Treatment Of Small Cell Lung Cancer Research Articles

Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor.

Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), a cancer whose aggressive clinical course making it exceedingly challenging to obtain tumor biopsies. Here, a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC, we study cfDNA low pass whole genome (0.1X coverage) and exome (130X) sequencing in comparison with time-point matched tumor, characterized using exome and transcriptome sequencing. Direct comparison of cfDNA versus tumor biopsy reveals that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not found in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Genomic sequencing coverage of plasma DNA fragments around transcription start sites shows distinct treatment-related changes and captures the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors, allowing prediction of SCLC neuroendocrine phenotypes and treatment responses. These findings have important implications for non-invasive stratification and subtype-specific therapies for patients with SCLC, now treated as a single disease.

Big Decisions on Small Cell Lung Cancer: A Focus on Clinical Care Updates and Patient Perspectives.

Small cell lung cancer (SCLC) is an uncommon, aggressive high-grade neuroendocrine carcinoma, associated with tobacco use. It is a highly chemosensitive disease that initially responds quickly to systemic therapy, although patients with SCLC tend to develop relapse. Although the landscape of SCLC treatment has remained stagnant for many decades, the field has seen notable advances in the past few years, including the use of immunotherapy, the development of further lines of systemic therapy, the refinement of thoracic and intracranial radiotherapy, and-most recently-the promise of more targeted therapies. Patients with SCLC also must face unique psychosocial burdens in their experience with their cancer, distinct from patients with other lung cancer. In this article, we review the latest literature and future directions in the management and investigation of SCLC, as well as the critical decisions that providers and patients must navigate in the current landscape. We also present the perspectives of several patients with SCLC in conjunction with this summary, to spotlight their individual journeys in the context of this challenging disease.

The role and mechanism of IFITM1 in developing acquired cisplatin resistance in small cell lung cancer

Platinum-based chemotherapies, historically the cornerstone of first-line treatment for small-cell lung cancer (SCLC), face a major hurdle: the frequent emergence of chemoresistance, notably to cisplatin (CDDP). Current understanding of the mechanisms driving CDDP resistance in SCLC is incomplete. Notably, Interferon inducible transmembrane protein1 (IFITM1) has been identified as a key player in the distant metastasis of SCLC. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IFITM1 expression is markedly elevated in tumor tissues as compared to that from adjacent normal tissues, correlating with a worse prognosis for patients with SCLC. Our research focused on investigating the role of IFITM1 in the acquisition of cisplatin resistance in SCLC. Further clinical sample analysis highlighted a significant increase in IFITM1 levels in SCLC tissues from cisplatin-resistant patients versus those were responsive to CCDP treatment, with similar trends observed in cisplatin-resistant SCLC cells. Crucially, overexpression of IFITM1 reduced the sensitivity of SCLC cells to cisplatin, while silencing IFITM1 enhanced chemosensitivity in cisplatin-resistant strains. Our in vivo studies further confirmed that silencing IFITM1 significantly boosted the efficacy of cisplatin in inhibiting growth of subcutaneous tumors of NCI–H466/CDDP cells (cisplatin-resistant SCLC cells) in a mouse model. Mechanistically, IFITM1 appears to foster cisplatin resistance through activation of the Wnt/β-catenin pathway. In summary, our findings suggest that targeting IFITM1, alongside cisplatin treatment, could offer a promising therapeutic strategy to overcome resistance and improve outcomes for SCLC patients.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis

BackgroundLeptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration.MethodsThe SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM.ResultsThe SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01).ConclusionThe SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

WITHDRAWN: Supinoxin blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through the RNA Helicase DDX5.

The authors have requested that this preprint be removed from Research Square.

Distinct regulation of ASCL1 by the cell cycle and chemotherapy in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive and lethal malignancy. Achaete-scute homolog 1 (ASCL1) is essential for the initiation of SCLC in mice and the development of pulmonary neuroendocrine cells (PNECs) which are the major cells of origin for SCLC. However, the regulatory mechanism of ASCL1 in SCLC remains elusive. Here, we found that ASCL1 expression gradually increases as the tumors grow in a mouse SCLC model and is regulated by the cell cycle. Mechanistically CDK2-CyclinA2 complex phosphorylates ASCL1, which results in increased proteasome-mediated ASCL1 protein degradation by E3 ubiquitin ligase HUWE1 during mitosis. TCF3 promotes the multi-site phosphorylation of ASCL1 through the CDK2-CyclinA2 complex and the interaction between ASCL1 and TCF3 protects ASCL1 from degradation. The dissociation of TCF3 from ASCL1 during mitosis accelerates the degradation of ASCL1. In addition, chemotherapy drugs greatly reduce the transcription of ASCL1 in SCLC cells. Depletion of ASCL1 sensitizes SCLC cells to chemotherapy drugs. Together, our study demonstrates that ASCL1 is a cell-cycle regulated protein and provides a theoretical basis for applying cell-cycle related antitumor drugs in SCLC treatment. Implications: Our study revealed a novel regulatory mechanism of ASCL1 by cell cycle and chemotherapy drugs in SCLC. Treating SCLC patients with a combination of ASCL1-targeting therapy and chemotherapy drugs could potentially be beneficial.

