Non-small Cell Lung Research Articles

Correlation of allele-specific HLA loss of heterozygosity in patients with cancer with driver mutations.

e14658 Background: While immunotherapies have revolutionized cancer treatment, the limited predictability of response and resistance mechanisms present challenges to the development of novel therapeutics for solid tumors. Many of these use a sensitive and specific T cell receptor (TCR)-HLA:peptide interaction as a mechanism of action and can be impacted by HLA loss of heterozygosity (LOH). Allele-agnostic HLA LOH analyses assessing loss of any MHC class I allele are relevant for HLA-agnostic approaches such as immune checkpoint inhibitors; however, context-specific studies remain limited. For example, adoptive TCR T cell therapies and bi-specific TCR T cell engagers target neoantigen peptides derived from oncogenic driver mutations, such as those of KRAS and TP53, presented by a specific HLA allele. Thus, allele-agnostic analyses may overestimate the frequency and relevance of HLA LOH for allele-specific modalities. Methods: A real-world comprehensive genomic profiling dataset consisting of 78,418 cases (1), germline heterozygous for one or more HLA class I locus, was analyzed for HLA LOH in the context of frequent driver mutations (KRAS G12C, G12D, G12V and TP53 R175H), the corresponding HLA alleles (A*02:01, A*03:01, and A*11:01), and within tumor subtypes. Results: Allele-agnostic HLA LOH was observed in 16.6% of all samples and varied between indications. Notably, allele-specific loss of HLAs A*02:01, A*03:01, and A*11:01 across all samples was much lower than allele-agnostic loss (6.3%, 6.6%, and 6.3% cases, respectively). Although, a trend for increased allele-specific HLA LOH was observed when analyzed by driver mutation, the frequency remained low. Specifically, across all cases, A*02:01, A*03:01, and A*11:01 allele-specific LOH ranged between 5.9% - 9.7% in relation to KRAS G12C, G12D, and G12V compared to 5.9% - 6.2% for wild-type (WT). Moreover, it did not achieve statistical significance for any HLA-KRAS mutation pairs in colorectal (CRC), non-small cell lung (NSCLC), and pancreatic (PDAC) cancers, except for A*11:01 and KRAS G12C in NSCLC, which was lower in mutated cases (5.3% for G12C vs 10.1% for WT KRAS, p=0.045). Both allele-agnostic and A*02:01-specific HLA LOH in TP53 WT samples were lower than average. The TP53 R175H mutation was associated with limited increase in HLA-A*02:01 LOH (from 4.4% for WT to 8.1% for TP53 R175H) and varied between indications, e.g. no significant increase was observed in R175H-positive breast cancer and NSCLC cases contrary to CRC and PDAC. Conclusions: Based on this real-world dataset, over 90% of cases retain the TCR-targeted allele and, therefore, preserve the molecular complex necessary for HLA/driver mutation-based therapies. Notably, the database is enriched for advanced cancer patients. Further studies should test correlations with treatments and whether tumors in earlier lines of treatment have an even lower rate of HLA LOH. 1. Montesion et al., PMID: 33127846.

Updated results of a phase 1/2 study of AU-007, a monoclonal antibody (mAb) that binds to IL-2 and inhibits CD25 binding, in patients with advanced solid tumors.

2527 Background: AU-007 is a computationally designed human mAb that binds interleukin-2 (IL-2) on its CD25 binding epitope. AU-007 bound IL-2 cannot bind trimeric (CD25, CD122, CD132) IL-2 receptors (IL-2R) on regulatory T cells (Tregs), vascular endothelium, or eosinophils, but IL-2’s binding to dimeric IL-2R (CD122, CD132) on effector T (T eff) and NK cells is unhindered. AU-007 thus redirects IL-2 towards T eff and NK cell activation, while diminishing Treg activation and vascular leak. AU-007 uniquely redirects IL-2 generated from T eff cell expansion, converting a Treg-mediated autoinhibitory loop into an immune stimulating loop. Methods: The study consists of three dose escalation arms followed by cohort expansion. Arm 1A evaluates escalating doses (0.5 – 12 mg/kg) of AU-007 (IV every 2 weeks [Q2W]). Arm 1B evaluates AU-007 Q2W + escalating doses (15K – 270K IU/kg) of one aldesleukin subcutaneous (SC) dose. Arm 1C evaluates AU-007 + escalating doses of SC aldesleukin, both Q2W. Nineteen solid tumor types are allowed in escalation. Cohort expansion Arm 2B evaluates 9 mg/kg AU-007 + one 135K IU/kg aldesleukin dose. Results: Fifty-three patients were enrolled as of 23 January 2024: 15 in Arm 1A, 12 in Arm 1B, 25 in Arm 1C, and 1 in cohort expansion. AU-007 (+/- aldesleukin) was well-tolerated, with no dose limiting toxicities through all Arm 1A and 1B cohorts and the 3rd cohort (of 4) in 1C. Enrollment is ongoing in the final Arm 1C cohort and Arm 2B expansion. All drug related adverse events (AE) were Grade 1 or 2 except for 4 patients with transient lymphopenia (Grade 3 and 4) and 1 patient with Grade 3 anemia. The most common drug-related AEs were pyrexia (18%), fatigue (16%), nausea (14%), lymphopenia (8%), and chills (6%). Two patients had transient Grade 2 drug-related serious AEs: pyrexia Arm 1B and cytokine release syndrome Arm 1C; both patients continued therapy. A confirmed partial response (32% decrease) occurred in a nasopharyngeal carcinoma patient in Arm 1C who progressed on anti-PD-1 therapy. Tumor shrinkage occurred in patients with non-small cell lung, bladder, head and neck, colorectal (CRC), and renal cancer. A melanoma patient (Arm 1B) who progressed on anti-CTLA-4 + anti-PD-1 therapy had a 48% decrease in target tumors; a small brain metastasis was found and irradiated at week 16 and the patient remains on treatment. A patient with microsatellite stable CRC had a 26% tumor shrinkage after the first cycle (Arm 1C). Serum Tregs and eosinophils decreased in patients while NK and CD8 cell counts trended upwards. The CD8:Treg ratio trends upward in all cohorts. Conclusions: The mild toxicity profile and promising early efficacy observed in dose escalation across multiple tumor types in heavily pretreated patients, along with initial pharmacodynamic data, warrant continued evaluation of AU-007 + low dose SC aldesleukin in the Phase 2 expansion cohorts of the study. Clinical trial information: NCT05267626 .

