bluuebunny/crossref_metadata_2025 huggingface dataset:
Benefit of post-operative radiation therapy for incompletely resected stage I-IIIA non-small cell lung cancer: An analysis of the National Cancer Database.
Authors: Iska Sindu , Mohanna Mohamed , Sabbagh Saad , Dominguez Barbara , Itani Mira , Liang Hong , Arteta-Bulos Rafael , Nahleh Zeina A. , Alley Evan W.
Published: June 2023

8558

Background: The presence of micro-residual (R1) or macro-residual (R2) disease in non-small cell lung cancer (NSCLC) is associated with a higher risk of recurrence. The benefits of post-operative radiation therapy (PORT) in incompletely resected NSCLC is not clear. The purpose of this study is to compare median overall survival (mOS) of treatment modalities in the post-operative setting for resected stage I-IIIA NSCLC with residual disease (R1/R2) and to determine if PORT provides benefit in this patient population using the National Cancer Database (NCDB). Methods: From the NCDB dataset for the years of 2006-2016, we extracted patients diagnosed with stage I-IIIA NSCLC and who had incomplete resection with residual disease (R1/R2). Kaplan-Meier analysis was performed to differentiate the effect of different post-operative treatment modalities, concurrent chemo-radiotherapy (CCRT), sequential chemo-radiotherapy (SCRT) and chemotherapy (CT) alone on mOS. Subsequently, univariate Cox regression was used to identify statistically significant variables, then multivariate Cox regression was performed to establish variables that contributed to the survival. Lastly, multinomial logistic regression was utilized to establish association of the independent factors. SAS version 9.4 was used to analyze the data. Results: Among the 2701 patients who met inclusion criteria, the average age was 64.1, 64.8 and 65.9 year old for CCRT, SCRT and CT, respectively. Male's constituted 53.6% and white's were 88.1%, and patient's were distributed equally across clinical stages. The majority of patients received SCRT (51.7%) followed by CT alone (39%), and CCRT (9.2%). There were no statistically significant differences in mOS between the different treatment modalities (p=0.220). Patients with R2 were 177% more likely to receive CCRT than CT compared to R1 (OR 2.77, CI 1.86-4.13 and p<0.001). Male's were 28% more likely to receive SCRT than CT compared to females (OR 1.28, CI 1.08-1.52 and p=0.0041). Nodal involvement was associated with decreased mOS with N2/N3 having 37% lower mOS compared to N0 (HR=1.37, CI 1.19-1.57 and p<0.0001). Patients who had R2 disease had a 38% lower mOS compared to those R1 (HR 1.38%, CI 1.19-1.62, p<0.0001). Conclusions: Despite the risk of unfavorable outcomes for patients with residual disease after surgery for NSCLC, the addition of radiotherapy, either concurrently or sequentially, to CT did not offer statistically significant mOS benefit compared to CT alone. Given the known toxicities of radiation, and the lack of impact on survival, the benefit of post-operative radiation is questionable among patients with residual disease after resection.
Large scale evaluation of pulmonary nodule workup: A real-world study of over 150,000 patients in New York State.
Authors: Velcheti Vamsidhar , Klump Erika , Long Andrew , Green Hadrian , Williams Tessa , Van Vleck Tielman , Wong Hesper , Legg Randall , Apple Jon , Arelli Bobby , Arslan Ilker
Published: June 2023

8559

Background: Around 1.6 million patients in the US annually have a pulmonary nodule (PN) found on imaging. Previous studies suggest 1-12% of PNs represent an underlying malignancy at a potentially curative stage. PNs ≥6mm are considered higher risk. Despite guideline availability, only about one-third of commercially insured patients with a PN receive recommended workup, which may include further investigation via imaging or surgery. In addition, patients and providers may delay workup of PNs identified during COVID-19. We aimed to describe variations in PN workup for different patient demographic and clinical characteristics at 7 healthcare institutions in New York (NY) state. Methods: We used a retrospective cross-sectional design in which structured demographic and unstructured clinical data were used to analyze patient documents from a NY state health information exchange from January 2018 to February 2022. Clinical features were abstracted using a clinical natural language processing platform, CLiX unlock. Results: 58 million documents from 5.5 million unique patients were analyzed. Of the overall 151,436 patients with PNs, workup was found in 47% (71,071). Across institutions, workup ranged between 24% and 52%; 40% (60,749) had evidence of a PN in the upper lung location. We found 52,789 patients (35%) had a maximum PN ≥6mm and of those, 55% (28,958) had a workup (Table). For patients with a PN ≥6mm, workup for non-English speaking patients was 9% lower than for English speaking patients (47% vs 56%), 17% lower for patients 18-44 years than patients 45-90 years (39% vs 56%), 47% lower for patients presenting with a chest injury rather than cancer screening (28% vs 75%), and 9% higher for patients with initial imaging via chest computed tomography (CT) rather than other CT (58% vs 49%). After the start of the COVID-19 pandemic (January 2020), overall workup decreased 3.8% and prevalence of symptoms such as dyspnea and chest pain increased. Conclusions: The descriptive findings of this analysis demonstrate gaps and variations in workup for patients with PNs across different demographics and clinical scenarios. A subsequent project is underway to explore strategies for improvement in adherence to guideline-recommended care to benefit patients by diagnosing lung cancer at an earlier, potentially curative stage. [Table: see text]
Mortality benefit of a blood-based biomarker panel for lung cancer and the PLCO cohort.
Authors: Fahrmann Johannes , Irajizad Ehsan , Ostrin Edwin J. , Vykoukal Jody , Dennison Jennifer , Long James Patrick , Do Kim-Anh , Feng Ziding , Hanash Samir M , Marsh Tracey
Published: June 2023