Hippocampal Avoidance Prophylactic Cranial Irradiation using Helical Tomotherapy in Small Cell Lung Cancer

OBJECTIVE Prophylactic cranial irradiation (PCI) is a standard treatment for small cell lung cancer (SCLC). Reduced radiation doses at the hippocampal region during PCI might protect against neurocognitive decline after radiotherapy (RT). The purpose of this study is to report the outcome of hippocampal avoidance PCI (HA-PCI) in our center. METHODS After the initial treatment of SCLC, patients whose radiographic data confirmed the absence of intracranial metastasis and controlled of the primary disease received HA-PCI. Thai Mental State Examination (TMSE) and bilateral hippocampal volumes were recorded and analyzed using the Wilcoxon Singed Rank test to compare baseline and two time points (3 and 6 months). The two-year overall survival (OS) and brain control rates were estimated using the Kaplan Meier method. RESULTS Between 2018 and 2021, a total of 10 patients were included in the analysis. The median TMSE and bilateral hippocampal volumes showed no statistically significant difference between baseline and 3 and 6 months. Two-year OS and brain control rates were 78.8% and 71.4%, respectively. Three patients developed intracranial relapses after HA-PCI which were located outside the hippocampal region. CONCLUSIONS HA-PCI did not increase intracranial relapse in this study. HA-PCI should be considered as a treatment option which can potentially protect neurocognitive functions.

Exploring effective biomarkers and potential immune related gene in small cell lung cancer

Small cell lung cancer (SCLC) is well known as a highly malignant neuroendocrine tumor. Immunotherapy combined with chemotherapy has become a standard treatment for extensive SCLC. However, since most patients quickly develop resistance and relapse, finding new therapeutic targets for SCLC is important. We obtained four microarray datasets from the Gene Expression Omnibus database and screened differentially expressed genes by two methods: batch correction and “RobustRankAggregation”. After the establishment of a protein–protein interaction network through Cytoscape, seven hub genes (AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, and AURKA) with high expression in SCLC samples were obtained by eight CytoHubba algorithms. The Least Absolute Shrinkage and Selection Operator regression and the Wilcoxon test were used to analyze the differences in the immune cells’ infiltration between normal and SCLC samples. The contents of seven kinds of immune cells were considered to differ significantly between SCLC samples and normal samples. A negative association was found between BIRC5 and monocytes in the correlation analysis between immune cells and the seven hub genes. The subsequent in vitro validation of experimental results showed that downregulating the expression of BIRC5 by siRNA can promote apoptotic activity of SCLC cells and inhibit their vitality, migration, and invasion. The use of BIRC5 inhibitor inhibited the vitality of SCLC cells and increased their apoptotic activity. BIRC5 may be a novel therapeutic target option for SCLC.

Small-Cell Lung Cancer: Is Liquid Biopsy a New Tool Able to Predict the Efficacy of Immunotherapy?

Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting in the current standard of care for SCLC. However, the advantage of immunotherapy only applies to a few SCLC patients, and predictive biomarkers selection are lacking for SCLC. In particular, due to some features of SCLC, such as high heterogeneity, elevated cell plasticity, and low-quality tissue samples, SCLC biopsies cannot be used as biomarkers. Therefore, the characterization of the tumor and, subsequently, the selection of an appropriate therapeutic combination may benefit greatly from liquid biopsy. Soluble factors, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) are now useful tools in the characterization of SCLC. This review summarizes the most recent data on biomarkers detectable with liquid biopsy, emphasizing their role in supporting tumor detection and their potential role in SCLC treatment choice.

