Small Cell Lung Cancer Trials Research Articles

Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC).

5012 Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years [y]) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . [Table: see text]

Surrogate endpoints and outcomes in modern small cell lung cancer trials.

8091 Background: Overall Survival (OS) may not always be a feasible primary endpoint. Endpoints such as Overall Response Rate (ORR), Disease Control Rate (DCR=CR+PR+SD), Progression Free Survival (PFS), are frequently used in the assessment of treatments. However, improvements in DCR, ORR, PFS may not translate into OS benefit. Resilient trial showed a doubling of ORR to PEGylated liposomal irinotecan1 compared to control but no improvement in PFS/OS. Furthermore, these associations may differ between 1st line (1L) and relapsed (2L) disease settings. This study analyzes the relationship between ORR, DCR, PFS, and OS in extensive-stage SCLC. Methods: MEDLINE, Embase, ClinicalTrials.gov were searched to identify randomized, phase III trials between 2014-2024. PRISMA guideline was followed. DCR, ORR, OS, PFS data were extracted. Weighted linear regression models investigated the association between treatment effects on DCR, ORR, OS, PFS. Weighted Pearson correlation analyses were performed under logarithmic transformation of DCR/ORR odds ratio besides DCR/ORR difference between treatment arms, with weights equal to the inverse of variance of DCR/ORR associated with the log PFS HR and the log OS HR. Logistic regression models were used to derive DCR/ORR odds ratios. Hazard ratios (HR) estimated from Cox proportional hazards regression models were used. All tests are two-sided; p-value < 0.05 is significant. Results: 115 trials were identified. 22 met the criteria. DCR: 1) 1L and 2L: DCR difference between arms and the log odds ratio and log PFS HR were strongly correlated: –0.63 (P = 0.001) for the DCR difference model; –0.64 (P = 0.0008) for the log odds ratio model. No correlation was found between DCR and OS; 2) 1L: No correlation between DCR and PFS & OS was found; 3) 2L: DCR difference between arms and the log odds ratio and log PFS HR were correlated: –0.84 (P = 0.01) for the DCR difference model; –0.84 (P = 0.01) for the log odds ratio model. ORR:1) 1L and 2L: ORR difference between arms and the log odds ratio and log PFS HR were correlated: –0.43 (P = 0.036) for the ORR difference model; –0.51 (P = 0.011) for the log odds ratio model; 2) 1L: No correlation between ORR and PFS & OS was found; 3) 2L: No correlation between ORR and PFS & OS was found. PFS:1)1L and 2L: The Pearson correlation coefficients between log HR of PFS and log HR of OS: 0.6 (p = 0.002); 2) 1L: The Pearson correlation coefficient between log HR of PFS and log HR of OS: 0.77 (p = 0.0005) 3) 2L: The Pearson correlation coefficients between log HR of PFS and log HR of OS: -0.14 (p = 0.732). Conclusions: In the 1L setting, neither DCR nor ORR predict PFS and OS. However, PFS predicts OS. In the 2L, ORR does not predict either OS or PFS; however, DCR predicts PFS and shows a trend with OS. Unlike in the frontline setting, PFS does not predict OS in the second-line setting. Reference: 1 Rudin CM, Dowlati A, Chen Y, et al.161O RESILIENT part 2: A randomized, open-label phase III study of liposomal irinotecan versus topotecan in adults with relapsed SCLC.

Challenges and opportunities in the immunotherapy era: balancing expectations with hope in small-cell lung cancer.