Retrospective evaluation of drug to drug interactions with paclitaxel use in military health.

e24118 Background: Paclitaxel is an antineoplastic agent used in the management of multiple metastatic and non-resectable tumor types approved for ovarian, breast, AIDS-related Kaposi sarcoma, non-small cell lung, pancreatic, cervical, endometrial, and thymoma or thymic carcinoma cancer by the US Food and Drug Administration. Cytochrome P450 (CYP) 3A4 or 2C8 inducers, inhibitors, or substrates may alter paclitaxel metabolism. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with paclitaxel and describe their clinical manifestations. Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved March 2022), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved October 2022). Patients’ medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients’ diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with paclitaxel, and evaluate DDIs with antidepressants. Results: Of 702 patients using paclitaxel, 338 completed treatments. The P value for paclitaxel discontinuation when used alone vs concomitantly or 1 drug (alone or before or after) vs combination (2 to 4 drugs) was < .001. Patients who took paclitaxel concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 9 to 56 prescription drugs, and those in the discontinued group were prescribed 6 to 70. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment. Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in paclitaxel discontinuation. There were no significant DDIs determined between paclitaxel and antidepressants.[Table: see text]

Angiogenesis inhibitors and cardiovascular outcomes in cancer: Real-world, population-based, matched cohort study.

e24024 Background: Angiogenesis inhibitors (AI) have vascular side effects and are now recognized forcardiovascular adverse events (CVAEs). Clinical trial outcomes can underestimate treatment-related adverse events due to restrictive eligibility criteria, limited sample size, and failure to anticipate specific toxicities. In contrast, observational studies have small sample sizes and insufficient adjustment of confounding covariates. In addition, prospective high-quality evidence in real-world settings is scarce. We evaluated the incidence of CVAEs in real-world populations on AI therapy. Methods: This large retrospective cohort study was conducted using the TriNetX database and included adult patients ( > 18 years) with new cancer diagnoses. We performed 1:1 propensity score matching (PSM) for demographics, BMI, nicotine dependence, comorbidities, cancer type, and medications to similar controls as cancer patients never treated with AIs. The primary outcome was the new incidence of CVAEs-like heart failure (HF), major adverse cardiovascular events (MACE; coronary artery intervention myocardial infarction, or unstable angina), arrhythmia, ischemic heart disease (IHD), venous thromboembolism (VT), and cerebrovascular events (CVE cerebral infarction, carotid intervention, stroke, transient ischemic attack). Sensitivity analysis assessed statistical robustness. Hazard ratios (HR) were calculated to compare the AI therapy association with incident CVAEs. Results: We identified 1,170,667 patients with diagnoses of colorectal, cervical, kidney, liver, nonsmall cell lung, or ovarian cancer between 2010 and 2022. Among these, 59,890 had an AI treatment history, and 110,777 did not, with a median follow-up time of 3.1 years. After PSM, both cohorts (59545 each) were well-matched. In the adjusted analysis, AI therapy was associated with higher risks of MACE (HR, 1.23; 95% CI 1.16 -1.31), HF (HR, 1.16; 95% CI 1.08 - 1.25), and VT (HR 2.07; 95% CI 1.95 - 2.19), IHD (HR 1.23; 95% CI 1.16- 1.31), arrhythmias (HR 1.19; 95% CI 1.12-1.27), CVEs (HR, 1.30; 95% CI 1.21- 1.40) at 1 year of exposure. These outcomes were still significantly higher “increased,” suggesting causation; this is an association at follow-up by increasing the lag exposure. Sensitivity analysis results were consistent, and all statistically significant associations remained unchanged. Conclusions: Angiogenesis inhibitor treatment was associated with a significantly higher risk of CVAEs and various malignancies. The increased risk ranges from approximately 1.16 to 2.07 fold, indicating a substantial elevation in risk. These findings highlight the importance of risk stratification and cardiovascular monitoring during and after AI therapy. There is an unmet need to define strategies for CVAE prevention in this high-risk population.

