Trials In Non-small Cell Lung Cancer Research Articles

Participation in Non-small Cell Lung Cancer Clinical Trials in the United States by Race/Ethnicity

IntroductionDespite efforts by Cancer Centers and community organizations to increase diversity in clinical trials, significant racial/ethnic disparities remain. Given the high mortality rates in non-small cell lung cancer (NSCLC), it is important to increase diversity in NSCLC trials, ensuring all patients benefit from advances in new treatment modalities. Materials and MethodsWe evaluated the distribution of racial/ethnic minority enrollment in NSCLC clinical trials using data from ClinicalTrials.gov. We extracted trial characteristics, including start year, study phase, tumor stage, sample size, sponsor, geographic region, and masking. The number of participants by race/ethnicity was obtained from ClinicalTrials.gov or linked publications. Using annual NSCLC incidence data from SEER*Stat for each racial/ethnic group from 2010 to 2019, we applied a 2-sample test for equality of proportions with continuity correction to assess differences between incidence and trial participation. ResultsA total of 147 unique studies were included in the final analysis. Of the 28,540 participants, 79.6% were White, with 3% Black, 10.4% Asian or Pacific Islander and 3.4% Hispanic/Latino. Most participants were enrolled in phase III trials (63.8%), industry-sponsored (93.9%), and open-label (67.7%). Black patients were more commonly enrolled in academic sponsored trials and less commonly enrolled in masked (i.e., blinded) studies. When comparing trial participation to annual incidence data, we observed underrepresentation among Black participants (Difference: −7.9%) and Hispanic/Latino participants (Difference: −3.2%). ConclusionPersistent underrepresentation exists in NSCLC clinical trials among Black and Hispanic/Latino patients. We urge further investigation of these findings through well-designed clinical trials among diverse patient populations.

Evaluation of completeness of commonly used data elements for clinical trial eligibility criteria using a registry-enhanced data collection process: Results from patients with non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) at three community oncology practices.

346 Background: Data elements required for clinical trial eligibility assessments are often unstandardized and incomplete in EHR making clinical research participant identification a challenging and biased process. Moreover, the absence of new patient records and disease codes results in monitoring large patient populations until records are completed. These issues can lead to missed opportunities for timely patient identification. N-Power Medicine (NPM) developed a registry-enhanced oncology network platform for unbiased, and real-time quality data collection. We report from this platform on completeness rates of key variables for eligibility assessment in NSCLC and CRC clinical trials. Methods: NPM’s platform consists of 3 parts: patient registry (Kaleido), onsite and remote staff to consent patients and ensure data completeness, quality and standardization, and technology to structure and process the data. Patients with NSCLC and CRC from 3 community oncology practices across different US regions were enrolled in Kaleido and visited the clinic between February and May 2024. Data for 11 key variables were abstracted. To minimize the need for extensive monitoring until a diagnosis was confirmed, we developed a machine learning (ML) model for lung cancer using non-C34 ICD10 codes to construct multiple classes of tunable predictive models. Results: A total of 728 (NSCLC=281, CRC=447) patients were evaluated. The male-to-female ratio was 1 for NSCLC and 1.3 for CRC and 90% of NSCLC and 68% of CRC patients were over 60 years of age. The platform achieved 99% completeness for critical data points such as diagnosis date, histology, metastatic status, recent systemic anti-cancer treatments, ECOG performance status and other cancer diagnoses with diagnosis date. 47% of NSCLC and 43% of CRC patients had metastatic disease at the time of evaluation. Over 90% of patients with metastasis had their current therapy line and relevant genomic test results successfully documented. Imaging-based cancer status completeness was 95% for NSCLC and 89% for CRC. The ML model would identify over 50% of all patients that would eventually receive a lung cancer diagnosis, with over 80% specificity up to 3 weeks before a diagnosis. Conclusions: NPM’s platform demonstrated high completeness rates for the majority of essential data elements, improving the inclusion of all eligible patients in clinical trials. The predictive ML model shows promise in identifying suitable patients before an ICD10 code is assigned, reducing the need for extensive monitoring and ensuring timely completeness of necessary assessments for eligibility. Importantly, these advancements were achieved without adding financial or resource burdens to clinical workflows.