Small-cell lung cancer (SCLC) is a biologically aggressive subtype of lung cancer, a lethal disease characterized by rapid tumor growth, early relapse, a strong tendency for early widespread metastasis, and high genomic instability, making it a formidable foe in modern oncology practice. While the management of non-SCLC has been revolutionized in the era of immunotherapy, progress in SCLC has been more muted. Recent randomized phase III clinical trials have combined programmed death ligand-1 inhibitors to a chemotherapy backbone and demonstrated improved survival; however, the absolute benefit observed is short months. There is an undeniable urgent need for better responses, better agents, novel therapeutic approaches, and more rational, biomarker-driven clinical trials in SCLC. In this review, we discuss the rationale and current understanding of the biology of SCLC in the modern era of immunotherapy, discuss recent advances in front-line immunotherapeutic approaches that have changed clinical practice globally, provide an overview of some of the challenges and limitations that have staggered immune checkpoint blockade in SCLC, and explore some of the novel immunotherapeutic approaches currently being investigated.

Abstract A066: TUSC2 immunogene therapy enhances checkpoint blockade through increased cytotoxic immune activation in chemo-resistant small cell lung cancer (SCLC) in humanized mice

Abstract Immunotherapy has been effective but has had limited effect in clinical trials for SCLC. We identified TUSC2, a potent tumor suppressor gene, as a novel immunogene, which mediates both apoptosis and induces a strong antitumor immune response. TUSC2 expression is reduced in almost all SCLC tumors and absent in 41%. We investigated the antitumor immune response to TUSC2 gene therapy in combination with immune checkpoint blockade (ICB) against a chemo-resistant inflamed SCLC tumors in humanized mice. Colony formation was markedly reduced in platinum resistant inflamed H841 cells transfected with TUSC2. Humanized mice were generated by transplanting fresh human cord blood derived CD34 stem cells into sub-lethally irradiated NSG mice(hu-NSG). The level of engraftment of human CD45, CD3 T, CD19 B, NK cells was verified before tumor implantation at > 25%. Subcutaneous tumors were developed in hu-NSG mice and treated with intravenous injections of TUSC2 loaded cationic lipid nanoparticles (quaratusugene ozeplasmid abbreviated quar oze) with or without pembrolizumab (pembro; anti-PD1). A dramatic antitumor effect was mediated by quar oze, whereas pembro remained ineffective. A synergistic antitumor effect was found when quar oze was combined with pembro. The antitumor effect of the quar oze + pembro was associated with increased infiltration of human TILs, CD3 T, cytotoxic T, and NK cells, and a decreased number of human regulatory T (Treg) cells, and PD1 expressing exhausted CD8 T cells in the tumor microenvironment. Quar oze was also combined with atezolizumab (atezo; anti-PD-L1) and the antitumor effect on H841 lung metastases in hu-NSG mice was tested. Metastases were treated with quar oze and atezo alone or in combination. Although quar oze alone and atezo alone showed a strong antitumor effect in controlling metastases, a greater antitumor effect was found when quar oze was combined with atezo. Infiltration of human CD45, CD3 T, CD8 T and NK cells increased in the quar oze and quar oze +atezo treated groups compared with others. A significantly higher number of CD8 T effector memory and lower number of naïve T cells were found in the quar oze +atezo which were associated with increased activated CD8 T cells (CD69+, PD1+ CD8 T cells). HLA-DR+ dendritic cells were increased, whereas myeloid derived suppressor cells were strongly inhibited by the combination. Quar oze was also combined with carboplatin+atezo which showed enhanced antitumor efficacy compared with carbo+atezo or quar oze alone. When quar oze was combined with carboplatin, a greater effect was found in inhibiting H841 cell growth, colony formation, and induction of apoptosis. Quar oze was combined with NPRL2, another tumor suppressor gene, in H841 tumors in humanized mice. Synergistic antitumor efficacy of the dual gene therapy occurred with the quar oze +NPRL2 treatment. Taken together, these data suggest that TUSC2 gene therapy in combination with ICB induces strong antitumor activity on a chemo-resistant inflamed SCLC through cytotoxic CD8 T and NK cell activation. Citation Format: Ismail M Meraz, Mourad Majidi, Renduo Song, Feng Meng, Lihui Gao, Qi Wang, Jing Wang, Elizabeth Shpall, Mark Berger, Hemant Kumar, Jack A Roth. TUSC2 immunogene therapy enhances checkpoint blockade through increased cytotoxic immune activation in chemo-resistant small cell lung cancer (SCLC) in humanized mice [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A066.

