 (fuc-GM1) with high affinity and specificity, thereby inducing immune-mediated tumor cell death. Fuc-GM1, a cell surface target, is expressed in 50%–90% of SCLC tumors. In a randomized, open-label phase 2 study, atigotatug combined with nivolumab and chemotherapy vs nivolumab and chemotherapy alone has shown a promising trend in overall survival (OS) with median OS of 15.6 mo vs 11.4 mo, respectively (HR 0.71; 95% CI 0.44–1.16), as a first-line treatment in ES-SCLC. Based on these results, a confirmatory trial comparing this regimen to the standard of care is warranted. TIGOS (NCT06646276) is a randomized, double-blind, multicenter phase 3 trial to compare the efficacy and safety of atigotatug + nivolumab fixed-dose combination with chemotherapy vs atezolizumab with chemotherapy. Methods: Approximately 530 eligible patients will be randomized 1:1 to receive either atigotatug + nivolumab fixed-dose combination with carboplatin and etoposide Q3W (induction) followed by atigotatug + nivolumab fixed dose combination (maintenance) Q4W or atezolizumab with carboplatin and etoposide Q3W (induction) followed by atezolizumab (maintenance) Q4W. Patients will be stratified by ECOG performance status (PS) 0–1, presence of liver metastases, and presence of brain metastases at baseline. Treatment will continue until disease progression, unacceptable toxicity, death, or withdrawal of consent. Eligible patients must be ≥18 years old, have histologically or cytologically documented SCLC, ≥1 measurable lesion outside the central nervous system (CNS), any previous limited-stage SCLC treatment completed ≥6 months prior to study treatment initiation, and an ECOG PS of 0–1. Key exclusion criteria include prior treatment for ES-SCLC, untreated symptomatic CNS metastases, and prior treatment targeting T-cell co-stimulation, checkpoint pathways, and/or fuc-GM1. The primary endpoint is OS, and the secondary endpoints are time to definitive deterioration, safety, objective response, duration of response, and progression-free survival, as assessed by the investigator. Assessment of pre- and on-treatment changes in biomarkers will be part of an exploratory analysis. This study will be conducted in 180 locations, with a primary completion date expected in April 2028. Clinical trial information: NCT06646276 .

Background Our study was designed to determine the safety, efficacy, and immunological effects of perioperative pembrolizumab in early-stage NSCLC.Methods This is a single-arm phase II study of perioperative pembrolizumab in patients with untreated, clinical stage IB to IIIA NSCLC. Patients received two doses of 200 mg pembrolizumab, surgery, standard adjuvant chemotherapy, followed by four doses adjuvant pembrolizumab. The primary objective of this study was to determine surgical feasibility rate, and secondary objectives are pathological response rate, treatment adverse events, efficacy data, and exploratory analysis of biomarkers.Results 30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. At median follow-up of 59 months after surgical resection, seven patients had disease progression, while six had died representing. A 5-year progression-free survival (PFS) from time of surgery was 72.0% (56.4%–91.9%) and overall survival (OS) from time of surgery was 75.8% (60.7%–94.7%). Major pathological response (MPR) was found in seven tumors (28%) including two complete responses (4%). Across all treated patients, four receiving neoadjuvant and four receiving adjuvant pembrolizumab experienced treatment-related adverse events of grade 3 or higher with no grade 5 events. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment. There was a significant difference between mean plasma PCSK9 levels for patients with MPR versus all other patients on study when checked postoperatively.Conclusions Perioperative pembrolizumab was safe and effective with promising MPR rate, PFS, and OS.