Abstract 675: Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118

Abstract Small cell lung cancer (SCLC) is an aggressive form neuroendocrine carcinoma with limited treatment options and poor prognosis, and novel approaches are urgently needed for the treatment of this disease. Bcl-2 and Bcl-xl are aberrantly expressed in 60-70% SCLC and have been considered as promising therapeutic targets for SCLC. However, navitoclax (ABT-263), a Bcl-2/Bcl-xl dual inhibitor, demonstrated limited efficacy in SCLC while induced sever adverse events, such as thrombocytopenia due to the platelet toxicity mediated by Bcl-xl inhibition. Therefore, agents with novel mechanisms of action and safety profile are to be developed for the treatment of SCLC with Bcl-2/Bcl-xl dependency. LP-118 is a new generation and super potent Bcl-2 inhibitor with moderate Bcl-xl activity, and it is being evaluated in Phase1 clinical trials in solid tumors and hematological cancers (NCT05025358, NCT04771572). In this preclinical study, we aimed to evaluate the single agent activity of LP-118 in a panel of 9 SCLC cell lines and to further determine if LP-118 can enhance the efficacies of Standard of Cares (SOC) in vitro and in vivo. The results show that LP-118 has high in vitro activity in a subset of SCLC cell lines, and it is particularly potent in Bcl-2-depended cell lines, such as NCI-H889, with the IC50 of 0.15 nM. LP-118 is also very potent in NCI-H1963, a Bcl-xl dependent cell line (IC50: 5nM), and NCI-H526, a Bcl-2/Bcl-xl co-dependent cell line (IC50: 4-5.1 nM). Overall, LP-118 is more potent than ABT-263 in Bcl-2 or Bcl-2/Bcl-xl co-dependent cell lines, and it is relatively less active in Bcl-2/Bcl-xl/Mcl-1 co-dependent cell lines, such as NCI-H69 (IC50: 169.7 nM). In addition, combinations of LP-118 and SN-38 (the active metabolite of irinotecan), topotecan, or etoposide, induced strong synergist effects in both NCI-H69 and NCI-H146 cell lines, suggesting that LP-118 could enhance the cytotoxicity of these drugs. Consistent with the in vitro data, treatment with LP-118 alone induced complete tumor remissions in NCI-H889-derived xenograft models (10/10), whereas no complete tumor remission was observed in the ABT-263-treated group. Moreover, LP-118 plus carboplatin or topotecan dramatically inhibited tumor growth of NCI-H526 xenograft models and has significantly better efficacy than either carboplatin or topotecan alone. Importantly, no significant body weight loss was observed in mice treated with LP-118 single agent or the combinations, indicating such regimens were well tolerated. In summary, LP-118, a new generation Bcl-2/Bcl-xl dual inhibitor, is highly active, as single agent or in combination with SOCs, in a large subset of SCLC cell lines. Clinical trials are ongoing to further evaluate the safety and efficacy of LP-118 in hematological cancers and solid tumors, including SCLC. Additional studies are also underway to develop predictive biomarkers for facilitating patient stratification in the clinic. Citation Format: Ling-Ling Lee, Huan Chen, Cong Zhu, Yao Chen, Brianna Feldmeier, Yue Shen, Yu Chen, Stephen P. Anthony, Fenlai Tan, Yi Chen, Bing Dai. Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118 [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 675.

Abstract 569: Targeting UHRF1’s proteasomal destruction as a novel approach for small cell lung cancer treatment

Abstract Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with a five-year survival rate of less than 8% due to rapid tumor growth, early metastasis, and a “cold” immune environment. Genetic alteration at the RB transcriptional corepressor 1 (RB1) is nearly universally present in SCLC patients. However, the therapeutic development was impeded by a lack of druggable oncogenic mutations. Studies in our laboratory identified ubiquitin-like, containing PHD and RING Finger domains 1 (UHRF1) as a critical protein overexpressed in many cancers with RB-pathway inactivation, including SCLC. Despite UHRF1 overexpression correlates with poor survival in SCLC patients, the roles of UHRF1 in SCLC progression remain to be elucidated. We hypothesized that UHRF1 overexpression is essential for SCLC tumor progression and can be targeted through endogenous proteasomal degradation. To define the role of UHRF1 in SCLC, we generated UHRF1 knockout and knockdown human SCLC cell lines. Using these mutants, we assessed changes in proliferation, clonogenicity, migration, and invasion capabilities. We report that UHRF1 overexpression present in human SCLC cell lines contributes to a more aggressive tumor presentation, affecting both tumor growth and metastasis. Besides human cell line models, we also generated genetically engineered mouse models of SCLC to study the role of Uhrf1 in tumor development, especially in an immune environment. Our results indicate that Uhrf1 overexpression promotes SCLC proliferation, angiogenesis, and pro-tumoral macrophage polarization, overall conditioning a tumor microenvironment that supports a more aggressive phenotype. Loss of Uhrf1 in this system results in a robust increase in overall survival. These results strongly support a critical role of UHRF1 in SCLC tumor progression and provide guidance for future SCLC therapeutics targeting UHRF1 or its key downstream effectors. One approach we apply is to utilize UHRF1’s endogenous degradative machinery by inhibiting its deubiquitinase USP7. In normal cells, UHRF1 abundance oscillates through cell cycle due to the regulation of ubiquitin machinery. USP7 cleaves ubiquitin marks on UHRF1, antagonizing UHRF1 degradation. We report that same as UHRF1, knocking out USP7 leads to decreased clonogenicity, migration, and invasion in human SCLC cell lines. Highly specific USP7 chemical inhibitors, XL-177A and FT671, were also tested and the same effects as USP7 knockout were observed. Collectively, our findings describe the oncogenic role of UHRF1 in SCLC proliferation, metastasis, and immune recognition and provide a therapeutic strategy of inhibiting USP7 for UHRF1 destruction. Citation Format: Yijun Gu, Claudia A. Benavente. Targeting UHRF1’s proteasomal destruction as a novel approach for small cell lung cancer treatment [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 569.