Unlocking New Horizons in Small-Cell Lung Cancer Treatment: The Onset of Antibody-Drug Conjugates.

Small-cell lung cancer (SCLC) is a highly aggressive disease, accounting for about 15% of all lung cancer cases. Despite initial responses to chemoimmunotherapy, SCLC recurs and becomes resistant to treatment. Recently, antibody-drug conjugates (ADCs) have emerged as a promising therapeutic option for SCLC. ADCs consist of an antibody that specifically targets a tumor antigen linked to a cytotoxic drug. The antibody delivers the drug directly to the cancer cells, minimizing off-target toxicity and improving the therapeutic index. Several ADCs targeting different tumor antigens are currently being evaluated in clinical trials for SCLC. Despite the negative results of rovalpituzumab tesirine (Rova-T), other ADCs targeting different antigens, such as B7-H3, seizure-related homolog 6 (SEZ6), and CEACAM5, have also been investigated in clinical trials, including for SCLC, and their results suggest preliminary activity, either alone or in combination with other therapies. More recently, sacituzumab govitecan, an anti-TROP2 ADC, demonstrated promising activity in lung cancer, including SCLC. Furthermore, an anti-B7-H3 (CD276), ifinatamab deruxtecan (DS7300A), showed a high response rate and durable responses in heavily pretreated SCLC. Overall, ADCs represent an intriguing approach to treating SCLC, particularly in the relapsed or refractory setting. Further studies are needed to determine their efficacy and safety and the best location in the treatment algorithm for SCLC. In this review, we aim to collect and describe the results regarding the past, the present, and the future of ADCs in SCLC.

Creating and Implementing a Principal Investigator Tool Kit for Enhancing Accrual to Late Phase Clinical Trials: Development and Usability Study.

BackgroundAccrual to oncology clinical trials remains a challenge, particularly during the COVID-19 pandemic. For late phase clinical trials funded by the National Cancer Institute, the development of these research protocols is a resource-intensive process; however, mechanisms to optimize patient accrual after trial activation are underdeveloped across the National Clinical Trial Network (NCTN). Low patient accrual can lead to the premature closure of clinical trials and can ultimately delay the availability of new, potentially life-saving therapies in oncology.ObjectiveThe purpose of this study is to formally create an easily implemented tool kit of resources for investigators of oncology clinical trials within the NCTN, specifically the NRG Oncology cooperative group, in order to optimize patient accrual.MethodsNRG Oncology sought to formally develop a tool kit of resources to use at specific time points during the lifetime of NRG Oncology clinical trials. The tools are clearly described and involve the facilitation of engagement of the study principal investigator with the scientific and patient advocate community during the planning, activation, and accrual periods. Social media tools are also leveraged to enhance such engagement. The principal investigator (PI) tool kit was created in 2019 and thereafter piloted with the NRG Oncology/Alliance NRG-LU005 phase II or III trial in small-cell lung cancer. The PI tool kit was developed by the NRG Oncology Protocol Operations Management committee and was tested with the NRG/Alliance LU005 randomized trial within the NCTN.ResultsNRG Oncology/Alliance NRG-LU005 has seen robust enrollment, currently 127% of the projected accrual. Importantly, many of the tool kit elements are already being used in ongoing NRG Oncology trials, with 56% of active NRG trials using at least one element of the PI tool kit and all in-development trials offered the resource. This underscores the feasibility and potential benefits of deploying the PI tool kit across all NRG Oncology trials moving forward.ConclusionsWhile clinical trial accrual can be challenging, the PI tool kit has been shown to augment accrual in a low-cost and easily implementable fashion. It could be widely and consistently deployed across the NCTN to improve accrual in oncology clinical trials.Trial RegistrationClinicalTrials.gov NCT03811002; https://clinicaltrials.gov/ct2/show/NCT03811002

Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data.