e14588 Background: CFH is a complement regulatory protein that protects cells from alternative complement pathway activation. Neutralizing antibodies against CFH on tumor cells increase deposition of C3b, facilitate antibody-dependent-cellular phagocytosis and complement dependent cytotoxicity, inhibit tumor growth, and modulate anti-tumor immunity. GT103 is a first-in class, fully human-derived IgG3 anti-CFH monoclonal antibody that recognizes a tumor specific epitope on CFH and has shown anti-tumor activity in preclinical models. Methods: We conducted a phase Ib, first-in-human, dose escalation trial evaluating safety and preliminary efficacy of GT103 in patients (pts) with advanced NSCLC refractory to standard therapies. Pts received GT103 intravenously across six dose levels/schedules following 3+3 design. Primary objectives were to determine maximum tolerated dose (MTD), recommended phase II dose (RP2D), and pharmacokinetic profile of GT103. Secondary objectives were to assess objective response rate, progression free survival (PFS), and overall survival (OS). Here we present updated safety and efficacy results of the study. Results: 31 pts were enrolled from 6/2020 to 9/2023 (median age 63yrs (range, 23-79), 61% had adenocarcinoma, 32% had previously treated brain metastasis). MTD was not reached. Treatment related AEs (TRAEs) observed in ≥10% pts included fatigue (19%), anemia (16%), diarrhea (16%), and nausea (13%). 3 pts developed ≥ grade 3 TRAE, including acute kidney injury, decreased lymphocyte count, and anemia. The best treatment response was stable disease in 9 (29%) pts. Median(m) PFS and mOS were 6 weeks (95% CI 6.0-6.1) and 25.7 weeks (95% CI 19.1-30.6), respectively. 24-week PFS and OS were 9.7% (95% CI 2.5-22.9%) and 50.6% (95% CI 31.9-66.6%), respectively. PD-L1 expression was available in 25 pts. No statistically significant difference (p=0.33) was noted in mPFS between PD-L1 positive (TPS > 1%) vs negative (TPS ≤1%) pts. KRAS and EGFR mutation status was available for 22pts. mPFS and mOS were numerically longer in pts with KRAS positive vs negative disease. While there was no difference in mPFS, 24-weeks PFS was 0 vs 16.7% (95% CI 4.1-36.5%) EGFR MUT vs wild type disease. Biomarker analysis of complement regulatory proteins, FcGR expression and polymorphisms, and changes in sC5b-9 is underway. Conclusions: GT103 was well tolerated across all dose levels. The RP2D of 10mg/kg IV every 3 weeks was selected, although PK modeling will be performed to optimize the dosing schedule. Encouraging anti-tumor activity was seen in heavily pretreated pts with advanced NSCLC with a subset of patients experiencing stable disease lasting for longer than 6 months. Additional biomarker analysis is ongoing. A phase II trial combining GT103 with pembrolizumab in pts with advanced NSCLC is currently enrolling. Clinical trial information: NCT04314089 .

AbstractPurpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3–2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. Results: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1 mg/kg, n = 40)]; the median age was 63 years (range, 41–79 years). Also, 32%, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. The most common treatment-emergent adverse events were fatigue (50%), nausea (42%), and thrombocytopenia (41%). The most common hepatic treatment-emergent adverse events were increased aspartate aminotransferase (22%), increased γ-glutamyltransferase (21%), and hyperbilirubinemia (17%); two patients experienced veno-occlusive liver disease. The objective response rate was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n = 40), the objective response rate was 25%; the median response duration was 4.2 months (95% confidence interval, 2.6–6.7); and the median progression-free survival was 3.5 months (95% confidence interval, 1.5–4.2). Conclusions: ABBV-011 1.0 mg/kg every 3 weeks monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Supplementary Data from Characterizing the Clinical Relevance of an Embryonic Stem Cell Phenotype in Lung Adenocarcinoma

Objectives: There are limited real-world data about patient-reported outcomes with immunotherapies (IO) in metastatic non-small cell lung cancer (mNSCLC). We describe patient-reported distress and clinical outcomes with IO-based treatments or cytotoxic chemotherapies (Chemo). Methods: We conducted a single-institution retrospective chart review of adults with mNSCLC treated at Duke from 03/2015 to 06/2020. At each visit, patients self-reported their distress level and sources of distress using the NCCN Distress Thermometer (DT) and its 39-item Problem List. We abstracted demographic, clinical, distress, and investigator assessed-clinical response data, then analyzed these using descriptive statistics and generalized estimating equations. Results: Data from 152 patients were analyzed in four groups: Chemo alone, IO + Chemo, single agent IO, dual agent IO. Distress was worse before treatment start in all groups, and the odds of actionable distress (DT score > 4) decreased by 10 % per month. The most frequent sources of distress were physical symptoms (e.g., fatigue, pain), which remained high longitudinally. Patients receiving IO had higher clinical response rates and a lower rate of unplanned healthcare encounters compared to patients treated with Chemo alone. Only one-third of all patients were seen by palliative care. Conclusions: This single-center, real-world evidence study demonstrates that patients with mNSCLC experience significant distress prior to starting first-line treatment. IO treatment was associated with higher clinical benefit rates and lower healthcare utilization compared to chemotherapy. Symptom distress persists over time, highlighting potential unmet palliative and supportive care needs in mNSCLC care in the IO treatment era.