8560

Background: A 4-protein biomarker panel (4MP) combined with the validated PLCOm2012 clinical risk model has been shown to improve lung cancer risk estimation over either metric alone. We investigated whether these panels in combination could also identify individuals at high risk of harboring a lethal lung cancer. Methods: We used data from an established logistic regression combining the 4MP and the PLCOm2012 risk model, which were assessed in pre-diagnostic sera from 552 lung cancer cases and 2,193 non-cases from the Prostate Lung Colorectal and Ovarian (PLCO) cohort. Of the 552 lung cancer cases, 387 (70%) died from lung cancer. Cumulative incidence of lung cancer death as well as sub-distributional and cause-specific hazard ratios were calculated based on 4MP+PLCOm2012 risk scores at a pre-defined 1.0% and 1.7% 6-year risk thresholds, which correspond to the 2013 and 2021 US Preventive Services Task Force lung cancer screening criteria, respectively. Results: When considering cases diagnosed within 1 year of blood draw and all non-cases, the AUC estimate of the 4MP+PLCOm2012 model for risk prediction of lung cancer death was 0.88 (95% CI: 0.86-0.90). Among cases, the cumulative incidence of lung cancer death was statistically significantly higher in individuals with 4MP+PLCOm2012 scores above the 1.0% 6-year risk threshold (modified χ2: 5.42, P: 0.02). Corresponding sub-distributional and lung cancer death-specific hazard ratios for test-positive cases were 1.69 (95% CI: 1.07-2.66) and 1.80 (95% CI: 1.15-2.82), respectively. Conclusions: The blood-based biomarker panel in combination with PLCOm2012 identifies individuals at high risk of a lethal lung cancer.
Impact of SARS-COV2 infection on the clinical outcomes in patients with lung cancer compared to all other cancers.
Authors: Deenadayalan Vaishali , Dasgupta Mona , Baloch Ali Shahbaz , Swarna Siri Chandana , Kim Junglee , Gupta Shweta
Published: June 2023

8562

Background: The outbreak of 2019 Novel coronavirus disease (COVID) has led to various deleterious outcomes in cancer patients. Those with lung cancer were noted to have increased morbidity and mortality when infected with COVID. We aimed to study the outcomes of COVID infection in patients with lung cancer compared to those with all other types of cancer. Methods: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database-2020 was queried to identify all COVID patients with lung cancer and those with all other types of cancer excluding lung cancer. The groups were compared for socio-demographic differences, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included a diagnosis of thrombocytopenia (TCP), Acute Respiratory Failure (ARF), sepsis, anemia, pancytopenia and shock. Statistics were performed using t-test, univariate and multinomial logistic regression. Results: A total 1,050,045 COVID-19 admissions in cancer patients were identified, of which 4,625 (8.7%) had lung cancer whereas 48,840 (91.3%) had other types of cancer other than lung cancer. Lung cancer patients were older (Mean age 72 vs 69 years, p < 0.01). There was a higher prevalence of lung cancer compared to other cancers in whites (71 vs 58%, p < 0.01), hispanics had a lesser prevalence of lung cancer (7 vs 17%, p < 0.01). Lung cancer patients has a higher Charlson Comorbidity burden ( > 2) compared to other cancers (91 vs 62%, p < 0.01). Lung cancer patients were less likely to have private insurance (14 vs 22%, p < 0.01). Among the comorbidity burden, lung cancer patients had a higher rate of dyslipidemia, COPD, Coronary artery disease, Smoking, venous thromboembolism (p < 0.05). A total of 8,135 cancer patients who were admitted with COVID died, among them 970 (11.9%) had lung cancer and 7,165 (88.1%) had other types of cancer making up 21% of all lung cancer admissions that died compared to 14.7% other cancer admissions (p < 0.05). On multivariate regression analysis, after adjusting for confounders those with lung cancer had a higher odds of all-cause mortality (aOR 1.37; 95% CI: 1.13-1.67,p = 0.002). Among lung cancer patients, adjusted LOS was reduced by 0.6 days (95% CI: -1.2 to -0.1, p = 0.017) and adjusted THC was decreased by $11,977 (95% CI: -19,010 to -4,943, p = 0.001). Among the secondary outcomes, lung cancer patients had lower rates of thrombocytopenia (6.5 vs 8.8%, p = 0.01) and anaemia (34.4 vs 38.5%, p = 0.02) compared to other cancer types. Conclusions: COVID-19 infection led to increased mortality in lung cancer patients compared to those with other types of cancer. The lower healthcare utilization was likely due to early mortality in the lung cancer cohort. This study calls attention to the increased vulnerability of lung cancer patients to the SARS COV2 infection than other cancer types.
Reevaluating the role of adjuvant chemotherapy in early-stage, resectable NSCLC with high-risk clinical and pathologic features.
Authors: Heiden Brendan , Eaton Daniel B. , Chang Su-Hsin , Yan Yan , Schoen Martin W. , Thomas Theodore Seth , Meyers Bryan F. , Kozower Benjamin D. , Puri Varun
Published: June 2023

