Citations

Abstract Background: Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated significant clinical efficacy in hematologic malignancies, but have proven challenging in solid tumors, in part owing to a lack of tumor-specific targets and unmanageable toxicity. Mesothelin (MSLN) expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (cancer.gov/tcga), making it a potential target for cancer therapy. MSLN-targeted cell therapy approaches, including CAR T and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (Beatty, et al. Gastroenterology. 2018.; Haas, et al. Mol Ther. 2023.; Hong, et al. ESMO 2021. Abstract 9590.). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker inhibits the CAR T activator when it binds human leukocyte antigen (HLA)-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 loss of heterozygosity (LOH), the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (Hamburger, et al. Mol Immunol. 2020). Through this unique selective mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients must have progressed following standard of care therapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. The first patient was enrolled on EVEREST-2 in April 2024. Dose escalation is ongoing. Citation Format: Julian R. Molina, Antonious Hazim, Oliver Dorigo, Salman R. Punekar, Monica Avila, Diane M. Simeone, Kedar Kirtane, Gottfried E. Konecny, Jeffrey Ward, Matthew Block, Jennifer Specht, Leslie Boyd, Yanyan Lou, Jong Chul Park, Jacqueline D. Xuan, Ramez N. Eskander, Gayanie Ong, Marco Davila, Wendy Langeberg, Marcela Maus, Armen Mardiros, Frederick L. Locke, Andrea Wise, David G. Maloney, John Welch, J. Randolph Hecht. EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod CAR T-cell therapy, in patients with mesothelin-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT186.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly half of all patients diagnosed at an advanced stage. Immune checkpoint inhibitors (ICIs) harness the host immune system to combat malignant cells. ICIs, which target programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), and cytotoxic T-cell lymphocyte-4 (CTLA-4), have transformed the treatment landscape for advanced NSCLC. While a subset of patients experiences a long-term durable response, most patients will develop disease progression. New drugs targeting novel pathways are being tested in clinical trials to improve the efficacy of immunotherapy and overcome resistance patterns. This review aims to summarize the currently available ICIs for advanced NSCLC and describe emerging immunotherapies with recently published data from phase I/II clinical trials.

The emergence of immunotherapy has ushered in a new era in the management of non-small cell lung cancer (NSCLC). Various immune check point inhibitors have demonstrated significant benefit in the management of locally advanced NSCLC that are treated with either surgery or concurrent chemoradiation. We provide a comprehensive and up-to-date review of data from key studies, discuss the challenging clinical issue regarding the timing and duration of immunotherapy in patients undergoing surgery, and highlight the unmet needs and future directions of immunotherapy in NSCLC.

Abstract Systematic multiomic analysis has revealed ancestry-dependent molecular alterations, but their impact on the efficacy of anticancer treatment is yet largely unknown. In this study, we analyzed clinical trials from ClinicalTrials.gov and found that only 8,779/102,721 (8.5%) oncology clinical trials posted information on enrollment by race/ethnicity. The underrepresentation of non-White populations suggests that it remains challenging to determine differences in the efficacy of antitumor treatments among different racial groups. Through a comprehensive analysis of clinically actionable genes, imputed drug responses, and immune features, we identified potential differences in treatment responses to targeted therapy, chemotherapy, and immunotherapy between different ancestral populations. Further analysis of multiple independent cohorts confirmed some of our key findings. Such potential ancestral effects are also identified in response to emerging new treatments like chimeric antigen receptor T-cell therapy and proteolysis-targeting chimeras. These findings are made publicly available in a comprehensive web portal, Ancestral Differences of Efficacy in Cancers (https://hanlaboratory.com/ADEC), to facilitate their further investigation. Significance: Our study charts a global landscape of ancestry-associated differences in therapeutic efficacy, highlighting the importance of considering ancestry in anticancer therapies.