The progress of tumor vaccines clinical trials in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains a significant global health challenge, with high mortality rates and limited treatment options. Tumor vaccines have emerged as a potential therapeutic approach, aiming to stimulate the immune system to specifically target tumor cells. This study screened 283 clinical trials registered on ClinicalTrials.gov through July 31, 2023. After excluding data that did not meet the inclusion criteria, a total of 108 trials were assessed. Data on registered number, study title, study status, vaccine types, study results, conditions, interventions, outcome measures, sponsor, collaborators, drug target, phases, enrollment, start date, completion date and locations were extracted and analyzed. The number of vaccines clinical trials for NSCLC has continued to increase in recent years, the majority of which were conducted in the United States. Most of the clinical trials were at stages ranging from Phase I to Phase II. Peptide-based vaccines accounted for the largest proportion. Others include tumor cell vaccines, DNA/RNA vaccines, viral vector vaccines, and DC vaccines. Several promising tumor vaccine candidates have shown encouraging results in early-phase clinical trials. However, challenges such as heterogeneity of tumor antigens and immune escape mechanisms still need to be addressed. Tumor vaccines represent a promising avenue in the treatment of NSCLC. Ongoing clinical trials are crucial for optimizing vaccine strategies and identifying the most effective combinations. Further research is needed to overcome existing limitations and translate these promising findings into clinical practice, offering new hope for NSCLC patients.

Evaluating the robustness of an AI pathfinder application on eligibility criteria in multiple myeloma trials using real-world data and historical trials.

Background: Eligibility criteria are pivotal in achieving clinical trial success, enabling targeted patient enrollment while ensuring the trial safety. However, overly restrictive criteria hinder enrollment and study result generalizability. Broadening eligibility criteria enhances the trial inclusivity, diversity and enrollment pace. Liu et al.proposed an AI pathfinder method leveraging real-world data to broaden criteria without compromising efficacy and safety outcomes, demonstrating promise in non-small cell lung cancer trials. Aim: To assess the robustness of the methodology, considering diverse qualities of real-world data and to promote its application. Materials/Methods: We revised the AI pathfinder method, applied it to relapsed and refractory multiple myeloma trials and compared it using two real-world data sources. We modified the assessment and considered a bootstrap confidence interval of the AI pathfinder to enhance the decision robustness. Results & conclusion: Our findings confirmed the AI pathfinder's potential in identifying certain eligibility criteria, in other words, prior complications and laboratory tests for relaxation or removal. However, a robust quantitative assessment, accounting for trial variability and real-world data quality, is crucial for confident decision-making and prioritizing safety alongside efficacy.

A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer.

This critical review investigates the impact of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations on survival outcomes in non-small cell lung cancer (NSCLC) through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. In addition, this review explores the clinicopathologic characteristics of SMARCA4 mutations and their impact on various treatment modalities, including immune checkpoint inhibitors (ICIs) both with and without Kirsten rat sarcoma viral oncogene homolog (KRAS) co-mutations. The potential ineffectiveness of ICI treatment in NSCLC is explored through the impact of SMARCA4/KRAS co-mutations on the tumor microenvironment. Moreover, this NSCLC review consistently reported statistically worse overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT), and KRAS G12C inhibitors. Designing prospective clinical SMARCA4-mutated or SMARCA4/KRAS co-mutated NSCLC trials to evaluate targeted therapies and immunotherapy may lead to a better understanding of how to improve cancer patients' outcomes and survival rates.