8572

Background: The preferred treatment for early-stage non-small cell lung cancer remains surgical resection with the consideration of adjuvant chemotherapy for tumors with certain high-risk features. It is commonly cited that such treatments confer a meager 5% 5-year survival benefit compared to observation alone. We sought to reassess the benefit of adjuvant chemotherapy using modern, real-world datasets. Methods: We performed a retrospective cohort study using a dataset from the National Cancer Database. All patients with early-stage stage NSCLC (3-5cm, node-negative) who would be eligible for adjuvant chemotherapy based on National Comprehensive Cancer Network guidelines were included (i.e., presence of at least 1 high-risk feature). High-risk clinical and pathologic features were defined as poor differentiation, tumor size (≥4cm), non-anatomic wedge resection, inadequate lymph node evaluation, vascular invasion, and visceral pleural involvement. We employed average treatment effect on the treated (ATT) weighting to match patients with similar demographic, tumor, and treatment-related variables to compare outcomes between chemotherapy versus observation groups. The primary outcome was overall survival. These findings were further validated in an independent cohort from the US Veteran Health Administration (VHA). Results: The study included 10,812 patients with early-stage NSCLC who had at least 1 high-risk feature. The frequencies of high-risk features were as follows: tumor size ≥4cm (n = 3,271, 30.3%), poor differentiation (n = 9,454, 87.4%), visceral-pleural invasion (n = 2,542, 23.5%), vascular invasion (n = 1,742, 16.11%), non-anatomic wedge resection (n = 781, 7.2%), and inadequate nodal sampling (n = 6,306, 58.3%). Despite the presence of high-risk features, only 1,427 (13.2%) patients received adjuvant chemotherapy. In the ATT weighted analysis, 1,261 (49.7%) patients received adjuvant chemotherapy and 1,278 (50.3%) patients received observation. The 5-year overall survival was 70.0% (95% CI 67.1-72.7) in the chemotherapy group versus 62.0% (95% CI 60.2-63.7%) in the observation group (absolute 5-year survival difference 8.0%). In the VHA cohort, 11.3% of patients received adjuvant chemotherapy. Similarly, the 5-year overall survival was 64.0% (95% CI 51.4-74.2) in the chemotherapy group versus 56.2% (95% CI 48.3-63.4) in the observation group (absolute 5-year survival difference 7.8%). Conclusions: These data suggest a notably larger benefit of adjuvant chemotherapy in eligible patients with high-risk clinical pathologic features compared to commonly cited statistics. With the addition of more robust treatment options in early-stage disease, adherence to adjuvant and neoadjuvant treatment guidelines may disproportionately improve early-stage NSCLC outcomes following curative-intent resection.
Association of single-click radiomic classifier with response and prognosis in non-small cell lung cancers (NSCLC) treated with immune checkpoint inhibitors.
Authors: Hiremath Amogh , Li Haojia , Clement Allison , Gupta Amit , Velcheti Vamsidhar , Mababhushi Anant , Braman Nathaniel
Published: June 2023

8574

Background: Radiomics has shown promise to non-invasively phenotype disease and address the limitations of extant biomarkers (e.g. PD for immune checkpoint inhibitors (ICI) in cancers, such as NSCLC. However, considerable barriers to the clinical adoption of these tools remain, such as their dependence on precise annotation of tumor extent by experienced clinical users. Here, we demonstrate a radiomic solution that requires only a single user mouse click within one or more target lesions on a baseline CT scan, to contour tumors in 3D and generate a patient-level radiomic prediction of response and outcome in ICI treated NSCLC patients. Methods: 1778 CT scans from 1261 patients were used to develop and validate an interactive, semi-automated tool for predicting ICI outcomes in NSCLC patients prior to therapy. A user click based deep learning contouring model was trained and validated on 1146 patients, then used to create annotations for radiomic analysis. A least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model was utilized to select features associated with post-ICI overall survival (OS) and derive a radiomic risk score within a training cohort (n=74) that can separate patients into high and low risk groups. The model was tested on held out pre-treatment CTs of 41 ICI recipients from 2 institutions for association with OS, progression-free survival (PFS), and objective response (OR). Results: A total of 77 lesions were identified and segmented within the testing set. Average volume per lesion was 54.10 mL and per patient was 101.60 mL. OR was observed in 48.70% of patients. A threshold of -0.31 defining high and low radiomic risk groups was chosen based on optimal separation within the training set (HR=2.59 [95% 1.48~4.50], p=0.0009). Radiomic risk groups significantly stratified patients by OS (C-index=0.64, HR=3.03 [95% 1.15~8.02], p=0.03) and PFS (C-index=0.59, HR=3.20 [95% 1.13~9.10], p=0.03). Radiomic IO risk group was independently prognostic of clinical variables (Table 1) and further predicted ICI response with AUC=0.74 [95% 0.71-0.78]. Conclusions: From a single click in target lesions, our model was able to predict response and prognosis of ICI recipients from a baseline radiology scan. Additional multi-site validation and prospective evaluation will assess the value of the radiomics classifier as a decision support tool in the clinic. [Table: see text]
A theranostic approach: Imaging and therapy of delta-like ligand 3–expressing small cell lung cancers.
Authors: Tendler Salomon , Hoang Tran T , Bauer David , Korsen Joshua , Michel Alexa , Degregorio Roberto , Carter Lukas , Pillarsetty Nagavarakishore , Poirier John T. , Lewis Jason Stuart , Rudin Charles M.
Published: June 2023