Estimating the impact of enhanced care at minority-serving hospitals on disparities in the treatment of breast, prostate, lung, and colon cancers.

The objective of this study was to quantify disparities in cancer treatment delivery between minority-serving hospitals (MSHs) and non-MSHs for breast, prostate, nonsmall cell lung, and colon cancers from 2010 to 2019 and to estimate the impact of improving care at MSHs on national disparities. Data from the National Cancer Database (2010-2019) identified patients who were eligible for definitive treatments for the specified cancers. Hospitals in the top decile by minority patient proportion were classified as MSHs. Multivariable logistic regression adjusted for patient and hospital characteristics compared the odds of receiving definitive treatment at MSHs versus non-MSHs. A simulation was used to estimate the increase in patients receiving definitive treatment if MSH care matched the levels of non-MSH care. Of 2,927,191 patients from 1330 hospitals, 9.3% were treated at MSHs. MSHs had significant lower odds of delivering definitive therapy across all cancer types (adjusted odds ratio: breast cancer, 0.83; prostate cancer, 0.69; nonsmall cell lung cancer, 0.73; colon cancer, 0.81). No site of care-race interaction was significant for any of the cancers (p>.05). Equalizing treatment rates at MSHs could result in 5719 additional patients receiving definitive treatment over 10 years. The current findings underscore systemic disparities in definitive cancer treatment delivery between MSHs and non-MSHs for breast, prostate, nonsmall cell lung, and colon cancers. Although targeted improvements at MSHs represent a critical step toward equity, this study highlights the need for integrated, system-wide efforts to address the multifaceted nature of racial and ethnic health disparities. Enhancing care at MSHs could serve as a pivotal strategy in a broader initiative to achieve health care equity for all.

Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression

BackgroundThe presence of mesenchymal stem cells has been confirmed in some solid tumors where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated. The aim of this study was to investigate the functions of mesenchymal stem cells isolated from tumor tissues of patients with non-small cell lung cancer.ResultsHuman lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of mesenchymal stem cells; they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of mesenchymal stem cells, the ability of peripheral blood mononuclear cell-derived natural killer and activated T cells to mediate tumor cell destruction was significantly compromised.ConclusionCollectively, these data support the notion that human lung cancer-derived mesenchymal stem cells protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of natural killer and T cells.

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

Comparing symptom clusters in cancer survivors by cancer diagnosis: A latent class profile analysis

PurposeResearch on symptom clusters in oncology is progressing, but knowledge gaps remain. One question is whether the number and types of symptom subgroups (i.e., latent classes) differ based on cancer diagnosis. The purpose of this study was to: (1) identify and compare latent class subgroups based on four highly prevalent symptoms (pain, fatigue, sleep disturbance, and depression), and (2) examine the differences in sociodemographic and clinical factors in the identified latent classes across the seven cancer types (i.e., prostate, non-small cell lung, non-Hodgkin’s lymphoma, breast, uterine, cervical, and colorectal cancer).MethodsThis study is a cross-sectional secondary analysis of data obtained from the My-Health study in partnership with four Surveillance, Epidemiology, and End Results (SEER) cancer registries located in California (two), Louisiana, and New Jersey. The sample included 4,762 cancer survivors 6-13 months following diagnosis of one of the seven cancer types mentioned. Latent class profile analysis was used.ResultsSubjects were primarily young (59% age 21-64 years), Caucasian (41%), married/cohabitating (58%) and unemployed (55%). The number and types of symptom subgroups varied across these seven cancer populations: four-subgroups were the common in prostate, lung, non-Hodgkin’s lymphoma, and breast cancer survivors. Unmarried, low education, and unemployment status were associated with high risk of symptom burden across the cancer types.ConclusionIdentifying symptom subgroups by cancer diagnosis has the potential to develop innovative and effective targeted interventions in cancer survivors. Further research is needed to establish extensive knowledge in symptom clustering between treatment regimens, and short-term and long-term cancer survivors.