The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150-wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state.

Small‐cell lung cancer (SCLC) is a heterogeneous disease, consisting of intratumoral and intertumoral neuroendocrine (ASCL1 and/or NEUROD1), mesenchymal‐like, and YAP‐driven transcriptional states. Lysine‐specific demethylase 1 (LSD1; also known as KDM1A) inhibitors have recently been progressed to clinical trials in SCLC based on a promising preclinical antitumor activity. A potential clinical limitation of LSD1 inhibitors is the heterogeneous drug responses that have been observed in SCLC cell lines and patient‐derived models. Based on these observations, we studied molecular and transcriptional signatures that predict patient response to this class of drug. Employing SCLC patient‐derived transcriptional signatures, we define that SCLC cell lines sensitive to LSD1 inhibitors are enriched in neuroendocrine transcriptional markers, whereas cell lines enriched in a mesenchymal‐like transcriptional program demonstrate intrinsic resistance to LSD1 inhibitors. We have identified a reversible, adaptive resistance mechanism to LSD1 inhibitors through epigenetic reprogramming to a TEAD4‐driven mesenchymal‐like state. Our data suggest that only a segment of SCLC patients, with a defined neuroendocrine differentiation state, will likely benefit from LSD1 inhibitors. It provides novel evidence for the selection of a TEAD4‐driven mesenchymal‐like subpopulation resistant to LSD1 inhibitors in SCLC patients that may require effective drug combinations to sustain effective clinical responses.

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

Combination of the EP and Anti-PD-1 Pathway or Anti-CTLA-4 for the Phase III Trial of Small-Cell Lung Cancer: A Meta-Analysis.

The morbidity and mortality of lung cancer remain one of the highest among multiple cancers, respectively. Small-Cell Lung Cancer (SCLC) accounts for around 10%–15% of all lung cancers. Approximately two-thirds of the diagnosed SCLCs are in extensive stage (ES). Decades later, we still rely on the same traditional regimen with etoposide and platinum (EP) as the mainstay of treatment with poor prognosis. This meta-analysis aims to assess the effect of adding Immune Checkpoint Inhibitors (CPIs) such as (ipilimumab, atezolizumab, pembrolizumab, and durvalumab) to the traditional EP regimen for small-cell lung cancer extensive stage (ES-SCLC). We searched through PubMed looking for studies that compare between EP and CPIs, with EP alone, and only Phase III randomized controlled trials were considered eligible for this study. A total of 3645 papers were the results of the initial search, and only 4 studies met our criteria. Each investigator extracted the data independently using the PRISMA MODEL (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Each author used a prespecified sheet. The primary endpoint was to calculate OS (overall survival) and PFS (progression-free survival) hazard ratios for both arms. We found that adding EP plus CPIs increased both OS (HR, 95% CI 0.80 [0.70, 0.93], P = 0.0001, I2 = 49%) and PFS (HR95% CI 0.81 [0.74, 0.88], P < 0.00001, I2 = 0%). On the other hand, ORR (overall response rate) was not affected by the addition of CPIs to EP compared to EP alone, and the same was true for adverse events. To conclude, CTLA-4 alone is not encouraging, but PD-1/PD-L1 adds survival benefits. A combined treatment regimen shows to be more effective, improving overall survival rate Durvalumab and atezolizumab showed improvement for OS, but pembrolizumab and ipilimumab did not show a significant increase of OS over EP; however, pembrolizumab showed significant prolongation of the disease-free period.