Spaghetti plots of CD4 and CD8 T cells by visits; stratified by overall response.

2626 Background: Loss of STK11 occurs in 20-25% of NSCLC and confers poor prognosis and resistance to ICB. STK11 loss affects lineage plasticity in murine models and differentiation phenotypes in patients. However, interactions between differentiation state, TME, and clinical outcomes are not well characterized. Methods: This is a retrospective and descriptive study across eight transcriptomic datasets of 2118 non-squamous NSCLC with 314 STK11 mutations, including 628 patients randomized to docetaxel or atezolizumab in the OAK and POPLAR clinical trials. STK11-DPC applies a validated gene signature to assess functional STK11 loss, then uses a rule-based classifier to define three differentiation lineages: “Neuroendocrine,” “TTF1-Low,” and TTF1-Positive.” TME is assessed by xCell immune deconvolution, and patient outcomes assessed by Cox proportional hazards regression models. Results: STK11-DPC significantly outperforms STK11 mutations in predicting decreased MHC-1, MHC-2, interferon-stimulated genes, and immune infiltration (P < 1e-8 for each). Each of the three differentiation groups has low immune infiltration compared to STK11 WT tumors, but we observe distinctive TME phenotypes corresponding to the Neuroendocrine and TTF1-Low groups. Neuroendocrine tumors have low expression of pro-inflammatory genes in the TNF/NFKB and JAK/STAT signaling pathways (P < 1e-10), while TTF1-Low tumors show hallmarks of increased inflammation, with higher PMN-MDSC, CD8 and NK signatures, but relative exclusion of dendritic cells (P < 1e-6 for each). These differences persist after controlling for KRAS, KEAP1, and TP53 mutations. Conversely, STK11-deficient tumors in WT-like or TTF1-Positive groups have TME more similar to STK11-WT tumors and show increased immune infiltration. STK11-DPC was prognostic when applied to OAK and POPLAR, with worse OS in Neuroendocrine (HR 1.6, P = 0.006) and TTF1-Low (HR 2.4, P = 5.8e-10) groups. Survival in both arms was equally poor in these groups. In contrast, STK11-deficient tumors with WT-Like or TTF1-Positive phenotypes had better OS with atezolizumab compared to docetaxel (HR 0.5, P = 0.03). Conclusions: STK11-DPC is highly predictive of immune exclusion and NSCLC patient outcomes. It identifies STK11-deficient subsets with increased immune infiltration and improved ICB response, and two putatively immune-resistant subgroups with markedly different TME phenotypes: Neuroendocrine tumors have an anti-inflammatory phenotype, while TTF1-Low tumors exhibit chronic inflammation. Performance of STK11-DPC as a predictive biomarker warrants further validation in additional patient cohorts, while the apparent TME differences suggest distinct and non-overlapping mechanisms of ICB resistance and may guide development of precision treatment strategies.

Supplementary Table S1: Efficacy by investigator assessment. Supplementary Table S2: Objective response rate by Central Radiographic Assessment in key subgroups of interest. Supplementary Table S3: Efficacy in 3L patients by Central Radiographic Assessment. Supplementary Table S4: Deaths attributable to drug-related, treatment-emergent adverse events (TEAEs). Supplementary Table S5. Overview of pleural effusions. Supplementary Table S6. Overview of pericardial effusions. Supplementary Table S7. Overview of edema. Supplementary Table S8: Overview of cutaneous reactions.

Signed-Rank Tests of V3-V2 Difference