Abstract CT084: A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress)

Abstract Background: Nectin-4 is a cell adhesion molecule expressed in multiple tumor types.1 Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) comprising a fully humanized nectin-4 antibody conjugated to the microtubule inhibitor, monomethyl auristatin E (MMAE), is approved for the treatment of advanced urothelial cancer (UC). However, skin toxicity, peripheral neuropathy, and hyperglycemia are clinically significant toxicities with EV. LY4101174 (ETx-22) is a next-generation nectin-4 targeting ADC comprising a humanized IgG1 Fc-silent monoclonal antibody linked to the topoisomerase I inhibitor, exatecan, via a maleimide-ß-glucuronide poly-sarcosine linker with improved stability and a homogeneous drug-antibody ratio (DAR) of 8. Preclinically, LY4101174 has demonstrated robust in vivo efficacy in tumor models across a range of nectin-4 expression levels and in the nectin-4-MMAE ADC treated resistant tumor model.2 Methods: LOXO-ENC-23001 is a global, open-label, multi-center, first-in-human phase 1 study of LY4101174 in patients (pts) with advanced or metastatic solid tumors known to express nectin-4. LY4101174 will be administered intravenously and evaluated initially on either every 2 weeks or 3 weeks schedule. Eligible pts (≥18 years) must have good performance status (ECOG PS 0-1) with metastatic UC, head and neck squamous cell carcinoma, esophageal, pancreatic, prostate, non-small cell lung, cervical, ovarian, or triple-negative breast cancer, and must have received or not be a candidate for available standard therapies. The study will be conducted in 2 phases: phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation will utilize a Bayesian optimal interval design. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. The dose-limiting toxicity evaluation period will be 21 or 28 days based on dosing schedules. Phase 1b dose expansion cohorts will enroll pts with selected tumor types: mUC with no prior EV treatment (cohort B1), mUC with prior EV treatment (cohort B2), and other selected non-UC tumors (cohort C). Primary objectives are to determine the recommended phase 2 dose (RP2D) and assess the safety of LY4101174. Key secondary objectives are to evaluate the pharmacokinetic profile, immunogenicity, and antitumor activity of LY4101174 per RECIST v1.1. Nectin-4 expression and other biomarker data will be generated and correlated with clinical activity. 1Challita-Eid PM et al. 2016 Cancer Res 76(10):3003-13. 2Azim H et al. 2023 Mol Cancer Ther 22(12_Suppl):B128. Citation Format: Jonathan Rosenberg, Renaud Sabatier, Armelle Viceneux, Thibault de La Motte Rouge, Stephane Champiat, Loic Lebellec, Philippe Barthélémy, Guru Sonpavde, Xin Gao, Scot Niglio, Tian Zhang, Craig Gedye, Matthew Galsky, Matthew Milowsky, Melissa Reimers, Andrew Weickhardt, Enrique Grande, Daniel E. Castellano, Mehmet Bilen, Amita Patnaik, Robert Zerbib, Minna Balbas, Xiaojian Xu, Kaitlyn Aptaker, Arjun V. Balar, Ahmad H. Awada. A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT084.

Abstract CT291: A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1

Abstract Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (deruxtecan [DXd]). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Trial design: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll a maximum of 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Citation Format: Noboru Yamamoto, Toshihiko Doi, Manish R. Patel, Ignacio Garrido-Laguna, Sutun Wu, Satoshi Nishioka, Keiko Nakajima, Benedito A. Carneiro. A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT291.

New pyridine-based chalcones and pyrazolines with anticancer, antibacterial, and antiplasmodial activities.

New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 μM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 μM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 μg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 μg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.

Abstract 6406: Clinical and translational results of the academic ARIANES Phase 2 basket study: Longitudinal single-cell analysis of patient tumors identifies biological correlates of response to PARP inhibitors and anti-PD-L1 therapy