Development and preliminary validation of a platform for systematic, unbiased pre-screening of non-small cell lung cancer (NSCLC) across three community oncology practices.

e23230 Background: With a rapidly increasing number of candidate drugs and clinical trials in oncology, efficiency in clinical trial execution has become a primary focus area for innovation. Currently, fewer than 5% of oncology patients enroll in clinical trials, and data suggests a lack of diversity in clinical trial patient populations compared to the broader patient demographic. To address these issues, we developed a systematic unbiased pre-screening platform for all patients. This approach holds the promise of hastening clinical trials by enhancing the identification of eligible patients and concurrently promoting diversity among those invited to participate in these trials. Methods: A framework for use of EMR ingested data and standardized abstraction of select 160 variables was developed for patients with NSCLC. An algorithm based on 7 key eligibility criteria was developed to generate an automated assessment of eligibility for a presumed trial. Abstracted data was compared to a medical oncologist’s assessment (gold standard) and the automated tool was validated by comparing eligibility assessment before each visit with that of a medical oncologist. Results: Three community oncology practices in the US participated. Source data-verified values for histology, ECOG PS, treatment history, line of therapy, and current metastatic status were available for > 90% of patients in real-time. Tumor NGS testing rates for actionable alterations exceeded 75%. From Oct 23, 2023 to Jan 14, 2024, 786 NSCLC pts had MD visits. Preliminary validation of the automated tool in 79 patients revealed concordant classification in 76/79 pts (96.2%). Sensitivity, specificity, PPV and NPV were > 90%. Concordance for all variables was 98% between the abstractor and medical oncologist. Conclusions: A platform for systematic, unbiased pre-screening of patients for clinical trials in NSCLC has been developed to support and facilitate oncology sites without imposing financial or resource burdens or affecting routine clinical workflow. Preliminary validation supports high performance. Updated validation data will be presented in the meeting. The high levels of data completeness and quality, including NGS testing rates that are substantially higher than what has previously been reported in community centers, underscore their suitability as clinical trial sites.

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors.

3008 Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1st, 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( > 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .

Current trends in lung cancer brain metastases trials.

e14006 Background: Brain metastases are the predominant central nervous system malignancy, primarily originating from lung cancer. In the era of precision medicine, enhanced control of extracranial disease is increasing the incidence of brain metastases, underscoring their status as a growing unmet need in modern Neurooncology. Methods: On December 12, 2023, we searched ClinicalTrials.gov for interventional and therapeutic clinical trials focusing on lung cancer brain metastases (LCBM). We gathered information on trial characteristics, including phase, study design, primary and secondary endpoints, status, enrollment criteria, size, duration, and results. Subsequently, the collected data was subjected to systematic analysis. Results: Among 198 identified trials, the majority were in early phases: 12% in phase I, 6% in phase I/II, and 60% in phase II. Only 27% of trials in phase II & II/III were randomized, with 92% lacking blinding. Trials were concentrated in North America (36%) and Asia/Africa/Australia (33%), predominantly targeting non-small cell lung cancer (NSCLC) (82%). Patients with leptomeningeal metastases were included in only about 10.5% of the trials. Out of 44 completed trials, only 21 resulted in published original articles. Termination occurred in 38 trials, primarily due to insufficient participant enrollment. Tyrosine kinase inhibitors emerged as promising treatments for brain parenchymal and leptomeningeal NSCLC metastases. Conclusions: This study highlights critical deficiencies in LCBM trials, ranging from inadequate trial numbers and recruitment difficulties to the overwhelming focus on NSCLC trials, insufficient randomization and blinding, and a marked scarcity of trials involving patients with leptomeningeal metastases. Addressing these issues is pivotal for advancing the understanding and treatment of LCBM.

Ultrasensitive circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection in early stage non-small cell lung cancer (NSCLC).