8575

Background: Small cell lung cancer (SCLC) is a highly radiosensitive tumor, with selective cell surface expression of the inhibitory Notch ligand Delta-like ligand 3 (DLL3). This facilitates targeted radionuclide therapy accompanied by complementary imaging agents to evaluate and monitor disease progression. The project aims to identify the next generation of DLL3-targeting radioimmunoconjugates to improve the clinical outcome for SCLC patients. Methods: In collaboration with the Tri-Institutional Therapeutics Discovery Institute, we screened and assessed >100 humanized antibodies for their binding affinities, internalization rates, and other pharmacodynamic properties. Here, we present data on two leading candidates (mAb1 and mAb2) holding highest promise in both imaging and therapy studies conducted in DLL3-expressing SCLC tumors. For in vivo imaging, antibodies were radiolabeled with Zirconium-89 (89Zr), which allows for immuno-positron emission tomography (immunoPET). Therapeutic studies were performed with the same antibodies conjugated with Lutetium-177 (177Lu). Human SCLC NCI-H82 xenografts were implanted in nude athymic female mice. ImmunoPET scans were acquired during multiple time points post-injection of the imaging agent, and terminal biodistribution analysis was performed. Treatment studies included administration of 400 and 600 Ci 177Lu-conjugated antibodies in cohorts of mice, with appropriate positive and negative controls. Results: Both lead antibodies demonstrated efficient radioconjugation with either isotope. ImmunoPET imaging utilizing 89Zr showed specific high-level tumor uptake for both clones with low background in non-tumor organs. Ex vivo gamma counting biodistribution analysis, performed 120 hours post-injection, confirmed these findings. Dosimetry estimates suggested a similar therapeutic index between the two clones, with the bone marrow being the dose-limiting organ. Preliminary results from therapy studies demonstrate a statistically significant (p <0.05) prolonged overall survival for the experimental arms compared to controls, and include durable tumor responses. As expected for radionuclide therapy, transient hematologic suppression was observed within 7-10 days after the beginning of the treatment, with normalization of blood cell counts for all groups within three weeks. Conclusions: This study highlights the promise held by novel DLL3-direct radioimmunoconjugates as a diagnostic tracer, prognostic biomarker, and therapeutic agent. Both lead candidates appear promising for translation as both imaging and therapeutic agents for patients with SCLC.
Reconsidering the cutoff between sensitive and refractory relapses in extensive-stage small cell lung cancer in the era of immunotherapy.
Authors: Torasawa Masahiro , Horinouchi Hidehito , Nomura Shogo , Igawa Satoshi , Asai Maiko , Ishii Hidenobu , Wakui Hiroshi , Ushio Ryota , Asao Tetsuhiko , Namba Yukiko , Koyama Ryo , Katayama Isana , Matsuda Hironari , Sasaki Shinichi , Takahashi Kazuhisa , Hosomi Yukio , Naoki Katsuhiko , Ohe Yuichiro
Published: June 2023

8576

Background: The use of platinum-based doublet chemotherapy combined with immune checkpoint inhibitors (ICIs) has demonstrated promising outcomes in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Relapsed SCLC has been classified into "sensitive" or "refractory" relapse types according to cutoff values (60 or 90 days) of duration from the last chemotherapy administration to disease progression. However, it is unclear whether these cutoff values can be applied to ICI combination therapy. Methods: We retrospectively analyzed a multicenter database of ES-SCLC patients who received second-line therapy after the platinum-etoposide plus ICI (atezolizumab or durvalumab). An optimal cutoff value for the platinum-free interval (PFI) was selected, which minimized the two-sided p-value and maximized hazard ratio (HR) regarding relapse type (sensitive or refractory according to a cutoff value) calculated from a multivariable Cox regression model for overall survival (OS) including performance status (PS) and sex as covariates. The internal validity of the selected cutoff value was assessed via two-fold cross-validation (CV) manner. Results: A total of 101 patients (61 deaths) from 10 hospitals were included in the study. The median follow-up period was 21.1 months. The optimal cutoff value was 75 days (p=0.0002), and when applying this cutoff value, median OS was 15.9 and 5.0 months of sensitive- (n=51) and refractory- (n=50) relapsed patients, and the HR calculated from a two-fold CV was 3.13 (95% confidence interval [CI], 1.66 to 5.90). Additionally, traditional cutoff values of 60 and 90 days also predicted prognosis better, but cutoff values of 110 days or longer did not (Table). Conclusions: Even in the era of combined immunotherapy in ES-SCLC patients, the threshold days for classifying as sensitive- or refractory- relapse did not exhibit a significant change compared to the pre-immunotherapy era. Although further validation studies with a larger sample size would be needed, relapse type classification using the selected cutoff value of 75 days is worth considering as a new prognostic factor for relapsed ES-SCLC patients. [Table: see text]
Characteristics and outcomes of patients with small cell lung cancer (SCLC) detected with CT screening at a single health system.
Authors: Godbole Manasi Manoj , Li Pin , Wani Kashmira , Meranda Matthew , Simoff Michael J. , Gadgeel Shirish M.
Published: June 2023

8581

Background: At diagnosis, the majority of SCLC patients have extensive-stage disease, and their median survival is only 13 months, even with the addition of checkpoint inhibitors. Previous CT screening trials did not reveal reduction in mortality for SCLC patients. The aim of our study was to analyze the baseline characteristics and clinical outcomes of SCLC patients diagnosed with low-dose CT scan as a part of lung cancer screening program. Methods: A retrospective chart review-based study of SCLC patients diagnosed clinically or by lung cancer screening between January 2018 and June 2022 at the Henry Ford Health System was conducted. Baseline characteristics, details of SCLC diagnosis and treatment, and outcome were recorded. Statistical analysis was performed using Chi-squared test, T-test and log-rank test. Results: Of the 258 patients who met eligibility criteria, 34 were diagnosed by lung cancer screening. Patients diagnosed with screening tended to be older (mean age- 70.5 years vs. 67.3 years, p=0.010). There were no differences in gender distribution, race and smoking status. Mean smoking history was 43 pack-years in both groups. Among screen-detected patients, 73.5% had limited-stage disease compared to 36.6% among clinically detected patients (p<0.001). No significant difference in the presence of brain metastases at diagnosis was observed. Among screen-detected patients, 97.1% received any therapy compared to 85.3% among the clinically detected patients (p=0.105). Overall survival (OS) was significantly better in screen-detected patients, with a 3-year survival rate of 45.5% vs. 17% (p=0.00027). By multivariable analysis, OS was better in screen-detected patients (HR=0.37, 95% CI 0.20-0.68; p=0.001) (Table). There was no significant difference in progression-free survival between the groups. Conclusions: Our results demonstrate that SCLC patients diagnosed through the lung cancer screening program have better overall survival rates than those diagnosed clinically. These results suggest that developing appropriate screening measures may impact SCLC-related mortality. [Table: see text]
Tarlatamab in small cell lung cancer (SCLC): Safety and efficacy analyzed by baseline brain metastasis.
Authors: Champiat Stephane , Boyer Michael J. , Govindan Ramaswamy , Paz-Ares Luis G. , Owonikoko Taofeek K. , Borghaei Hossein , Izumi Hiroki , Steeghs Neeltje , Blackhall Fiona Helen , Terbuch Angelika , Johnson Melissa Lynne , Yoshida Tatsuya , He Kai , Zhang Yuyang , Jones Simon , Chen Xi , Martinez Pablo , Hummel Horst-Dieter
Published: June 2023