Abstract 3842: Neuroendocrine differentiation and treatment of human SCLC: NRF2 has a role

Abstract SCLC is a lethal form of lung cancer and highly metastatic disease with limited therapeutic options. Four main neuro and non-neuroendocrine SCLC molecular subtypes have been identified which further complicate the efforts of finding targeted therapies. NRF2 is a transcription factor that is known to protect cells from oxidative damage by regulating more than 500 cytoprotective genes. NRF2 is frequently mutated in non-small cell lung cancer (NSCLC), however, whether alterations occur in small cell lung cancer (SCLC) is not clear due to limited sequencing data. Recently, our group has discovered a previously unrecognized role of NRF2 signaling pathway in the development of SCLC using a novel genetically engineered mouse model (GEMM). In this study, we have investigated the role of NRF2 in the progression and regression of human SCLC. Human SCLC cell lines were generated with NRF2E79Q/+ mutation (one of the most common mutations found in human tumors) to allow the constitutive activation of NRF2 in these cells. Results from hSCLC cell lines showed that NRF2 activation in NRF2-negative SCLCs can significantly inhibit their growth. Further, human SCLC gene expression data showed reduced levels of a NRF2 signature as hSCLC neuroendocrine SCLC transforms to non-neuroendocrine subtypes. As an anti-inflammatory pathway, NRF2 is known to inhibit immune cell gene signature. Our in vivo and invitro studies showed that NRF2 inhibits immune cell infiltration in SCLC; and increases PDL1 protein expression. Currently, we are investigating the effect of NRF2 activation in hSCLC growth, neuroendocrine differentiation and immune gene activation in vitro and in vivo. We are also using immune checkpoint inhibitors to determine the best therapeutic options for each SCLC subtype. Citation Format: Samera Hamad, Hansa Joshi, Yahui Li, Helen Toma, Nasrine Bendjilali, Stuart Jefferys, David Corcoran, Weam Elbezanti, Ben Major, Weissman Bernard, Francis Spitz. Neuroendocrine differentiation and treatment of human SCLC: NRF2 has a role [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 3842.

Abstract 7164: Exposure-efficacy and exposure-safety relationships of tarlatamab to inform dose selection and benefit-risk assessment in patients with advanced small cell lung cancer (SCLC)