8078 Background: Translation of ctDNA MRD in NSCLC has been hampered by suboptimal sensitivity of 1st-generation assays. Here, we explore how improvements in analytical sensitivity can drive improved clinical sensitivity for MRD after surgery in NSCLC. Methods: To understand MRD kinetics, we analyzed longitudinal ctDNA in early stage NSCLC using data from the TRACERx study. Patient-specific mathematical models were generated to predict MRD levels at the postsurgical landmark and estimate the impact of an assay’s 95% limit of detection (LOD95) on clinical sensitivity. To test these predictions, tumor-informed ctDNA testing was performed using an SNV-based assay (CAPP-Seq) and a phased variant-based assay (PhasED-Seq, Foresight Diagnostics) on 269 samples from 46 patients. We also assessed MRD performance for predicting 1) patient outcomes at the landmark timepoint and 2) the effect of adjuvant treatment. Results: ctDNA MRD dynamics were assessed in 23 patients from TRACERx with ≥3 consecutive samples with detectable ctDNA without intervening therapy. MRD kinetics strongly correlated with exponential growth, with a median ctDNA doubling time of 51 days. Extrapolating MRD levels to the postsurgical landmark predicted that improving MRD assay LOD95 from 100 ppm (0.01%) to 1 ppm could increase clinical sensitivity by 2.1-fold. We then evaluated 46 NSCLC cases using two assays. The median LOD95 was 1 ppm for PhasED-Seq and 84 ppm for CAPP-Seq. Twelve cases were MRD+ by PhasED-Seq, all of whom recurred (100%), with MRD levels as low as 0.19 ppm. In contrast, 6 cases were MRD+ by the SNV-based approach, of whom 5 (83%) recurred. Accordingly, PhasED-Seq had a higher clinical sensitivity than the SNV-based method (12/18 [67%] vs. 5/18 [28%], P = 0.022). Kaplan Meier analysis for freedom from recurrence revealed significantly worse outcomes for patients with detectable MRD regardless of the method used; however, outcomes were better stratified using PhasED-Seq (HR 3.1 vs. 11.4). Patients who were MRD- after surgery by both assays had similar outcomes regardless of adjuvant therapy (chemotherapy and/or radiotherapy). However, MRD+ patients by PhasED-Seq receiving adjuvant therapy had significantly better outcomes than those who did not (HR 8.2, P = 0.00035). A similar benefit for adjuvant therapy was not observed with the SNV-based assay. Using PhasED-Seq, 80% (4/5) of MRD+ patients receiving adjuvant therapy cleared their MRD, compared to 0% (0/3) without adjuvant treatment. Conclusions: Ultrasensitive ctDNA detection improved the clinical sensitivity of MRD at key landmarks in early stage NSCLC. PhasED-Seq detected MRD at levels below 1 ppm and was associated with significantly better outcomes, revealing potential benefits of adjuvant therapy in MRD+ patients. This suggests that ultrasensitive MRD detection is promising for use in risk-adapted trials in early stage NSCLC.

Augmenting external control arms using Bayesian borrowing: a case study in first-line non-smallcell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab+chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR=1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR=0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR=1.30; 95% CI: 1.08-1.54, borrowing weight=1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight=1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

Abstract 6187: Multimodal characterization of tertiary lymphoid structures identified via deep learning on digitized H&E images in NSCLC