8582

Background: Tarlatamab, a BiTE molecule targeting DLL3 and CD3, is being studied in patients (pts) with extensive stage small cell lung cancer (ES-SCLC).1 Up to 25% of pts diagnosed with SCLC have brain metastases (BM) and 50% or more will develop BM during the course of the disease. Pts with ES-SCLC and BM have poor prognosis and quality of life. We analyzed the characteristics and outcomes of pts included in the tarlatamab phase 1 study (NCT03319940) who had baseline BM vs those who did not. Methods: Pts included in the phase 1 trial had SCLC that progressed after ≥1 platinum-based regimen and received tarlatamab (0.003–100 mg IV). Pts with treated BM were eligible if local therapy was delivered ≥ 2 weeks prior to first tarlatamab dose. Results: As of 03 January 2023, 192 pts had received tarlatamab as monotherapy. Median age was 62 (range, 32–80) y; 188 pts (98%) had ECOG PS 0–1 and median prior therapy lines was 2 (range, 1–6), with 107 pts (56%) receiving prior anti-PD1/PD-L1. 48 pts (25%) had BM at screening and 142 (74%) did not (No BM); data was missing for 2 pts (1%). Pts with BM were more likely to have received > 3 prior lines of therapy (BM, 29%; No BM, 9%) and have a record of prior brain radiation (BM, 85%; No BM, 40%); otherwise, characteristics of pts with BM were generally similar to those without. Tarlatamab delivered comparable activity in pts with BM vs. those without in terms of objective response rate (ORR; 20%, 25%) and disease control rate (DCR; 59%, 50%) (Table). Median duration of response (DoR) was 14.9 months (BM) vs. 13.0 months (no BM). Median overall survival (OS) was 13.2 months in the BM group vs 15.5 months in the no BM group. Safety outcomes were similar in terms of treatment-related AEs (TRAEs; BM, 90%; No BM, 94%) and grade (gr) ≥ 3 (BM, 38%; No BM, 39%). Groups were also comparable with respect to immune effector cell-associated neurotoxicity syndrome (ICANS) and associated neurologic events (any-grade, 6% vs 9%; gr ≥ 3, 4% vs 4%) and neutropenia (any-grade, 10% vs 15%; gr ≥ 3, 8% vs 8%). AEs numerically different in the BM vs No BM group included gr ≥ 4 TRAEs (17%, 7%) and any-grade CRS (67%, 54%). The only grade 5 TRAE (pneumonitis) occurred in the BM group. Conclusions: Tarlatamab continues to show promising efficacy and is generally safe in pts with ES SCLC irrespective of the presence of BM. Rates of ICANS and associated neurologic AEs were comparable between those with and without BM at baseline. Reference: 1. Paz-Ares L, et al. J Clin Oncol. DOI:10.1200/JCO.22.02823. Clinical trial information: NCT03319940 . [Table: see text]
Phase Ib/IIa study assessing the safety and efficacy of AL8326 monotherapy in patients with ≥3rd line small cell lung cancer (SCLC) treatment.
Authors: Zhang Xiaochun , Li Xingya , Bi Minghong , Su Chunxia , Fang Yong , WANG Zibing , Yuan Ying , Du Xiuping , Lv Tangfeng , Li Yingyin
Published: June 2023

8585

Background: AL8326 is a novel, orally administered, small molecule tyrosine kinase inhibitor (TKI). The primary objective of this Phase Ib/IIa study is to evaluate the safety and efficacy of AL8326 monotherapy in patients with ≥3rd line small cell lung cancer (SCLC) treatment. Methods: Patients with a diagnosis of small cell lung cancer either limited or extended stage requiring third or further line treatment were eligible for enrollment. The regimen was a 28-day cycle with oral AL8326 administered at 60 mg once per day via RECISIT1.1 evaluation until disease progression (PD), or intolerable toxicity or any other reason discontinuations. Results: At the cut-off date Nov 30, 2022, total n = 30 patients were enrolled. The objective response rate (ORR) was 20% (6/30) (4 confirmed). The disease control rate (DCR) was 56.7% (17/30). Median progression-free survival (PFS) was 3.65 months (95% CI: 1.9 – 5.5) and median overall survival (OS) was 10.42 months (95% CI: 5.4, NE). The median duration of response (DOR) was 5.6months. All 30 subjects had reported AE at least once. Common treatment emergent adverse events (TEAE) were similar to other TKI drug and included (incidence ≥20%): thyroid stimulating hormone (TSH) increase (46.67%), proteinuria (43.33%), weight loss (40.00%), hypertension (36.67%), thrombocytopenia (33.33%), diarrhea (33.33%), positive fecal occult blood (30.00%), hypercholesterolemia (26.67%), hypertriglyceridemia (26.67%), hand- foot syndrome (HFS) (20.00%), loss of appetite (20.00%). Most of these AEs were grade 1-2 (CTCAE V5.0). Conclusions: AL8326 has demonstrated acceptable tolerability and positive efficacy on small cell lung cancer treatment. A US Phase 2 (NCT05363280) study is ongoing and a phase 3 study is in preparation. Clinical trial information: NCT04890795 .
Tumor microenvironment-mediated immune profiles and efficacy of platinum doublet chemotherapy plus ICIs stratified by DLL3 expression in small cell lung cancer.
Authors: Shirasawa Masayuki , Yoshida Tatsuya , Shiraishi Kouya , Yagishita Shigehiro , Matsumoto Yuji , Masuda Ken , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Naoki Katsuhiko , Tsuchida Takaaki , Hamamoto Ryuji , Yamamoto Noboru , Motoi Noriko , Kohno Takashi , Watanabe Shun-ichi , Ohe Yuichiro
Published: June 2023