Abstract Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have immunomodulatory properties that may potentiate anti-PD-L1 therapy. To explore this, we developed the academic ARIANES phase 2 basket trial, which evaluated the PARPi rucaparib (R) and the anti-PD-L1 atezolizumab (A) in selected patients (pts). We performed single-cell RNA + T cell receptor sequencing (scRNA+TCR-seq) on 3 sequential tumor biopsies in a pts subset. Methods: ARIANES comprised 4 molecularly-selected DNA damage response deficient (DDRd), 3 platinum-sensitive, and 2 unselected cohorts of pts with non-small cell lung (NSCLC), prostate (CRPC), and other non-breast non-ovarian cancers. R was administered for 3 weeks, followed by R+A. Primary endpoint was overall response rate (ORR) at 12 weeks per cohort. scRNA+TCR-seq was performed on fresh biopsies collected at baseline, on R, and on R + A in the same lesion, with concomitant plasma collection. We tracked the evolution over time of tumor and microenvironment cells, differentially expressed genes and signatures within each cell population, and TCR clonal dynamics. Results: ARIANES enrolled 130 pts, including 27 DDRd CRPC and 3 DDRd NSCLC pts, on which we focus here. Best ORR by RECIST v1.1 was 22% (6/27) in CRPC pts, and mPFS: 7.9 months (95% CI 4 - 11.1) at data cut-off. ORR was 0% in NSCLC pts. We successfully profiled 3 sequential fresh biopsies in 2 BRCA2-mutant CRPC, 1 ATM-mutant, and 1 RAD54L-mutant NSCLC pts. Tumor, T and B lymphoid, myeloid, plasma, dendritic, NK, endothelial, and stromal cells were identified in all samples. Differential expression testing unveiled PARP1 upregulation in tumor cells on R. One CRPC pt with prolonged partial response displayed activation of innate immune sensing pathways (including cGAS-STING and IFN signaling) in tumor and immune cells, as well as JAK/STAT and CCL5, all increasing gradually on R and R + A; scTCR-seq revealed the expansion of specific T cell clonotypes on R + A. One ATM-mutant NSCLC pt with 6-month stable disease displayed increased cGAS/STING, JAK/STAT and CCL5 activation on R in NK cells only, and no TCR expansion. None of the above was observed in the 2 pts who progressed. Complete clinical and translational study results will be presented at the congress. Conclusion: Sequential scRNA+TCR-seq enables the dynamic assessment of tumor and immune cells on therapy. Our data confirms the potential of R to activate innate immune pathways in pt tumors, and R + A to induce T cell activation and clonal expansion. To our knowledge, this is the first study providing a longitudinal single-cell resolution analysis of the clonal evolution of tumor and immune cells in pts on PARPi + anti-PD-L1. We identify potential biological correlates of therapy response, including the activation of innate immune pathways and TCR expansion. Citation Format: Julien Vibert, Clémence Hénon, Lambros Tselikas, Baptiste Bonnet, Arnaud Pagès, Alice Bernard-Tessier, Léo Colmet-Daage, Roman Chabanon, Nicolas Dorvault, Clémence Astier, Anas Gazzah, Aurore Jeanson, Aurélien Parpaleix, Ronan Flippot, Natacha Naoun, Anna Patrikidou, Pernelle Lavaud, Giulia Baciarello, Emeline Colomba, Alina Fuerea, Laurence Albiges, Christophe Massard, Santiago Ponce, Yohann Loriot, Stéphane Champiat, Capucine Baldini, Fanny Bouquet, Nathalie Droin, Karim Fizazi, Damien Vasseur, Patricia Martin-Romano, Etienne Rouleau, Kaïssa Ouali, Sophie Postel-Vinay. Clinical and translational results of the academic ARIANES Phase 2 basket study: Longitudinal single-cell analysis of patient tumors identifies biological correlates of response to PARP inhibitors and anti-PD-L1 therapy [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 6406.

Abstract 3892: Systematic generation of a clinicogenomic harmonized oncologic real-world dataset (MSK-CHORD)

Abstract Clinical data storage in unstructured notes and siloed datasets present a major challenge for large-scale cancer informatics. Whether natural language processing (NLP) combined with multimodal integration across datasets can produce a mineable resource and improve discovery of relationships between tumor genomics and clinical phenotypes is unknown. We hypothesized that NLP could automatically annotate a pan-cancer corpus of 82,464 patients with tumor genomic sequencing. To develop algorithms to annotate free-text reports, we leveraged the AACR Project GENIE Biopharma Collaborative (BPC), a structured curation of EMR from five cancer types (non-small cell lung (NSCLC), breast, colorectal, prostate, and pancreatic cancer), to train and validate several Transformer and rule based-based NLP models. After automating the generation of NLP annotations alongside medication, demographic, tumor registry, survival, and tumor genomic sequencing data, we tested whether clinicogenomic relationships not apparent in the smaller BPC cohort might be discoverable in the larger cohort. In 5-fold cross-validation, NLP Transformers accurately annotated the presence of cancer (AUC=0.99), cancer progression (AUC=0.97), and sites of disease (AUC=0.99) from radiology reports, and presence of prior outside treatment (AUC=0.98) and hormone receptor (HR) and HER2 receptor status (AUC=0.98, 0.98) from clinician notes. In addition, rule-based models, trained on non-BPC data and validated on the whole BPC cohort, annotated smoking status from clinician notes (ACC=0.95), and Gleason score (ACC=1.0), PD-L1 status (ACC=0.98), and mismatch repair deficiency (ACC=0.98) from histopathology reports. NLP annotations were merged with genomic and other structured clinical data to create a Clinicogenomic, Harmonized Oncologic Real-world Dataset (MSK-CHORD). Finally, we tested if associations not apparent in the BPC might be discoverable in MSK-CHORD. We found positive associations between Gleason score and gene-level alterations in prostate cancer including TP53, PTEN and BRCA2 (q<0.1), none of which were adequately powered for detection in the BPC. We found PD-L1 status was associated with better survival following immunotherapy treatment in NSCLC, but only in the larger MSK-CHORD was this association statistically significant. In breast cancer, NF1 mutations were associated with prior therapy in both cohorts, but this association was only significant in MSK-CHORD. The infrastructure generating MSK-CHORD uses a combination of on-premise and cloud computing resources and open-source development operation applications to automate processes. Once annotations are created, data is imported into a local instance of cBioPortal, where researchers can visualize data and perform analyses. The system generating MSK-CHORD demonstrates how large-scale data delivery and integration can fuel cancer research. Citation Format: Christopher J. Fong, Karl Pichotta, Thinh Tran, Michele Waters, Tom Fu, Mono Pirun, Mirella Altoe, Brooke Mastrogiacomo, Anisha Luthra, Mehnaj Ahmed, Arfath Pasha, Armaan Kohli, Raymond Lim, Tom Pollard, Darin Moore, Benjamin Gross, Avery Wang, Calla Chennault, Ritika Kundra, Ramyasree Madupuri, Ino de Bruijn, Aaron Lisman, Walid K. Chatila, Subhiksha Nandakumar, Anika Begum, Doori Rose, Kenneth L. Kehl, Deborah Schrag, Michael Berger, Jian Carrot-Zhang, Pedram Razavi, Bob Li, Peter Stetson, Nikolaus Schultz, Justin Jee. Systematic generation of a clinicogenomic harmonized oncologic real-world dataset (MSK-CHORD) [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 3892.