Abstract Background: Tertiary lymphoid structures (TLS) have recently shown association with improved outcomes for patients treated with immunotherapy across several cancer types. But pathologist-led identification of TLS on routine hematoxylin and eosin (H&E) stained images is time-consuming & lacks standardization. We developed a deep learning (DL) approach to identify TLS on digitized H&E whole slide images (WSI) of non-small cell lung cancer (NSCLC). We also elucidate underlying identified TLS biology by investigating corresponding transcriptomic profiles & multiplex immunofluorescence (mIF) images. Methods: DL model was trained using mature TLS (mTLS) annotated by 5 board-certified pathologists following standardized definitions across WSI of NSCLC, breast & bladder cancers. Model was validated using blinded, exhaustive annotations on 60 WSI by the same pathologists in consensus. To identify underlying biology associated with model-identified TLS presence, phase 3 clinical trial of advanced NSCLC with H&E and corresponding bulk RNA-Seq was analyzed using differentially expressed genes(DEG). Cellular phenotypes of model-identified TLS were elucidated in procured NSCLC WSI labeled with mIF panel & then H&E stained. Results: DL model achieved a validation F1-score of 0.56 (precision=0.52). DEG analyses resulted in significant association of TLS related gene signatures with model-identified TLS presence (q<0.05). Immuno-histopathological evaluation of model-identified mTLS revealed concordance with central clusters of CD20+ B cells surrounded by a mix of CD20+ B & CD3+ T cells. Conclusions: We developed a DL model to detect TLS in H&E WSI & demonstrated their concordance in transcriptomics and mIF. With further validation, DL identified TLS could potentially serve as an imaging-based biomarker in clinical outcome datasets. Table 1. Data distribution for instance-based deep learning model training, validation and independent deployment A. Model development Cancer type Training Validation Digitized H&E Slides with mTLS by Pathologists mTLS countby Pathologists Digitized H&E Slides tested mTLS count by Pathologists (in consensus) True positive mTLS count(Model identified) NSCLC 98 283 20 99 57 Breast 107 315 20 48 35 Bladder 103 262 20 65 48 B. Model deployment in independent cohorts NSCLC Dataset H&E images Other corresponding modality Samples Total Digitized Slides Digitized H&E Slides with mTLS by Pathologists Digitized H&E Slides with model identified TLS OAK (clinical trial, NCT02008227) 320 68 55 Matched patients with RNA seq 282 Procured 23 6 4 Matched slides with mIF panel (pan-cytokeratin, CD3, CD8, CD163/68, CD20, CD138, BCMA, DC-LAMP) 23 Citation Format: Niha Beig, Evan Liu, Geoffrey Schau, Assaf Amitai, Barzin Nabet, Rajiv Jesudason, Eloisa Fuentes, Hartmut Koeppen, Sertan Kaya, Namrata S. Patil, Minu K. Srivastava, Robert Johnston, Cleopatra Kozlowski, Jennifer Giltnane, Daniel Ruderman. Multimodal characterization of tertiary lymphoid structures identified via deep learning on digitized H&E images in NSCLC [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 6187.

Exploratory Assessment of Galectin-1, -3, and -9 in Non-Small Cell Lung Cancer.

Galectins play a pivotal role in lung cancer oncogenic pathways, influencing apoptosis, angiogenesis, and tumor metastasis. Biomarkers that diagnose, prognose, and guide cancer treatment are crucial, with galectins having the biomarker potential for non-small cell lung cancer (NSCLC). Using enzyme-linked immunosorbent assay (ELISA), we assessed serum galectin-1, -3, and -9 levels in NSCLC patients. A retrospective chart review was performed to examine patient demographics, cancer stage, tumor biology, cancer treatment, and patient outcomes. Galectin levels were then compared across these factors. In this exploratory analysis, galectin-3 levels were significantly lower in patients with squamous cell lung cancer (p = 0.0019) and in patients exposed to chemotherapy (p = 0.0375). Galectin-1 levels were significantly lower in patients with previous metastasis but had no correlation with future metastasis. Abnormal galectin-1 levels were significantly correlated with decreased overall survival (OS) in NSCLC (p = 0.0357) and specifically in patients with surgically resectable NSCLC (p = 0.0112). However, abnormal galectin-1 levels were not found to correlate with decreased OS in multivariable analysis (p = 0.0513). These findings may have clinical implications as galectin-3 inhibitors are in trials for NSCLC. Additionally, they suggest that galectin-1 has potential as a prognostic marker for surgically resectable NSCLC.

Examining crossover and postprotocol therapies in first-line immunotherapy trials in non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

Development of clinical trials for non-small cell lung cancer drugs in China from 2005 to 2023.