Non–Small Cell Lung Cancer Symptom Assessment Questionnaire: Psychometric Performance and Regulatory Qualification of a Novel Patient-Reported Symptom Measure

BackgroundThe Non–Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to incorporate the patient's perspective into evaluation of clinical benefit in advanced non–small cell lung cancer trials and meet regulatory expectations for doing so. Qualitative evidence supported 7 items covering 5 symptom concepts.ObjectiveThis study evaluated measurement properties of the NSCLC-SAQ's items, overall scale, and total score.MethodsIn this observational cross-sectional study, a purposive sample of patients with clinician-diagnosed advanced non–small cell lung cancer, initiating or undergoing treatment, provided sociodemographic information and completed the NSCLC-SAQ, National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index (FLSI-17), and a Patient Global Impression of Severity item. Rasch analyses, factor analyses, and assessments of construct validity and reliability were completed.ResultsThe 152 participants had a mean age of 64 years, 57% were women, and 87% where White. The majority were Stage IV (83%), 51% had an Eastern Cooperative Oncology Group performance status of 1 (32% performance status 0 and 17% performance status 2), and 33% were treatment naïve. Rasch analyses showed ordered thresholds for response options. Factor analyses demonstrated that items could be combined for a total score. Internal consistency (Cronbach α = 0.78) and test–retest reliability (intraclass correlation coefficient = 0.87) were quite satisfactory. NSCLC-SAQ total score correlation was 0.83 with the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index-17. The NSCLC-SAQ was able to differentiate between symptom severity levels and performance status (both P values < .001).ConclusionsThe NSCLC-SAQ generated highly reliable scores with substantial evidence of construct validity. The Food and Drug Administration's qualification supports the NSCLC-SAQ as a measure of symptoms in drug development. Further evaluation is needed on its longitudinal measurement properties and interepretation of meaningful within-patient score change. (Curr Ther Res Clin Exp. 2021; 82:XXX–XXX)

Abstract D081: Geographic relationship between lung cancer clinical trial sites and patient prevalence and demographics in the Medicare Fee-for-service program

Abstract Racial and ethnic minority groups have low rates of inclusion in cancer clinical trials (CCTs). For example, African American patients comprise 5% of patients enrolled in CCTs that support US Food and Drug Administration approval of new drugs but represent 13.3% of the general US population. Though cancer is the leading cause of death for Asian Americans, only 3% of CCTs is composed of Asian American participants. With the promise and rise of precision medicine, it is critical that study populations in clinical research reflect the changing US demographics. Expanding access to health data and analytics empower stakeholders to better understand and advocate for equitable research and treatment access in cancer. Research question: To what extent does the current US CCT site placement for non-small cell lung cancer (NCSLC) and small cell lung cancer (SCLC) reflect the reality of lung cancer patient prevalence and demographics in the US? Methods: Researchers used the following two primary data sources: (1) Medicare Fee-for-Service (FFS) patient-level claims data from 2016, including the following data elements: prevalence, co-morbidities, hospital encounters, and costs for patients with ICD-10 codes for NCSLC and SCLC, by demographic (age, gender, race, and ethnicity). Locations were designated as high (greater than 0.87%) or low (less than 0.87%) prevalence, based on national average prevalence. (2) CCT placement data was sourced from 2018 Clinical Trials.gov to determine ongoing NCLSC and SCLC studies where there are US study sites. Data were mapped on the Lung Cancer Index™, a National Minority Quality Forum (NMQF) geographic information system (GIS) with an interactive data warehouse and data visualization system, including geomapping. Preliminary data conclusions: 1) Of the 2812 interventional CCTs, the study team mapped 495 therapeutic, interventional, currently enrolling CCTs (after excluding trials for behavioral interventions and palliative care). 2) Of the 10015 zip codes mapped, 58.8% of those were designated as zones of high prevalence (HP) of lung cancer. Of the 5888 HP zip codes, only 10.5% had NSCLC trials and 5.6% percent had SCLC trials. 3) When analyzed by counties, of the 59% of counties with high prevalence of African American patients, only 3% and 1% of counties had more than 10 NSCLC trials and 10 SCLC trials respectively. Similarly, of the 24% of counties with high prevalence of Asian American lung cancer patients, only 3% and 1% of counties had more than 10 NSCLC and 10 SCLC trials respectively. Implications: While additional analyses are ongoing, preliminary findings suggest that there is a major disconnect between US lung CCT placement and where patients live. The advent of precision medicine creates urgency to improve CCT enrollment of racial and ethnic minority groups, for equitable benefit of resulting innovation and access to optimal treatment. Lung cancer prevalence, including by population demographics, at the zip code and county level can be a critical guide to CCT site placement. Citation Format: Upal Basu Roy, Liou Xu, Laura Lee Hall, Gary Puckrein, Andrea Ferris, Jeanne Regnante. Geographic relationship between lung cancer clinical trial sites and patient prevalence and demographics in the Medicare Fee-for-service program [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D081.