Abstract 4009: Discovery of inhibitory CAR target DSG1 for damping NECTIN4 on-target off-tumor toxicity in iPSC-derived CAR-T cell therapy

Abstract Century Therapeutics is developing NECTIN4 targeted induced Pluripotent Stem Cell (iPSC) derived Chimeric Antigen Receptor (CAR) T cell therapy. NECTIN4 targeted antibody drug conjugate enfortumab vedotin, while generally well tolerated, causes severe skin adverse events in some patients, thought to be driven by on-target off-tumor toxicity against NECTIN4 displaying skin keratinocytes. We include a safety switch in our first clinical-stage iPSC-derived CAR-NK cell therapy, CNTY-101, which provides an antibody target for elimination of the engineered cells should that be necessary. An additional method for reducing the incidence and severity of this type of adverse event is through the incorporation of an inhibitory CAR, also known as a NOT-gate, directed against antigen expressed on normal skin keratinocytes, but the optimal surface protein to target with such an inhibitory CAR for a NECTIN4 targeted therapy is unknown. Here, we identify DSG1 (Desmoglein-1) as a top inhibitory CAR target for NECTIN4 targeted CAR-T cell therapy by conducting a multi-omics analysis of public single-cell RNAseq, bulk RNAseq, and protein microarray immunohistochemistry datasets. We find that DSG1 is constitutively and uniformly displayed on the surface of skin keratinocytes in the layers of epidermis where they display NECTIN4, and DSG1 gene expression in normal skin is uniformly high across individuals. Conversely, DSG1 mRNA and protein are rarely expressed in NECTIN4 expressing cancer indications including bladder, breast, non-small cell lung, ovarian, and pancreatic. Further, autoimmune antibodies specific to DSG1 have been described, suggesting that DSG1 is targetable by a CAR in situ. Finally, DSG1 is not expressed by our iPSC-derived CAR-T cells. While NECTIN4 expression is greatest in skin keratinocytes, epithelial cells in other tissues express NECTIN4 at lower levels. In this study, we compare the expression levels of NECTIN4 to targets associated with tissue and cell-type specific on-target off-tumor toxicity in primary CAR-T cell clinical trials. Our findings support the strategy of DSG1-directed inhibitory CAR incorporation into NECTIN4 specific CAR-T cell therapeutic candidates. Citation Format: Matthew S. Hall, Christopher M. Dower, Michael Miller, John Wheeler, Jill Carton, Ohad Manor, Hyam Levitsky. Discovery of inhibitory CAR target DSG1 for damping NECTIN4 on-target off-tumor toxicity in iPSC-derived CAR-T cell therapy [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 4009.

Abstract 4235: PD3D®models as jacks-of-all-trades for cancer research and therapy response prediction