Over the past few decades, the development of anti-cancer drugs in China has made outstanding achievements based on the support of national policies. To assess the progress of non-small cell lung cancer (NSCLC) drugs, we conducted a statistical analysis of clinical trials of drugs targeting NSCLC in China from 2005 to 2023. We downloaded, screened and analysed the data from three official websites, the Centre for Drug Evaluation of China National Medical Products Administration website (NMPA), ClinicalTrials.gov and the Chinese Clinical Trial Registry (ChiCTR). From January 1, 2005 to April 15, 2023, a total of 1,357 drug clinical trials that met the standards were included, and the number of registered drug clinical trials has been increasing year by year, reaching the maximum of 199 in 2021. Among them, the maximum of 462 items (34.05%) in phase II clinical trials, followed by 333 (24.54%) in phase III clinical trials, and 139 (10.24%) in phase IV clinical trials. In all drug clinical trials, industry sponsored trials (ISTs) have 722 items (53.21%), which are higher than investigator-initiated trials (IITs). The clinical trials of chemical drugs have a maximum of 723 items (53.28%), while biopharmaceuticals have grown rapidly in the past 10 years, with a total of 374 (27.56%), and 48.19% of the drug clinical trials of combined medication. In addition, the geographical distribution of the leading units and participating units of Chinese drug clinical trials are uneven, and economic regions such as Beijing, Shanghai, Jiangsu are obviously ahead of other regions. From 2005 to 2023, the clinical trials of registered drugs for the treatment of NSCLC increased rapidly. Among them, due to the development of immunotherapy, the clinical trials of biopharmaceuticals and drugs for combined medication are growing most rapidly, while the exploration of the original drugs is a little far from enough. Our research provides a direction for the future drug clinical trials of NSCLC, laying foundation for further extending the survival rate of patients with NSCLC.

THU374 Fulminant Type 1 Diabetes Mellitus And DKA Secondary To Pembrolizumab

Abstract Disclosure: I. Iqbal: None. M. Khan: None. M. Ahmad: None. R. Mehreen: None. Introduction: Pembrolizumab is a programmed cell death receptor (PD-1) binder on T cells, which promotes their activation against cancer cells. It can also cause unwanted T cell activation against the body’s own cells, leading to type 1 diabetes mellitus (DM1), among other autoimmune phenomena. We are reporting a case of a new onset pembrolizumab-induced fulminant DM1 who presented with diabetic ketoacidosis (DKA). Despite the emerging data on immune checkpoint inhibitors (ICPI), fulminant DM1 with DKA in a previously nondiabetic patient is still uncommon. Case Presentation: A 66-year-old female with a history of recurrent metastatic non-small cell lung cancer (NSCLC) presented to the emergency room (ER) with an extensive itchy rash. She was enrolled in a clinical trial for NSCLC, where she received immunotherapy with pembrolizumab for five months. Rash was treated outpatient for scabies, with no improvement. She was then started on prednisone 40mg daily and betamethasone 0.05% cream. She applied the cream daily but took prednisone orally for only one day, after which she could not tolerate it due to anxiety and restlessness. She ran out of betamethasone three days before coming to ER. On admission, vitals were: Heart rate 90 beats per minute, blood pressure 119/95 mmHg, respirations 20/minute. The exam showed flushed cheeks, red and dry macules on the skin with excoriations, and dry mucus membranes. Random blood glucose levels (BSL) were 660mg/dl. Labs were; HCO3 16mmol/L, Beta-hydroxy butyrate 20mmol/L, anion gap 17mmol/L, Hemoglobin A1c: 5.6%. For DKA, we started an insulin drip. Workup revealed very low C-peptide levels of 0.2ng/ml, with a concomitant BSL of 500mg/dL. Anti-islet cell and anti-glutamic acid decarboxylase antibodies (anti-GAD) were positive with levels of 0.04 nmol/L and 0.07 nmol/L, respectively. Once she stabilized and the anion gap closed, she was transitioned to subcutaneous insulin and discharged on 42 units of Lantus, along with 12 units of premeal Lispro and sliding-scale insulin. She was removed from the clinical trial due to complications. Unfortunately, she got readmitted with influenza A, Staphylococcus aureus bacteremia, and another episode of DKA, complicated with respiratory failure, and she decided on hospice. The patient passed away after two days. Conclusion: Immune-related adverse event of new-onset fulminant DM1, leading to DKA, is a serious and potentially fatal complication of pembrolizumab. For patients receiving pembrolizumab, who have uncontrolled BSL, we suggest checking the anti-islet cell and anti-GAD antibody levels and DKA risk stratification to allow the timely initiation of insulin and prevent further complications. Presentation: Thursday, June 15, 2023