Representing cancer clinical trial criteria and attributes using ontologies: An NLP-assisted approach.

e14079 Background: Low patient recruitment is one of the main reasons clinical trials fail. Identifying eligible patients for clinical trials using electric health records (EHRs) can help reach accrual targets. Ontology reasoning implemented in Trial2Patient, a scalable system we developed for matching patient to clinical trials, forms the basis for generating patient cohorts in our system. For efficient cohort definition, an attribute ontology for eligibility criteria and entity categorization is a necessary first step. To meet this requirement, we constructed an ontology platform for lung cancer trials. Methods: We classified 128 non-small cell lung cancer and 38 small cell lung cancer trials into different therapy groups. Among the 166 trials we examined, 110 were immuno-oncology therapy-based, 48 were targeted therapy-based, and 8 were chemotherapy or device trials. We analyzed the eligibility criteria for each trial manually to identify entities from all trials as well as indication specific and further therapy group specific entities. To incorporate a semi-automated, natural language process (NLP)-assisted named entity recognition (NER) into the future cohort definition process, we trained NLP and deep learning models for NER and ontology encoding. Attributes generated from 50 processed NSCLC trials were evaluated with our manually curated attributes. The ontology generated from lung cancer was tested in 74 prostate cancer trials for generalizability. Results: The ontology for lung cancer trials, which is generalizable to prostate cancer and other cancer clinical trials, were constructed. Total 507 attributes were extracted and entities were categorized into 8 groups. Evaluation of attributes generated by NLP and deep learning models compared with manually extracted attributes showed high consistency and accuracy. The average precision, recall and F1 values of 15 most commonly appearing entities (disease, histology, targeted therapy, immunotherapy, radiotherapy, neoadjuvant therapy, age, gender, test, vitals, value, drug, gene, mutation, problem) are 0.873, 0.769, and 0.805, respectively. Conclusions: We contribute to a clinical trial ontology platform for lung cancer and prostate cancer trial recruitment. This ontology platform can be expanded to other solid tumors or hematologic malignancies for clinical trial analysis, and can also be applied to generate synthetic control arm cohorts. We believe NLP-assisted NER can be successfully incorporated for the future work of large scale of clinical trial cohort definition.

Phenotyping clinical trial treatment regimens in cancer: An integrative ontology, artificial intelligence and knowledge engineering approach.