Abstract Physiologically relevant in vitro tumor models are crucial in any research setting from preclinical drug development to functional precision oncology. Patient-derived 3D cell culture models (PD3D®) are validated cancer models which recapitulate the biology of the original tumor tissue. PD3D® can be used to model intratumoral heterogeneity in medium and high throughput screens. Using a reverse clinical engineering approach, PD3D® models are already applied in personalized oncology to identify treatment for an individual patient. We successfully established a living biobank of more than 500 PD3D® models, spanning from common cancers like colorectal, breast (incl. TNBC), non-small cell lung and pancreatic carcinoma, to orphan indications including various subtypes of sarcomas. Not surprisingly, PD3D® model morphology and culture requirements differ between tumor entities. Treating PD3D® models with standard of care drugs in a semi-automated high-throughput assay, we observed heterogeneity in drug sensitivity between models of the same cancer type, recapitulating clinical response of patients. Combining drug sensitivity profiles with genomic and proteomic data of the same PD3D® models, we successfully identified a biomarker for predicting chemosensitivity towards MEK-targeting drugs. For application of PD3D® in truly personalized oncology, we developed a protocol that allows us to generate a PD3D® culture and perform a drug sensitivity assay for an individual patient within a therapy-relevant timeframe. Within 38 days we identified a systemic therapy for a young patient with a relapsed metastasized synovial sarcoma. After surgery and initiation of recommended chemotherapy, the patient is now under remission. To further expand the scope of PD3D® for therapy response prediction, we established a method for irradiation of PD3D® cultures with different dosages of photon and proton radiation. We observed significant, model specific differences in radiosensitivity between PD3D® sarcoma models which also reflect clinically heterogenous responses. Additionally, PD3D® models can be employed for a tumor organoid-on-chip platform (TumOC), delivering real-time information on physiological parameters like drug response-mediated oxygen consumption in a microfluidic system. In conclusion, PD3D® models act as jacks-of-all-trades in current and future cancer research, delivering robust and reliable data that not only is of academic value, but speeds up the drug development process, and are ready for prime time in functional precision oncology. Citation Format: Lena Wedeken, Samantha Forbrig, Katja Herrera-Glomm, Juergen Loskutov, Ulrike Pfohl, Irina Piven, Michael Poehle, Manuela J. Regenbrecht, Barbara Seller, Cynthia Yapto, Sabine Finkler, Larissa Ruhe, Quirin Graf Adelmann, Christoph Reinhard, Marie Flechner, Katja Uhlig, David Kaul, Siyer Roohani, Maya Niethard, Rica Sauer, Christian R. Regenbrecht. PD3D®models as jacks-of-all-trades for cancer research and therapy response prediction [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 4235.

Abstract 2916: Discoidin domain receptor 1 (DDR1) expression is associated with degree of immune exclusion across epithelial tumors

Abstract Background: Discoidin domain receptor 1 (DDR1) is highly expressed in epithelial cancers and has been implicated in tumor growth, invasion, and lack of response to therapy. DDR1 contributes to immune exclusion by promoting tumor collagen alignment in in vivo models. However, it is unclear how DDR1 expression impacts immune cell infiltration in human tumors. A first-in-human trial of PRTH-101, a DDR1-targeted therapeutic antibody, is underway. Establishing a correlation between DDR1 expression and immune infiltration in the tumor microenvironment (TME) will shed light on the role of DDR1 in the TME and inform indication and patient selection strategies for DDR1-targeted therapies. Methods: Adjacent formalin fixed paraffin embedded slides from colorectal (CRC), non-small cell lung (NSCLC), ovarian (OC), pancreatic (PDAC), and triple-negative breast cancers (TNBC) were stained by H&E and a multiplex immunofluorescence (mIF) panel containing DDR1 and immune cell markers CD8 and CD45. Tumor-stromal segmentation and cell identification was done from H&E using AI-powered models developed by PathAI (PathExplore™) or from mIF by image analysis using QuPath. DDR1 mRNA expression was measured by bulk RNA-sequencing, while DDR1 protein expression was measured by mIF. Immune Exclusion Scores (IESs) were calculated for each tumor based on lymphocyte density (from H&E), CD8+ T cell density (from mIF), or CD45+ cell density (from mIF). Each IES is the orthogonal distance between the coordinate of immune cell density in tumor epithelium and stroma, and the regression line representing equal density in epithelium and stroma. Correlations between lymphocyte, CD8, and CD45 IESs and DDR1 mRNA or protein expression levels were evaluated. Results: Both DDR1 mRNA and protein expression levels were significantly correlated with all Immune Exclusion Scores (IESs) measured by the distribution of lymphocytes (H&E), CD8+, or CD45+ cells (mIF) in tumor epithelium and stroma (R: 0.31-0.55, adjusted p: <0.001-0.01) at a pan-cancer level. While the degree of the correlation varied between tumor indications by IES immune cell type, pancreatic cancer exhibited the strongest correlation between the lymphocyte-based IES and DDR1 mRNA and protein expression (R: 0.48-0.54, adjusted p: 0.04-0.07). DDR1 mRNA was also moderately correlated with lymphocyte IES in NSCLC and TNBC (R: 0.37-0.48, adjusted p: 0.12-0.14). Conclusions: We developed a continuous scoring method to quantify the degree of immune exclusion in tumors based on the spatial distributions of lymphocytes, CD8+ T cells, and CD45+ immune cells from H&E and mIF images. DDR1 mRNA and protein expression are correlated with immune exclusion at both the pan-cancer and specific indication level. This adds additional insight into the role of DDR1 in human cancers and may be useful in selecting indications and stratifying patients for DDR1-targeted therapies. Citation Format: Xinwei Sher, Fredrick D. Gootkind, Thomas Schürpf, Florent Peyraud, Jean-Philippe Guégan, Antoine Italiano, G. Travis Clifton, Laura A. Dillon. Discoidin domain receptor 1 (DDR1) expression is associated with degree of immune exclusion across epithelial tumors [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 2916.

A radiotherapy community data-driven approach to determine which complexity metrics best predict the impact of atypical TPS beam modeling on clinical dose calculation accuracy.

