G12C Mutation Research Articles

Redefining pancreatic cancer management with tumor-agnostic precision medicine.

Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

KRAS G12C mutation in NSCLC in a small genetic center: insights into sotorasib therapy response potential

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

A novel label-free impedance biosensor for KRAS G12C mutations detection based on PET-RAFT and ROP synergistic signal amplification

The KRAS G12C mutations, as crucial biomarkers, are closely associated with non-small cell lung cancer. Here, a novel label-free electrochemical biosensor with synergistic signal amplification of photocell energy transfer-reversible addition fragmentation chain transfer (PET-RAFT) and ring-opening polymerization (ROP) was developed for the first time for sensitive detection of KRAS G12C mutations. Specifically, hairpin DNA (hDNA), which act as biomolecular probe, was self-assembled on Au electrode surface by Au-S bond. 4-cyano-4-[(dodecylsulfanylthiocarbonyl) sulfanyl] pentanoic acid (CDTPA), the chain transfer agent of PET-RAFT reaction, was then attached to hDNA via amide bond. After that, the target DNA (tDNA) was captured on the electrode surface by complementary base pairing with hDNA. Subsequently, large numbers of electro-active monomers N-acryloxysuccinimide (NAS) were successfully grafted to the electrode surface via PET-RAFT reaction, which provided plenty of junction sites for doxorubicin-polycaprolactone (Dox-PCL) synthesized by ROP. Finally, the Dox-PCL was connected to the electrode surface by ester bond, significantly amplifying the electrochemical signal. Under optimized conditions, the biosensor has a wide linear detection range of 0.1 pM to 1 μM, with a detection limit of 86.9 fM. Attribute to its high sensitivity, specificity, reproducibility and stability, this biosensor possesses considerable potential in early diagnosis of disease and biomedical research.

Comparative Efficacy of Adagrasib and Sotorasib in KRAS G12C-Mutant NSCLC: Insights from Pivotal Trials.

Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal clinical trials. Methods: We analyzed data from three key clinical trials: KRYSTAL-1, CodeBreak100, and CodeBreak200. Our methodology involved reconstructing individual patient data from published Kaplan-Meier curves using the IPDfromKM tool (Version 0.1.10). The primary endpoints were progression-free survival (PFS) and overall survival (OS), evaluated through hazard ratios (HRs) and the restricted mean survival time (RMST) method. Results: The HR for PFS favored adagrasib (HR: 0.90 [95% CI: 0.69, 1.19], p = 0.473), suggesting a non-significant trend toward better disease control compared to sotorasib. For OS, the HR was 0.99 [95% CI: 0.75, 1.33] (p = 0.969), indicating no significant difference between the two drugs. RMST analysis supported these findings, with adagrasib showing a consistently higher RMST in PFS at 6, 12, and 18 months. However, OS benefits converged over time, with adagrasib marginally surpassing sotorasib by the 18-month mark. Conclusions: This comprehensive analysis reveals that while adagrasib may offer a slight advantage in PFS, both drugs demonstrate comparable efficacy in OS for KRAS G12C-mutated NSCLC. The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.

Bringing Hope to Improve Treatment in Pancreatic Ductal Adenocarcinoma—A New Tool for Molecular Profiling of KRAS Mutations in Tumor and Plasma Samples