e14054 Background: Matching clinical attributes (i.e. indications, lab tests, treatment regimens) of clinical trial eligibility criteria with real world patient data is extremely challenging. Attribute phenotyping is one of the key components of Trial2Patient, a customized system developed by Sema4 to find patients for clinical trials. Transforming treatment regimens to a standard ontology and encoding drugs with standard nomenclatures will facilitate the semantic retrieval of treatments mentioned in clinical trial criteria. This will also enable the interoperation between different data sources that is often required for fast-learning and scalable healthcare information system. Methods: Free text containing treatment regimen/medication terms were extracted and preprocessed from three sources: 1) clinical trials listed in a commercial database citeline.com, 2) clinical trials listed in clinicaltrials.gov, and 3) National Comprehensive Cancer Network (NCCN) Guidelines. The regimen terms such as neoadjuvant therapy for non-small cell lung cancer, checkpoint inhibitor, EGFR inhibitor, androgen deprivation therapy (ADT), among many others, were profiled by AI methods (i.e. pattern reorganization and rule-based) and knowledge engineering via Sema4’s in-house knowledge base (CAV), Pharmaprojects in citline.com and NCCN Guidelines. The drugs related to each regimen were identified and mapped to RxCUI via RxNorm ontology. Results: We identified 76 regimen terms for non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and prostate cancer (e.g. PD-L1 ≥1% nonsquamous NSCLC, bone antiresorptive therapy for M1 castration resistant prostate cancer), and 14,476 drug-category pair (e.g. pembrolizumab is a PD-1 inhibitor, pembrolizumab is used as the third line and beyond systemic therapy for M1 CRPC). All drugs identified were mapped to RxCUI for real world patient matching. Conclusions: This approach systematically extracted and normalized regimens and medications mentioned in clinical trials in NSCLC, SCLC and prostate cancer to standard codes. These standardized data can be used in mapping treatment histories of a patient to the eligibility criteria for clinical studies or for identifying studies relevant to a patient. The outcome of profiling cancer treatment regimens through standard ontology RxNorm may be particularly valuable in cancer studies based on real-world evidence.

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: a trend over decades

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: a trend over decades

A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS

A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC. In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily. Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies. A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.

P1.12-05 Microenvironment Characterization of Small Cell Lung Cancer Xenografts Implanted in Hematopoietic Humanized Mice

With the high mutational burden seen in small cell lung cancer (SCLC) there is the theoretical potential to improve SCLC outcome through immunotherapy. Recent immunotherapeutic clinical trials in SCLC have demonstrated promising results. However, to better understand the immune response and the potential role of immunotherapy in SCLC, immunocompetent models are needed. To this end, we have applied a hematopoietic humanized mouse model, Hu-CB-BRGS to investigate the mechanisms underlying SCLC immunotherapy and develop novel strategies to improve therapeutic efficacy. BALB/c-Rag2nulllll2rynullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. SCLC flank tumors were initiated in BRGS mice using two characterized SCLC cell lines (CDX) and 1 patient derived xenograft (PDX). Upon verification of human T-cell chimerism in the Hu-CB-BRGS mice, SCLC tumors grown in BRGS mice were engrafted into the flanks of Hu-CB-BRGS mice by trocar transfer. Tumor growth was quantified by twice weekly measurement and harvested on reaching 1200 mm3. At harvest, tumor tissue as well as host immune organs (lymph node, spleen) were collected for immunological assessment. Humanized immune system and tumor were evaluated by flow cytometry and immunohistochemistry (IHC). Flank tumors from two CDX tumors (H82 and H187) and one PDX tumor (LX-95) were successfully developed in the Hu-CB-BRGS mice with take rates averaging 82%. SCLC tumor growth rate in Hu-CB-BRGS mice was comparable to that seen in BRGS mice. Although human T cells were well represented in the lymph nodes and spleens of the Hu-CB-BRGS mice, we detected very few tumor infiltrating immune cells in the engrafted SCLC tumors by IHC and flow cytometry as defined by CD45 and CD3, which is consistent with the observations in SCLC patient tumor tissue. Tumor cells, identified by EpCAM expression, expressed low levels of MHC class I, II and PD-L1. PD-1 was expressed by human T cells found in the lymph nodes and spleen of Hu-CB-BRGS mice, while the SCLC xenografts expressed varying levels. We demonstrate that both SCLC PDX and CDX tumors can be grown in the context of a humanized immune system within mouse recipients. SCLC Hu-CB-BRGS mice demonstrate persistence of human immune cells, including T cells and B cells in the immune organs. The xenograft tumor microenvironment included variable human immune infiltrates. The SCLC Hu-CB-BRGS mouse model may be a valuable preclinical platform for testing human specific immune-oncology therapeutics for SCLC patients.