8586

Background: Delta-like ligand 3 (DLL3) frequently expressed in small cell lung cancer (SCLC) and has been emerged as a therapeutic target. However, it remains unclear how DLL3 expression status affects tumor microenvironment (TME)-mediated immune profiles and clinical outcomes of platinum doublet chemotherapy plus ICIs in SCLC patients. Methods: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC, and extensive-stage (ES)-SCLC patients treated with platinum and etoposide (PE) plus anti-PD-L1 antibody. In LS-SCLC cohort, the transcriptome and whole-exome sequencing (WES) analysis were performed to assess the immune profiles, mutation status and neoantigen status. In ES-SCLC cohort, the association between the efficacy of immunochemotherapy and DLL3 expression by transcriptome analysis were evaluated. Results: Fifty-nine and 17 patients were included in the LS- and ES-SCLC cohort, respectively. In LS-SCLC cohort (n = 59), WES analysis revealed that SCLC with DLL3High had a significantly higher number of neoantigens (77 [95% confidence interval [CI] 65-113 ] vs. 48 [95% CI 17-58], p = 0.004), and a significantly higher rate of signature SBS4 associated with smoking (43% [95% CI 28-53] vs. 28% [95% CI 15-36], p = 0.02), although TMB did not differ according to DLL expression (6.6 mut/Mb [95% CI 5.3-9.6] vs. 6.5 mut/Mb [95% CI 5.2-9.9], p = 0.26). The transcriptome analysis in LS-SCLC cohort revealed that SCLC with DLL3High tumors had significantly suppressed immune-related pathways (IFN-γ response, inflammatory response, and TNFα signaling via nfkb), and dendritic cells (DC) function (DC Differentiation, DC Antigen Processing and Presentation, DC Migration). Profiling tumor infiltrating immune cells with CIBERSORT showed that SCLC with DLL3High had significantly lower proportions of T-cells, macrophages, and DCs compared with those with DLL3low. These results suggested that DLL3High tumors suppressed tumor immunity by inhibiting antigen-presenting function. In ES-SCLC cohort (n = 17), the PFS of PE plus anti-PD-L1 antibody in patients with DLL3High was significantly worse than those in patients with DLL3Low (4.1 months [95% CI, 2.0-6.3] vs. 7.4 months [95% CI, 2.5-12.3]; HR 3.78 [95% CI, 1.1-12.5], p = 0.03). Conclusions: SCLC with high DLL3 expression was characterized by resistance to immunochemotherapy due to suppressed tumor immunity, although those tumors had higher neoantigen loads.
Dissecting small cell lung cancer subtypes with cell-free DNA fragmentomes.
Authors: Rinaldi Lorenzo , Skidmore Zachary L. , Alipanahi Bahar , Graham Garrett , Chesnick Bryan , Takahashi Nobuyuki , Kumar Rajesh , Goyal Shubhank , Abel Melissa Lauren , Malin Justin , Desai Parth Anil , Dracopoli Nicholas C. , Velculescu Victor E. , Thomas Anish , Leal Alessandro
Published: June 2023

8592

Background: Although small cell lung cancer (SCLC) is managed as a single cancer type, new evidence supports that subtypes (high vs low neuroendocrine) of SCLC acquire diverse transcriptional and epigenetic states. Furthermore, distinct SCLC subtypes acquire unique therapeutic vulnerabilities, such as the low-neuroendocrine highly inflamed SCLC subtype that has been linked to immunotherapy sensitivity. We have previously shown that DELFI (DNA evaluation of fragments for early interception) can be used to non-invasively distinguish SCLC from non-small cell lung cancer (NSCLC). Here, we report a preliminary analysis of using the DELFI approach for distinguishing among SCLC subtypes. Methods: Circulating cell-free DNA (cfDNA) was isolated from plasma samples of patients diagnosed with relapsed SCLC and treated with durvalumab plus olaparib in a phase II trial (NCT02484404). Over 200 cfDNA libraries were prepared for whole genome sequencing in batches with internal controls. To infer tumor gene expression profiles in cfDNA, we investigated genome-wide signals of tissue-specific transcription factors differentially regulated in SCLC, and applied a novel DELFI-based approach to inform SCLC molecular subtypes. Clinical information, patient-matched tissue transcriptome (RNA-seq), and chromatin accessibility data (ATAC-seq) were examined in orthogonal analyses. Results: The DELFI classifier detected SCLC cases (N = 47) with a median DELFI score of 1.0 (95% CI 0.99-1), significantly higher than previously reported scores for other lung cancer subtypes. Comparison of DELFI fragmentome signals to publicly available tumor transcriptomes shows subtype-level concordance ( r = 0.78, p < 0.001, Pearson), particularly in pre-treatment SCLC cases separating high- vs low- neuroendocrine subtypes. High-neuroendocrine SCLCs exhibited a decrease in aggregate cfDNA fragment coverage at ASCL1 transcription factor binding sites relative to low-neuroendocrine SCLCs (r = 0.90, p < 0.001, Pearson). Additionally, low-neuroendocrine SCLCs revealed a significant decrease in aggregate cfDNA fragment coverage at genomic binding sites regulated by hematopoietic transcription factors, reflecting the inflamed phenotype of this SCLC subtype. Integration of these approaches provided a cfDNA fragmentation-based machine learning model that distinguished SCLC subtypes with high performance. Conclusions: Genome-wide cfDNA fragmentome analyses can differentiate high- and low-neuroendocrine SCLC subtypes. Given the challenges for performing SCLC biopsies in a clinical setting, we believe this approach could be a viable method of subtyping SCLC in a non-invasive manner.
Brain metastasis burden and management in small cell lung cancer: An analysis of 8705 patients.
Authors: Gaebe Karolina , Erickson Anders W. , Leighl Natasha B. , Chan Kelvin K. , Lok Benjamin H. , Das Sunit
Published: June 2023