Tackling the immunotherapy conundrum: advances and challenges for operable non-small-cell lung cancer treatment.

Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases, and its standard treatment is primarily surgery. Nonetheless, this type of cancer exhibits an important rate of tumor recurrence. Immune checkpoint inhibitors (ICIs) have demonstrated significant survival benefits in many cancers, especially in early-stage NSCLC. This review considers the latest CheckMate816, IMpower010 and KEYNOTE-091 trials that led to US FDA approvals. The new wave of resectable NSCLC trial results are also summarized. Finally, the latest challenges for these treatment modalities, such as the choice between neoadjuvant and adjuvant use, the accurate identification of biomarkers and the presence of driver mutations such as EGFR, are discussed.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Analysis of phase III clinical trials in metastatic NSCLC to assess the correlation between QoL results and survival outcomes

BackgroundIn addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients’ quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC).MethodsThe systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was “superior,” “inferior,” or with “non-statistically significant difference” in the experimental arm compared to the control arm.ResultsExperimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X2 = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X2 = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232).ConclusionsOur study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC.

Outcome differences by sex in oncology clinical trials.

e18808 Background: NIH guidance advises clinical trials to analyze participants by sex to improve inclusivity. We performed a systematic analysis of reported differences in outcomes between males and females in a registry of oncology clinical trials to characterize treatment response differences more broadly by sex for future trials. Methods: We analyzed Trialtrove ( https://citeline.informa.com/trials/results ), a trial repository using over 58,000 sources, to search for oncology trials that compared outcomes in male and female participants. We implemented algorithms using Python3 programs to search for all trials that contained terms regarding sex in the context of terms suggesting comparison or outcome and considered these as candidate comparison trials. Candidate trials were manually curated to record comparisons by sex across cancer type, treatment, outcome measure, “similar” or “different” by sex and evidence. Outcomes were classified as either “survival / response / other outcome” (SRO) or side effects (E). Evidence for each comparison was labeled as statistically significant (multivariate or univariate), having non-significant numerical evidence, or having no numerical evidence. We counted only those trials in which all comparisons by sex were consistent. Results: 472 of 89,221 oncology trials in Trialtrove (data freeze 12/23/22) (0.5%) performed 532 post-treatment comparisons by sex. Among 288 trials that did statistical SRO comparisons, 47 (16%) trials reported that males showed better, statistically significant treatment responses, while 122 (42%) trials reported better results for females. We observed the strongest differences by sex for two disease-treatment pairs: EGFR inhibitors (EGFRi) in non-small cell lung cancer (NSCLC) and rituximab in non-Hodgkin’s lymphoma (NHL). In 82 trials with SRO comparisons in NSCLC, 35 (43%) showed better treatment responses in females, and 13 (16%) showed better treatment responses in males. Among the 36 NSCLC trials using EGFRi, 21 (58%) showed better treatment responses in females, versus only 1 (3%) in males. In contrast, among all 46 other NSCLC trials with SRO comparisons, 14 (30%) favored females and 12 (26%) favored males. These results suggest that EGFRi may have treatment-specific benefits in females with NSCLC. Among 33 trials with SRO comparisons in NHL, 20 (61%) showed better treatment response in females, versus only 4 (12%) in males. 13 of these trials used rituximab, among which 10 (77%) favor females and only 1 (8%) favors males. Better response in females to rituximab has been reported in single trials but not characterized in aggregate. Conclusions: Our search identified two clinically important disease-treatment pairs that showed markedly improved outcomes in females versus males. Better understanding of differences in treatment response by sex across clinical trials is needed, both to improve inclusivity and as a basis for potential future combination treatments.