Abstract Introduction: Tarlatamab is a first in class, half-life extended bispecific T-cell engager (BiTE) immunotherapy targeting delta-like ligand 3 (DLL3) that has shown promising anti-tumor activity and survival outcomes with manageable safety profile in clinical studies of patients with previously treated SCLC (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we characterized the exposure-efficacy and exposure-safety profiles associated with tarlatamab treatment in SCLC, including the effects of patient-specific covariates (brain or liver metastasis, smoking status, number of prior lines of therapy, prior PD-1/PD-L1 inhibitor therapy, sum of target lesion diameters, and presence of anti-drug antibody). Methods: The analysis dataset consisted of 412 subjects with SCLC from ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). Serum tarlatamab exposure averaged over the first cycle (28 days) was utilized as the predictor of response in the regression analysis. Efficacy endpoints included objective response rate, disease control rate, best tumor size response, progression-free survival and overall survival (OS). Safety endpoints included overall treatment related adverse event (TRAE), overall treatment emergent adverse event (TEAE), and TEAEs of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and associated neurologic events, and neutropenia. Only the grade ≥ 3 adverse events (AEs) were evaluated. Results: Significant exposure-response relationships were established for all key efficacy measures across the dose range investigated. Plateau in the exposure-efficacy relationship (maximal efficacy) was observed at the recommended dose of 10 mg Q2W. Exposures associated with lower doses were estimated to have lower efficacy. No clear trends for exposure-response relationships were identified for the evaluated AEs except for grade ≥ 3 neutropenia, where a shallow trend was observed for increased neutropenia rate with increasing tarlatamab exposures. Of all the evaluated covariate relationships, only higher baseline sum of target lesion diameters was statistically significantly correlated with worsening of OS. Conclusions: Overall results in this SCLC population suggest tarlatamab exposures associated with the recommended dose of 10 mg Q2W exhibited near maximal efficacy and a favorable benefit-risk profile. None of the evaluated patient-specific covariates resulted in clinically meaningful changes in efficacy or safety, and therefore do not warrant a dose adjustment. Citation Format: Po-Wei Chen, Mukul Minocha, Stephanie M. Kong, Erik S. Anderson, Amanda Parkes, Pablo Martinez, Brett E. Houk, Chih-Wei Lin. Exposure-efficacy and exposure-safety relationships of tarlatamab to inform dose selection and benefit-risk assessment in patients with advanced small cell lung cancer (SCLC) [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 7164.

Abstract 3148: ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers

Abstract Lung cancer has the highest rates of incidence (2.1 million cases/year) and mortality (1.8 million deaths/year) among all cancers worldwide. Approximately 15% of lung cancers are small cell lung cancer (SCLC). SCLC is typically diagnosed at late stages, with approximately 70% of patients having extensive stage disease at time of diagnosis. Unfortunately, these patients have a dismal 5-year survival rate of approximately 3%. In contrast to non-small cell lung cancer (NSCLC), there has been little advancement in the treatment of SCLC, with no biomarker directed therapies available for patients. SEZ6 is overexpressed in most SCLC’s and other neuroendocrine tumor types. This overexpression and limited normal tissue expression suggest SEZ6 would be a good target for the development of an antibody drug conjugate (ADC). Validation of SEZ6 as an ADC target was supported by signs of clinical activity for ABBV-011, a SEZ6-targeting calicheamicin ADC. Preclinical and clinical data suggest an increased therapeutic index for Top1i ADCs relative to calicheamicin ADCs. Furthermore, Top1i inhibition is an effective mechanism of action in SCLC with topotecan approved in 2L, although significant toxicity limits broad utility. As such, we hypothesized that a SEZ6-Top1i ADC would enable effective Top1 inhibition in tumor cells and reduce toxicity relative to ABBV-011 or systemic chemotherapy, driving increased therapeutic benefit. ABBV-706 is an ADC comprised of the same SEZ6 targeting antibody as ABBV-011 conjugated to AbbVie’s topoisomerase-1 (Top1) inhibitor. ABBV-706 is a potent anti-proliferative agent in SEZ6 positive SCLC cell lines, with sub- to low-nanomolar activity. SEZ6 dependence was demonstrated by the correlation of SEZ6 mRNA expression to ABBV-706 growth inhibition. On-target Top1i activity was confirmed in cells treated with ABBV-706 as measured by dose-dependent induction of γ-H2AX, a marker of DNA damage, and G2/M arrest. ABBV-706 possessed superior anti-tumor activity compared to ABBV-011 in a panel of SCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models with a range of SEZ6 expression levels. In addition, ABBV-706 had activity in the setting of resistance to cisplatin/etoposide (1L SoC in SCLC), in combination with cisplatin, and in SEZ6-expressing neuroendocrine liver and cervical PDX models. ABBV-706 has favorable pharmacokinetics and is well-tolerated in cynomolgus monkeys with bone marrow and gastrointestinal tract toxicities common to other Top1 inhibitors. ABBV-706 shows promise as an agent for the treatment of SCLC and other difficult to treat SEZ6 expressing neuroendocrine tumors. ABBV-706 has completed dose escalation, and dose expansion is currently ongoing in a Phase 1 FIH clinical study (NCT05599984). Citation Format: Emily J. Faivre, Marybeth A. Pysz, Eoghainín Ó hAinmhire, Laura Kreckler, Kelly Doyle, Aloma D'Souza, Zhiyong Ding, Trusha Sondkar, Dolonchampa Maji, Fan Zhao, Andrew Phillips. ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers [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 3148.