8596

Background: Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for intracranial metastatic disease (IMD), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. These patients traditionally receive whole brain radiation therapy (WBRT) for IMD, however, a recent systematic review has indicated that OS following stereotactic radiosurgery (SRS) may be non-inferior compared with WBRT. We aim to describe the clinical characteristics and outcomes of patients with SCLC and IMD in Ontario, Canada. Methods: We included all patients diagnosed with SCLC between April 2007 and March 2018 identified through a provincial health administrative database. Information on patient and treatment characteristics, incidence and time to IMD, and OS from time of SCLC diagnosis were collected and analyzed using R. Results: A total of 8705 patients were included. Median age was 68 years (range 18-103). Most patients presented with extensive disease (n = 5625) and were diagnosed after 2011 (n = 5768). Patients who received chemotherapy (n = 5563) had significantly longer OS than those who did not (median 10.64 vs 1.58 months (mo), hazard ratio (HR) 0.36, 95% confidence interval (CI) 0.34-0.37). 6662 patients received brain imaging at the time of primary diagnosis (CT: 5126, MRI: 1536), and 88% of patients surviving longer than 6 mo received more than one follow-up brain scan. 31% developed IMD (synchronous: 1175, asynchronous: 1511) with median intracranial progression-free survival of 5.65 mo. Median OS of patients with IMD was 9.76 mo, 29 and 1300 received SRS and WBRT as first treatment for their IMD, respectively. OS was in favour of SRS over WBRT (median 20.47 vs 8.74 mo, HR 0.57, 95% CI 0.39-0.84), which remained significant in multivariate analysis (p < 0.001). Conclusions: OS for patients with SCLC remains poor, and many patients present with IMD. With careful selection, patients with SCLC may benefit from SRS treatment.
Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results.
Authors: Wang Mengzhao , Fan Yun , Sun Meili , Wang Yongsheng , Zhao Yanqiu , Jin Bo , Hu Ying , Han Zhigang , Song Xia , Liu Anwen , Tang Kejing , Cuimin Ding , Liang Li , Wu Lin , Gao Junzhen , Wang Jianghong , Cheng Ying , Zhou Jianying , He Yong , Zheng Li
Published: June 2023

9002

Background: Sunvozertinib(DZD9008) is a rationally designed selective, irreversible EGFR exon20 insertion (exon20ins) inhibitor with wild-type EGFR selectivity. Here we reported the results of WU-KONG6, the first pivotal study of sunvozertinib in previously treated NSCLC patients with EGFR exon20ins. Methods: WU-KONG6 (NCT05712902 and CTR20211009) is a phase II, multi-center pivotal study in NSCLC patients with EGFR exon20ins, whose diseases had progressed on or were after platinum-based chemotherapy. Tumor tissue EGFR exon20ins status was tested by local or central laboratory. The primary and key secondary endpoint were objective response rate (ORR) and duration of response (DoR), respectively, assessed by Blinded Independent Central Review (BICR). Patients received 300 mg sunvozertinib once daily until discontinuation criteria were met. Results: Between July 19, 2021, and May 6, 2022, a total of 104 Chinese patients were enrolled into WU-KONG6 study. The efficacy analysis set included 97 patients, whose EGFR exon20ins status was retrospectively confirmed by a central laboratory. A total of 30 different exon20ins subtypes were enrolled. The median age was 58 years; 59.8% (58/97) were female; 95.9% (93/97) were adenocarcinoma; 95.9% (93/97) had metastatic diseases at study entry; 32% (31/97) had baseline brain metastasis; the median prior lines of therapy were 2. By the data cutoff date (October 17, 2022), the BICR assessed confirmed ORR (cORR) was 60.8% (59/97). In patients with baseline brain metastasis, the cORR was 48.5% (15/31). Anti-tumor efficacy was observed irrespective of age, gender, smoking status, prior lines of therapies, prior onco-immunotherapies, mutation subtypes, and baseline brain metastasis. By the data cut-off date, median follow-up time for responders was 7.1 months, and 64.4% (38/59) of responders were still responding. The longest DoR was > 11 months, and the median DoR has not been reached. The safety analysis set included all enrolled 104 patients. The most common treatment emergent adverse events (TEAEs) were similar as what have been previously reported for sunvozertinib, and also similar as that of other EGFR inhibitors. Majority of the TEAEs were grade 1 or 2, and clinically manageable. Conclusions: The first pivotal study results confirmed sunvozertinib’s superior anti-tumor efficacy than the current available therapy for NSCLC with EGFR exon20ins. The safety profile from WU-KONG6 study was consistent with previously reported findings. The updated data will be presented at the meeting. A multinational phase II pivotal study (WU-KONG1, NCT03974022) with the same study design is ongoing in the USA, Australia, and countries/regions in Asia, Europe and South America. Clinical trial information: NCT05712902 .
Intracranial and systemic efficacy of repotrectinib in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC) and central nervous system metastases (CNS mets) in the phase 1/2 TRIDENT-1.
Authors: Lin Jessica Jiyeong , Drilon Alexander E. , Cho Byoung Chul , Felip Enriqueta , De Langen Adrianus , Yang Nong , Kim Sang-We , Lu Shun , Kao Steven Chuan-Hao , Velcheti Vamsidhar , MORO SIBILOT Denis Lucien , Solomon Benjamin J. , Dziadziuszko Rafal , Krebs Matthew G , Cheema Parneet Kaur , Dooms Christophe Alfons , Stopatschinskaja Shanna , Trone Denise , Ades Felipe , Camidge D. Ross
Published: June 2023