e20588 Background: MET exon 14 skipping mutations are seen in about 3% of patients (pts) with NSCLC, with 2 FDA approved METi for pts with stage IV NSCLC harboring it. Besides the original clinical trials, there is a paucity of real-world data about their outcomes, and adverse events (AE). Our aim was to compare and analyze the utilization of capmatinib (cap) and tepotinib (tep) in this population. Methods: We performed a retrospective chart review of the electronic medical records of all pts with stage IV NSCLC treated with METi between the date of FDA-accelerated approval of these drugs, 5/6/20 for cap and 2/3/21 for tep, and 12/1/23. All pts were treated at the Mayo Clinic Health System. We collected data about baseline characteristics, diagnosis, AE, and outcomes. Chi-squared test was used to compare the frequency of AE, while Kaplan-Meier method was used to calculate median progression free survival (mPFS). Results: A total of 49 pts were treated with METi. Cap was used in 45 pts, 14 received tep, and 10 pts received both, with tep following cap. In the cap group, median age of diagnosis was 74 years (y), 42.22% were male, and the median number of previous lines of therapy (mPLT) was 0. In the tep group, median age of diagnosis was 72 y, 21.43% were male, and the mPLT was 2. Median ECOG at the time of diagnosis was 1 in both groups. There was no statistically significant difference between AE in both groups. Peripheral edema occurred in 75.56% pts who received cap, and in 64.29% with tep (p = 0.41). Pneumonitis happened in 4.44% with cap, and 7.14% with tep (p = 0.69). Creatinine elevation was seen in 37.78% with cap, while 42.86% with tep (p = 0.73), grade 3 elevation was seen in 5.88% and 16.67% respectively. Abnormality in liver function tests occurred in 35.56% of pts in the cap group, and 28.57% in the tep group (p = 0.63), grade 3/4 abnormality occurred in 31.25% and 0% respectively. Finally, pancreatic enzymes elevation was seen in 33.33% of patients in each group (p = 0.67), with none being grade 3/4. Cap was discontinued in 20% of pts due to AE, while it happened in 28.57% of pts with tep. Dose reduction happened in 64.44% of pts who received cap, and 42.86% who received tep. The mPFS was 12.03 months (m) in the cap group, and 8.94 m in the tep group, which was not statistically significant (p = 0.18). Similarly, the mPFS in those treated with tep following cap was 8.94 m. Conclusions: We performed the first real-word comparison between cap and tep. The results demonstrated similar outcomes with both drugs, and no significant differences in AE, suggesting these agents can be employed equivalently. Importantly, rates of therapy discontinuation and dose reduction were high with both, indicating the importance of closely monitoring these pts. The retrospective nature and small sample size are initial limitations that can be overcome with future multi-centric prospective studies.

TPS2700 Background: Though immunotherapy with anti-PD-1 immune checkpoint inhibitors (ICIs) has led to improvements in clinical outcomes in patients with cancer, when used as monotherapy in the advanced setting, only 18-25% of patients respond to ICI. Notably, ICI frequently lacks anti-tumor activity in immune-cold cancers where T cell priming is missing. Recent breakthroughs in identifying personal neoantigens via a comprehensive analysis of cancer sequencing data have brought increased attention to neoantigen cancer vaccines. Personalized cancer vaccines targeting neoantigens have shown early promise. While neoantigens have recently been investigated in some cancer types, the current neoantigen prediction algorithms have often focused on the MHC class-I subtype, single nucleotide mutations (SNM), small insertions and deletions (INDEL). We recently developed an informatics workflow, REAL-neo, for the identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic SNM, INDEL, aberrant RNA splicing, and gene fusions, generating much more potent neoantigen candidates. Furthermore, we demonstrated robust T-cell response and prolonged survival by combining ICI and cancer vaccines in preclinical models. This single-arm phase I clinical trial is in progress to assess the safety, feasibility, and immunogenicity of personalized neoantigen vaccines in combination with pembrolizumab in patients with advanced solid cancers. Methods: The vaccine consists of up to 20 peptides (15-30 mer) comprising patient-specific neoantigens identified from tumor DNA and mRNA sequencing data using REAL-neo and delivered with GM-CSF as an adjuvant. The first cohort of three patients will be treated at dose level 1 consisting of 4 or 5 peptides at 300 mcg/peptide and GM-CSF 125 mcg per injection site in each of four limbs. After Cohort 1 is deemed safe, the study will expand to cohort 2, when patients will be enrolled at the same dose level for vaccine plus Pembrolizumab 200 mg i.v. Neoantigen vaccine will be given via subcutaneous injection on days 1, 4, 8, 15, and 21 (cohorts 1 and 2) and weeks 5 and 8 (booster dose for cohort 2 only). Cohort 1 has been completed without dose-limiting toxicity (DLT). Enrollment in Cohort 2 began in January 2024. AEs are assessed according to CTCAE v5. and safety findings are reviewed by data safety medical board (DSMB). Key eligibility criteria include 1) histologically confirmed locally advanced or metastatic solid malignancies and 2) cancer progression after at least one line of the standard-of-care (SOC) systemic treatment. For cohort 2, patients must be eligible to receive pembrolizumab per SOC or the treating physician’s judgment. Clinical trial information: NCT05269381 .

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher’s exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18–102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.