Abstract 2153: The impact of socioeconomic and racial segregation on cancer stage at diagnosis, treatment and mortality among patients with small cell lung cancer

Abstract Background: Although studies have revealed the adverse impact of residential segregation on early detection, treatment, and survival of non-small cell lung cancer―a predominant type of lung cancers, it remains unknown regarding the role of residential segregation in treatment and outcomes of small cell lung cancer (SCLC)―a rare type of lung cancer characterized by rapid growth and poor prognosis. Therefore, we examined the associations of racialized socioeconomic segregation with risks of extensive-stage diagnosis, non-adherence to guideline-recommended treatment, and mortality among non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients with SCLC. Methods: This population-based retrospective cohort study included patients who were diagnosed with SCLC as a first primary malignancy at age 20 and older between January 2007 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results. County-level racialized socioeconomic segregation was measured using the Index of Concentration at the Extremes (ICE). Multilevel logistic regression accounting for county-level clustering was used to estimate odds ratios (ORs) for extensive-stage diagnosis and non-adherence to guideline-recommended treatment. Hazard ratios (HRs) for lung cancer-specific mortality and all-cause mortality were computed using multilevel Cox regression. Results: Among 38,393 patients, 90.1% were NHW and 9.9% were NHB. Patients dwelling in the counties with the highest concentration of low-income NHB households (highest ICE quartile) had higher risks of non-adherence to guideline-recommended treatment (OR=1.23, 95% CI: 1.08-1.40; Ptrend &amp;lt;0.01), lung cancer-specific mortality (HR=1.08, 95% CI: 1.04-1.12; Ptrend &amp;lt;0.01), and all-cause mortality (HR=1.13, 95% CI: 1.09-1.17; Ptrend &amp;lt;0.0001) as compared with patients dwelling in the counties with the highest concentration of high-income NHW households (lowest ICE quartile). These associations were comparable between NHB and NHW patients. Racialized economic segregation was not significantly associated with extensive-stage diagnosis. Conclusions: Residing in the segregated, low-income NHB counties had adverse impacts on stage-appropriate treatment for SCLC and survival outcomes. Future research on the pathway(s) linking residential segregation to SCLC treatment underutilization and poor outcomes is warranted. Citation Format: Bayu B. Bekele, Min Lian, Ying Liu. The impact of socioeconomic and racial segregation on cancer stage at diagnosis, treatment and mortality among patients with small cell lung cancer [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 2153.

Abstract 3142: NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models

Abstract c-Kit (CD117) is a type III receptor tyrosine kinase (RTK), which is known to be activated upon binding to its cognate ligand stem cell factor (SCF) to induce critical signaling pathways involved in cell proliferation, survival, and differentiation. Indicative of poor prognosis, overexpression and activating mutations of c-Kit have been implicated in a variety of human cancers including small cell lung cancer (SCLC), gastrointestinal stromal tumors (GIST), and acute myelogenous leukemia (AML). While imatinib, a small molecule c-Kit inhibitor, has been a beneficial treatment for GIST, resistance eventually develops to the drug, moreover, shows limited efficacy in c-Kit overexpressing tumors such as SCLC. Herein, we developed NN3201, a novel c-Kit targeting antibody-drug conjugate (ADC), comprised of fully human 2G4 antibody with a picomolar binding affinity to c-Kit and cytotoxic monomethyl auristatin E (MMAE) as the payload. NN3201 displayed potent in vitro cytotoxicity in various wild-type and mutant c-Kit positive SCLC and GIST cell lines with IC50 in the nanomolar range. In addition, NN3201 was rapidly internalized and inhibited c-Kit-mediated signaling., NN3201 treatment resulted in the increased proportions of the sub G1 and G2/M in the c-Kit positive cancer cell lines, indicating that release of MMAE induced cell cycle arrest. Moreover, bystander effect was confirmed by co-culturing c-Kit high and negative cell lines. Most importantly, in mouse xenograft models, NN3201 showed a remarkable tumor growth inhibition of several wild type, mutant c-Kit positive, and imatinib resistant SCLC and GIST cell lines. Enhanced anti-tumor activity and delayed tumor growth were observed in an SOC-treated (etoposide and carboplatin) SCLC xenograft model, by NN3201 in comparison to second line SOC (topotecan or irinotecan). In the GLP study, repeated intravenous administration of NN3201 was well tolerated at all doses (0.5, 1, 2 mg/kg Q3Wx3) without unscheduled death. Dose-dependent, yet transient, cytotoxicity of NN3201 was observed in the bone marrow. We confirmed HNSTD (Highest Non-Severely Toxic Dose) of NN3201 to be 2 mg/kg through exploratory and GLP repeat dose toxicity studies as no serious irreversible toxicity was observed. Accumulating data suggest that NN3201 is a promising therapeutic alternative for the treatment of SCLC and GIST regardless of wild-type or activating mutations in c-Kit. Citation Format: Chansik Kim, Jin Gu Cho, TaeMin Wi, Jiwoo Moon, Han-Jik Ko, Jina Lee, Jin Woo Park, Yeonjy Lee, Sanghee Kim, Jin-Ock Kim, Jaeyoung Song, Sun-Hwa Lee, Sang Gyu Park. NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models [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 3142.