Analytical and clinical validation of oncomine Dx target (ODxT) test and local testing for identifying patients with HER2 (ERBB2)-mutant (HER2m) non–small-cell lung cancer (NSCLC) for treatment with trastuzumab deruxtecan (T-DXd) in DESTINY-Lung01/02 (DL-01/02).

9033 Background: Based on the international DL-01 trial, the US Food and Drug Administration (FDA) approved the ODxT Test as a companion diagnostic (CDx) to identify patients (pts) with NSCLC harboring activating HER2 mutations who may benefit from T-DXd. The ODxT Test uses next-generation sequencing (NGS) to detect genomic alterations in formalin-fixed, paraffin-embedded tumor tissue. The accuracy of the ODxT Test by central testing and its agreement with clinical trial assays (CTAs; NGS, polymerase chain reaction, etc.) by local testing was evaluated using analytical and clinical validation data from DL-01 cohort 2 and DL-02 arm 1. Methods: ODxT Test and Illumina TruSight Tumor170 NGS assay results were compared for analytical accuracy in NSCLC samples from DL-01 and commercial vendors. Diagnostic agreement was assessed for DL-01/02 by concordance between the ODxT Test and CTAs. Clinical accuracy per objective response rate (ORR) and duration of response (DoR) to T-DXd were evaluated in all pts with HER2m NSCLC identified by ODxT Test vs CTA. Activating HER2 mutations included single nucleotide variants and exon 20 insertions. Pts received T-DXd 6.4 mg/kg in DL-01 or 5.4 mg/kg (FDA-approved dose) in DL-02 every 3 weeks. Results: NSCLC samples from DL-01 (n = 91), DL-02 (n = 102), and commercial vendors (n = 129) were individually assessed. The ODxT Test met requirements for analytical accuracy (≥90% agreement when excluding unknown results), with a positive percent agreement (PPA) of 100% and negative percent agreement (NPA) of 99.1% for detecting HER2 mutations. Clinical accuracy of the ODxT Test also met FDA requirements (excluding unknowns) for NPA (≥98%) and PPA (95% CI lower bound ≥85%). DL-01 PPA (95% CI) was 98.0% (89.2%-100%) and NPA was 100.0% (96.6%-100%); for DL-02, PPA was 96.7% (88.7%-99.6%) and NPA was 100% (96.6%-100%). In DL-01, confirmed ORR (95% CI) for pts with HER2m NSCLC identified by central ODxT Test was 58.3% (43.2%-72.4%) vs 54.9% (44.2%-65.4%) of pts identified by local CTA; median DoR (95% CI) was 12.0 mo (5.5 mo-18.2 mo) per the ODxT Test vs 9.3 mo (5.7 mo-14.7 mo) per CTA. In DL-02 (prespecified interim analysis early cohort), ORR (95% CI) was 53.6% (33.9%-72.5%) per ODxT Test vs 53.8% (39.5%-67.8%) per CTA; median DoR (95% CI) was not estimable (NE [NE-NE]) per the ODxT Test and NE (4.2 mo-NE) per CTA. Conclusions: This study demonstrates the analytical and clinical accuracy of the ODxT Test as a CDx for detecting activating HER2 mutations in NSCLC to identify pts who may benefit from T-DXd. A high level of agreement was also shown between the ODxT Test and CTAs. Clinical trials for HER2m NSCLC may successfully use a central testing assay as a CDx while allowing adequately validated local testing assays to expedite patient enrollment. Clinical trial information: NCT03505710 , NCT04644237 .