To quantify the impact of treatment planning system beam model parameters, based on the actual spread in radiotherapy community data, on clinical treatment plans and determine which complexity metrics best describe the impact beam modeling errors have on dose accuracy. Ten beam modeling parameters for a Varian accelerator were modified in RayStation to match radiotherapy community data at the 2.5, 25, 50, 75, and 97.5 percentile levels. These modifications were evaluated on 25 patient cases, including prostate, non-small cell lung, H&N, brain, and mesothelioma, generating 1,000 plan perturbations. Differences in the mean planned dose to clinical target volumes (CTV) and organs at risk (OAR) were evaluated with respect to the planned dose using the reference (50th-percentile) parameter values. Correlation between CTV dose differences, and 18 different complexity metrics were evaluated using linear regression; R-squared values were used to determine the best metric. Perturbations to MLC offset and transmission parameters demonstrated the greatest changes in dose: up to 5.7% in CTVs and 16.7% for OARs. More complex clinical plans showed greater dose perturbation with atypical beam model parameters. The mean MLC Gap and Tongue & Groove index (TGi) complexity metrics best described the impact of TPS beam modeling variations on clinical dose delivery across all anatomical sites; similar, though not identical, trends between complexity and dose perturbation were observed among all sites. Extreme values for MLC offset and MLC transmission beam modeling parameters were found to most substantially impact the dose distribution of clinical plans and careful attention should be given to these beam modeling parameters. The mean MLC Gap and TGi complexity metrics were best suited to identifying clinical plans most sensitive to beam modeling errors; this could help provide focus for clinical QA in identifying unacceptable plans.

Determinants of Symptomatic Intracranial Progression After an Initial Stereotactic Radiosurgery Course

Purpose: Clinical and imaging surveillance of patients with brain metastases (BMs) is important after stereotactic radiosurgery (SRS), as many will experience intracranial progression (ITCP) requiring multidisciplinary management. The prognostic significance of neurologic symptoms at the time of ITCP is poorly understood. Materials/MethodsThis was a multi-institutional, retrospective cohort study from 2015-2020, including all patients with BMs completing an initial course of SRS. The primary outcome was overall survival (OS) by presence of neurologic symptoms at ITCP. OS, freedom from ITCP (FF-ITCP), and freedom from symptomatic ITCP (FF-SITCP) were assessed via Kaplan-Meier method. Cox proportional hazard models tested parameters impacting FF-ITCP and FF-SITCP. Results: Among 1383 patients, median age was 63.4 years, 55% were female, and common primaries were non-small cell lung (49%), breast (15%), and melanoma (9%). At a median follow up of 8.72 months, asymptomatic and symptomatic ITCP were observed in 504 (36%) and 194 (14%) patients respectively. The majority of ITCP were distant ITCP (79.5%). OS was worse with SITCP (median 10.2 vs 17.9 months, p<0.001). SITCP was associated with clinical factors including total treatment volume (P = 0.012), melanoma histology (P = 0.001), prior WBRT (P = 0.003), number of brain metastases (P < 0.001), interval of 1-2 years from primary and brain metastasis diagnosis (P = 0.012), controlled extracranial disease (P = 0.042), and receipt of pre-SRS chemotherapy (P = 0.015). Patients who were younger and received post-SRS chemotherapy (P = 0.001), immunotherapy (P < 0.001), and targeted or small-molecule inhibitor therapy (P < 0.026) had better FF-SITCP. Conclusions: In this cohort study of BM patients completing SRS, neurologic symptoms at ITCP is prognostic for OS. This data informs post-SRS surveillance in clinical practice as well as future prospective studies needed in the modern management of BMs.

Microwave-induced one-pot synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole hybrids as antiproliferative agents and density functional theory study.

Herein, we outline a highly efficient PEG-4000-mediated one-pot three-component reaction for the synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole derivatives (5a-r) at up to 96% yield as antiproliferative agents. This three-component protocol offers the advantages of an environmentally benign reaction, excellent yield, quick response time, and operational simplicity triggered by the copper catalyst under microwave irradiation. All the synthesized compounds were tested for antiproliferative activity against six human solid tumor cell lines, that is, A549 and SW1573 (nonsmall cell lung), HBL100 and T-47D (breast), HeLa (cervix), and WiDr (colon). Among them, six compounds, 5g-j, 5m, and 5p, demonstrated effective antiproliferative action with GI50 values under 10 μM. Furthermore, density functional theory (DFT) calculations were performed for all the synthesized molecules through geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The theoretical DFT calculation was performed using the DFT/B3LYP/6-31+G (d,p) basis set. Moreover, the biological reactivity of all the representative synthesized molecules was compared with the theoretically calculated quantum chemical descriptors and MESP 3D plots. We also investigated the drug-likeness characteristic and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. In general, our approach enables environmentally friendly access to 3-imidazolyl indole clubbed 1,2,3-triazole derivatives as prospective antiproliferative agents.