Abstract 6554: Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and limited therapeutic options. Repression of the MHC-I and reduced tumor infiltration of cytotoxic T-lymphocytes is often associated with immunotherapy resistance in SCLC. Lurbinectedin is FDA-approved as a second-line treatment for SCLC and we previously showed lurbinectedin as an effective therapeutic strategy in SCLC preclinical models. There are ongoing clinical trials combining immune checkpoint blockade with lurbinectedin in ES-SCLC. However, there is no insight into the effect of lurbinectedin on the immune microenvironment in SCLC. In this study, we evaluated the effect of lurbinectedin on the immune microenvironment and the anti-tumor effect with or without PD-L1 blockade. Results: To determine the effect of lurbinectedin in SCLC models, we treated immunocompetent flank RPP (Rb1, Trp53, and p130) and RPM (Rb1, Trp53, and MYCT58A) tumor-bearing mice with lurbinectedin (0.2 mg/kg, 1/7days) and/or anti-PD-L1 (300µg, 1/7days) for 3 weeks. Mice treated with anti-PD-L1 alone showed no anti-tumor response, and single-agent lurbinectedin caused a delay in tumor growth. However, 6 of the 10 mice treated with the combination of lurbinectedin and anti-PD-L1, had a complete response (100% reduction) and the other 4 had 90% tumor regression. Tumors were resected and analyzed by multicolor flow cytometry for changes in tumor-infiltrating lymphocytes (TILs). Furthermore, analysis of immune cells infiltrating into the tumors post- treatment showed significant induction of cytotoxic T-cells and a reduction of exhausted and regulatory T cells in the combination treatment arm. Similarly, pro-inflammatory M1 type macrophages and dendritic cells were increased, while immunosuppressive M2 type macrophages and MDSC cells were decreased. These effects are consistent with data showing that lurbinectedin treatment leads to an activation of the cGAS/STING pathway, type I/II interferons (IFNα/β), and pro-inflammatory chemokines (CCL5, CXCL10) in tumors. Interestingly, lurbinectedin treatment led to significant upregulation of mRNA and surface expression of MHC class-I genes (HLA-A/B/C) in vitro and in vivo. Finally, bulk RNA sequencing as well as RT-PCR of pre- and post-lurbinectedin treatment demonstrated an increase in DAMPs associated with immunogenic cell death. Conclusion: We provide the first mechanistic insight into the lurbinectedin-induced multimodal immune modulation in SCLC leading to a dramatic anti-tumor activity accompanied by the establishment of a strong anti-tumor immune microenvironment. Since lurbinectedin is already approved as a second-line agent in SCLC, our preclinical data provide a strong rationale for combining this regimen with inhibitors of the PD-L1 pathway and also highlight the immune subsets that the combination targets. Citation Format: Subhamoy Chakraborty, Yazhini Mahendravarman, Utsav Sen, Avisek Banerjee, Charles Coleman, Deniz Demircioglu, Dan Hasson, Triparna Sen. Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell lung cancer [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 6554.

Abstract 3986: Exploring nonsense-mediated decay inhibition as a novel approach to improve immunogenicity in small cell lung cancer