Abstract 3713: Strong expression of EZH2 and H3K27me3 is associated with poor survival time in small cell lung cancer

Abstract BACKGROUND: Small-cell lung cancer (SCLC) is a highly aggressive neoplasm, characterized by early development of metastasis and very poor clinical outcome. The therapeutic possibilities are limited and poorly changed over the past three decades. Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb repressive complex 2. It is involved in epigenetic gene silencing through the trimethylation of H3K27 and it has been identified as a biomarker of aggressive and highly proliferating tumors, emerging as a potential target for cancer therapy. OBJECTIVE: We aimed to correlate the expression profile of the EZH2 and H3K27me3 proteins in tumor tissues of non-treated SCLC patients with patient's outcome. METHODS: EZH2 and H3K27me3 expression were analyzed by immunohistochemistry in 48 SCLC tumor biopsies. The expression of the markers was quantified in a semi quantitative way and correlated with clinic pathological factors and patients overall survival. To mimic an EZH2 loss, H209 SCLC cells were treated with an EZH2 inhibitor for 48h and the in vivo growth pattern was investigated in the chorioallantoic membrane (CAM) assay. RESULTS: All patients died within one year after diagnosis. There was a heterogeneous expression pattern for EZH2 and H3K27me3. Strong expression of EZH2 and H3K27me3 was observed in appr. 50% of the patients. The Kaplan Meier curve showed a significant association of high expression pattern of EZH2 and shorter overall patient survival time after 12 and 25 weeks of follow up, respectively (p=0.030; p=0.014) Different markers of tumor aggressiveness after EZH2 inhibition were investigated in the CAM model. CONCLUSION: Strong EZH2 and H3K27me3 expression in non-treated SCLC patients was related to worse prognosis. EZH2 inhibitors should be considered in future trials for SCLC. Citation Format: Ana Paula Fernandes, Rita deCassia S Alves, Guilherme Watte, Philipp Kunze, Adriana Vial Roehe, Regine Schneider-Stock. Strong expression of EZH2 and H3K27me3 is associated with poor survival time in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3713.

Non Small Cell Lung Cancer Trial of Durvalumab and Tremelimumab in Advanced Epidermal Growth Factor Receptor (EGFR) Mutant Disease.

Non Small Cell Lung Cancer Trial of Durvalumab and Tremelimumab in Advanced Epidermal Growth Factor Receptor (EGFR) Mutant Disease.

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: A trend over five decades.

e18048 Background: ASCO and Friends of Cancer Research have proposed that cancer clinical trials must ease eligibility criteria to make the trials more generalizable in “real-world” patient populations. The specific items in exclusion criteria included presence of brain metastasis (BM), which is commonly seen in small cell lung cancer patients. Frequency and trend of BM as exclusion criteria in extensive-stage (ES) SCLC trials is unknown. Methods: We conducted a comprehensive search to identify prospective clinical trials in patients with ES-SCLC. Pubmed search was conducted with key words “small cell lung cancer” and “extensive” in title. Websites of 20 oncology journals were also searched by their online archives. Recent review articles in ES-SCLC were also investigated for additional articles. Eligible studies must have enrolled primarily ES-SCLC and been published in English. Studies involving brain/chest radiation and brain metastasis specific trials were excluded. Studies were categorized into allowed/undefined, conditional, or complete exclusion of BM. Chi-squire test was used for categorial group comparison. Results: A total of 491 published studies were identified by Pubmed (240), journal websites (198), and review articles (53). Early publication year (1970-1999) and first-line/maintenance setting were associated with higher incidence of complete exclusion of cases with BM (p &lt; 0.0001, 0.0233, respectively). Studies in the 1990s had the highest incidence (27%) of exclusion. In 2010, only 12% allowed or undefined BM. There is no correlation between complete exclusion of BMs and other clinical characteristics including journal impact factor, region, trial phase, randomization, sample size, patient performance status, and age limit. Conclusions: A significant number of ES-SCLC trials continue to exclude patients with BM. Future studies need to ease eligibility regarding BM according to ASCO/Friends recommendations.[Table: see text]