9017

Background: Repotrectinib is a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI) that has demonstrated durable activity with a manageable safety profile in TKI-naïve and TKI-pretreated patients (pts) with advanced ROS1+ NSCLC. We report the first analysis of outcomes on repotrectinib in pts with ROS1+ NSCLC by baseline (BL) CNS met status in the global pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: ROS1 TKI-naïve, 1 ROS1 TKI and no chemotherapy (chemo), 1 ROS1 TKI and 1 platinum-based chemo, and 2 ROS1 TKIs and no chemo. Treated or untreated asymptomatic CNS mets were permitted. Brain scans were mandated for all pts in phase 2 at screening and at protocol-specified intervals until progression. Endpoints included confirmed objective response rate (cORR) and duration of response (DOR) by blinded independent central review (BICR; RECIST v1.1); intracranial ORR (icORR) in pts with measurable brain mets at BL by BICR per mRECIST v1.1; and safety. Results: In pts with BL measurable CNS mets who were TKI-naïve (n = 8) and in those with 1 TKI and no chemo (n = 12), icORR (95% CI) was 88% (47-100) and 42% (15-72), respectively. At data cutoff (June 20, 2022), 0 of 7 responders in the TKI-naïve cohort and 2 of 5 in the cohort with 1 prior TKI and no chemo had intracranial progression or death; intracranial DOR range was 1.9-14.8+ mo (TKI-naïve) and 3.0-11.1+ mo (1 TKI and no chemo), with 86% and 80% of pts with an intracranial response remaining on treatment, respectively. Median follow-up and systemic response by CNS met status are shown in the Table. In pts with ROS1+ NSCLC with (n = 118) or without (n = 178) CNS mets, most common any-grade neurologic treatment-emergent adverse events were dizziness (57% / 63%), dysgeusia (42% / 53%), paresthesia (32% / 34%), headache (27% / 12%), ataxia (17% / 22%), and memory impairment (14% / 10%). Conclusions: In TRIDENT-1, repotrectinib showed durable clinical activity in ROS1 TKI-naïve and -pretreated pts with or without BL CNS mets, including intracranial responses. Repotrectinib safety profile was similar in pts with ROS1+ NSCLC with or without CNS mets. Clinical trial information: NCT03093116 . [Table: see text]
Real-world testing and treatment patterns among patients with stage IV non-small cell lung cancer: A retrospective observational study.
Authors: Scott Jeffrey A. , Katzen Harvey I. , Lennerz Jochen K , Johnson Melissa Lynne , Gordan Lucio N. , Dumanois Robert H , Quagliata Luca , Ritterhouse Lauren , Cappuzzo Federico , Vasudevan Anupama , Sura Teena , English Sandy , Wang Brandon , Varughese Prateesh , Choksi Rushir J.
Published: June 2023

9030

Background: Guidelines (NCCN, CAP/IASLC/AMP) recommend clinical molecular testing of patients with advanced NSCLC to inform therapy decisions. We investigated the testing and treatment patterns of patients with stage 4 NSCLC treated in the real-world setting. Methods: This retrospective observational study included de-identified stage 4 NSCLC patients from the Integra Connect PrecisionQ database (ICD) enriched with information obtained by curation. Patients with a positive mutation for EGFR, ALK, ROS1, BRAF, MET, RET, HER2, or NTRK and who initiated treatment for stage 4 NSCLC between 01/01/2018 and 12/31/2021 were included with follow-up through 05/31/2022. Also included were demographics, ECOG score, time of ordering test, and date of death. Genomic test data were classified by method and type of test. Overall survival (OS) was calculated using Kaplan-Meier curves and data are presented using descriptive statistics. Results: Of 5195 patients in the ICD with stage 4 NSCLC, 3532 patients initiated first line of therapy (LOT1), and 2899 had somatic molecular testing ordered, specifically via tissue-based next-generation sequencing (NGS, 30%), plasma-based NGS (26%), or non-NGS methods (44%). A total of 934 patients tested positive for a driver mutation at any time during the study observation period, and 671 patients (72%) had test results available before initiating treatment. Of those treated after receiving biomarker results, 407 (61%) initiated treatment with a tyrosine kinase inhibitor (TKI), 43 (6%) with chemotherapy (chemo), 156 (23%) with chemo + immuno-oncology (IO), and 65 (10%) with IO. The median OS (95% confidence interval [CI]) was 24.46 (21.90-29.18) months for patients treated with TKI and 14.2 (11.6-16.5) months for patients treated without TKI (unadjusted hazard ratio [95% CI], 1.56 [1.26, 1.92]; P < 0.001). Conclusions: Among patients with stage 4 NSCLC treated in the real-world setting, patients treated with TKI after receiving test results had better overall survival than patients treated without TKI. While subject to the limitations of a retrospective observational real-world data study, this study suggests that, with regard to utilizing genomic testing and appropriate selection of targeted treatment, adherence to treatment guidelines may improve patient outcomes. As new targeted agents continue to emerge in NSCLC, these data encourage utilization of genomic testing data to guide treatment selection. We acknowledge the significant contributions of our dear friend, Dr. Robert E. Smith, whose cheerful enthusiasm and deep expertise were a driving force of this work.