Abstract Cancer immunotherapy has revolutionized the field of oncology and is one of the most promising treatments for lung cancer. Small cell lung cancer (SCLC) is highly aggressive and patients often relapse due to chemotherapy resistance. In the recent years, chemotherapy has been combined with immune checkpoint inhibition (ICI) for SCLC treatment, leading to improved responses in some patients, but also leaving a high number of non-responders to address. Paradoxically, SCLC has one of the highest tumor mutational burden, including remarkably abundant frameshifts (FS) which could create highly immunogenic neoantigens (NeoAg). However, FS-harbouring transcripts are often degraded via Nonsense-Mediated Decay (NMD). We therefore aimed to inhibit the NMD pathway to increase the immunogenicity of SCLC. Our lab has so far profiled the mutational landscape of more than 400 SCLC patients and generated over 100 patient-derived xenotransplant models. We analyzed genome and transcriptome sequencing data of multiple tumors to interrogate the NMD target repertoire in SCLC. We determined tumor-specific mutations and predicted NeoAg based on the HLA-I-binding ability of mutant peptides. Upon NMD inhibiton, we validated the expression and presentation of NeoAg via transcriptomics, proteomics and HLA-I-immunopeptidomics. NMD-sensitive mutated transcripts included a wide range of somatic alterations beyond FS-mutations, suggesting an overall increase of potential tumor-specific NeoAg. We furthermore evaluated immunogenicity after NMD perturbation employing in vitro co-cultures as well as immunocompetent in vivo mouse models. Inhibition of NMD in tumor cells resulted in an HLA-I-dependent enhancement of T cell-mediated tumor killing in vitro, and in vivo experiments showed reduced tumor growth accompanied by increased immune infiltration upon controlled induction of NMD inhibition. Altogether, NMD inhibition in SCLC led to an upregulation of NeoAg expression in tumor cells accompanied by enhanced T cell responses in vitro and in vivo. Our strategy provides a novel approach for the treatment of low immunogenic tumors which could be combined with ICI to enhance the efficacy of immunotherapy. Citation Format: Lucia A. Torres Fernández, Volker Böhm, Lukas Maas, Anna Schöllhorn, Joel Kaufmann, Joshua D'Rozario, Laura Kaiser, Niels Gehring, Martin Peifer, Cécile Gouttefangeas, Roman K. Thomas, Julie George. Exploring nonsense-mediated decay inhibition as a novel approach to improve immunogenicity in small cell lung cancer [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 3986.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Lurbinectedin in prostatic small cell and neuroendocrine carcinoma.

164 Background: Lurbinectedin (L) is a novel inhibitor of oncogenic transcription that was granted accelerated approval by the Food and Drug Administration in June 2020 for the treatment of metastatic small cell lung cancer (SCLC) following disease progression on or after platinum-based chemotherapy (PBC). Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) is a high-grade, invasive malignancy that accounts for &lt; 1% of all prostate cancers. SC/NEPC is distinct from prostatic adenocarcinoma and behaves similar to SCLC. NCCN guidelines for SC/NEPC recommend following the SCLC treatment guidelines. Using these guidelines, L may be used as a second-line treatment in patients (pts) with SC/NEPC who progress on or after PBC. We aimed to characterize the baseline characteristics, clinical course and therapeutic outcomes of pts treated with L for SC/NEPC. Methods: After IRB approval, 18 cases were gathered from 4 academic oncology centers. Baseline patient data, prior treatments and L treatment outcomes, including best radiographic and serologic responses, overall survival (OS), progression-free survival (PFS) and treatment toxicity were assessed. The Kaplan-Meier method was used to calculate OS and PFS from the L start date. Clinical benefit rate (CBR) included pts with complete response (CR), partial response (PR) and stable disease (SD) on imaging. Results: At the time of first L dose, all had metastatic disease with 2-6 distinct sites of metastases, most commonly bone (14/18, 77.8%), lymph nodes (14/18, 77.8%) and liver (13/18, 72.2%); median age was 63.5 (Range: 53-84); 11 pts (61.1%) had an ECOG 0-1; 4 pts (22.2%) had an ECOG of 2-3. The median total number of systemic therapies administered prior to L was 4 (Range: 2-7). All pts received PBC prior to L. The most common dose of L prescribed was 3.2 mg/m2 every 21 days (15/18, 83.3%). Androgen deprivation therapy was administered in conjunction with L in 9 pts (50%). The median number of cycles of L was 5 (Range: 1-10). L was discontinued due to toxicity in 1 patient (5.6%), disease progression in 10 pts (55.6%), transition to hospice in 2 pts (11.1%), 3 pts (16.7%) died while receiving treatment (not due to L toxicity), and 2 pts (11.1%) remained on L at the time of data reporting. The median OS and PFS from date of first L dose was 6.01 months (0.23 – 16.69) and 3.35 months (0.16 – 7.79), respectively. CBR was 9/16 (56.3%) with partial response in 5 pts (31.3%), stable disease in 4 pts (25%), and progressive disease in 7 pts (43.8%). Two pts did not have post-treatment imaging available to assess response. There were no hospitalizations for L treatment related adverse events (tRAE). The most common tRAE were grade I and II fatigue and anemia; 9 pts (50%) experienced no tRAE. The only grade IV toxicity was neutropenia in 3 pts (16.7%). Conclusions: L is a well-tolerated and active treatment option for patients with SC/NEPC. Prospective studies are needed to determine the role of L in the treatment of SC/NEPC.