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising, and prognosis remains poor due to late diagnosis and limited effective therapies. Currently, patients are treated based on TNM staging, without molecular tumor characterization. This study aimed to validate a technique that combines the amplification refractory mutation system (ARMS) with high-resolution melting analysis (HRMA) for detecting mutations in codon 12 of KRAS in tumor and plasma, and to assess its prognostic value. Methods: Prospective study including patients with newly diagnosed PDAC with tumor and plasma samples collected before treatment. Mutations in codon 12 of KRAS (G12D, G12V, G12C, and G12R) were detected using ARMS–HRMA and compared to Sanger sequencing (SS). Univariate and multivariate analyses were used to evaluate the prognostic significance of these mutations. Results: A total of 88 patients, 93% with ECOG-PS 0–1, 57% with resectable disease. ARMS–HRMA technique showed a higher sensitivity than SS, both in tumor and plasma (77% vs. 51%; 25 vs. 0%, respectively). The most frequent mutation was G12D (n = 32, 36%), followed by G12V (n = 22, 25%). On multivariate analysis, patients with G12D and/or G12C mutations, either in tumor or plasma, had lower PFS (HR 1.792, 95% CI 1.061–3.028, p = 0.029; HR 2.081, 95% CI 1.014–4.272, p = 0.046, respectively) and lower OS (HR 1.757, 95% CI 1.013–3.049, p = 0.045; HR 2.229, 95% CI 1.082–4.594, p = 0.030, respectively). Conclusions: ARMS–HRMA is a rapid and cost-effective method for detecting KRAS mutations in PDAC patients, offering the potential for stratifying prognosis and guiding treatment decisions. The presence of G12D and G12C mutations in both tumor and plasma is associated with a poorer prognosis.

Comprehensive liquid biopsy analysis for monitoring NSCLC patients under second-line osimertinib treatment.

The heterogeneous and complex genetic landscape of NSCLC impacts the clinical outcomes of patients who will eventually develop resistance to osimertinib. Liquid biopsy (LB) analysis as a minimally invasive approach is a key step to efficiently identify resistance mechanisms and adjust to proper subsequent treatments. In the present study, we combined plasma-cfDNA and CTC analysis from 30 NSCLC patients in samples collected before treatment and at the progression of disease (PD). We detected molecular alterations at the DNA mutation (EGFR, PIK3CA, KRAS G12C, BRAF V600E), DNA methylation (RASSF1A, BRMS1, FOXA1, SLFN1, SHISA3, RARβ,, WIF-1, RASSF10 and APC), gene expression (CK-19, CK-18, CK-8, AXL, TWIST-1, PD-L1, PIM-1, Vimentin, ALDH-1, and B2M) and chromosomal level (HER2 and MET amplification) as possible resistance mechanisms and druggable targets. We also studied the expression of PD-L1 in single CTCs using immunofluorescence. In some cases, T790M resistance EGFR mutation was detected at baseline in CTCs but not in the corresponding plasma cfDNA. PIK3CA mutations were detected only in plasma-cfDNA but not in corresponding CTCs. KRAS G12C and BRAF V600E mutations were not detected in the samples analyzed. MET amplification was detected in the CTCs of two patients before treatment whereas HER2 amplification was detected in the CTCs of three patients at baseline and in one patient at PD. DNA methylation analysis revealed low concordance between CTCs and cfDNA, indicating the complementary information obtained through parallel LB analysis. Results from gene expression analysis indicated high rates of vimentin-positive CTCs detected at all time points during osimertinib. Moreover, there was an increased number of NSCLC patients at PD harboring CTCs positive in PD-L1. AXL and PIM-1 expression detected in CTCs during treatment suggesting new possible therapeutic strategies. Our results reveal that comprehensive liquid biopsy analysis can efficiently represent the heterogeneous molecular landscape and provide prominent information on subsequent treatments for NSCLC patients at PD since druggable molecular alterations were detected in CTCs.

Multigene Panel Next-Generation Sequencing Techniques in the Management of Patients with Metastatic Colorectal Carcinoma: The Way Forward for Personalized Treatment? A Single-Center Experience

The efficacy and cost-effectiveness of Multigene Panel Next-Generation Sequencing (NGS) in directing patients towards genomically matched therapies remain uncertain. This study investigated metastatic colorectal cancer (mCRC) patients who underwent NGS analysis on formalin-fixed paraffin-embedded tumor samples. Data from 179 patients were analyzed, revealing no mutations in 39 patients (21.8%), one mutation in 83 patients (46.4%), and two or more mutations in 57 patients (31.8%). KRAS mutations were found in 87 patients (48.6%), including KRAS G12C mutations in 5 patients (2.8%), PIK3CA mutations in 40 patients (22.4%), and BRAF mutations in 26 patients (14.5%). Less common mutations were identified: ERBB2 in five patients (2.8%) and SMO in four patients (2.2%). Additionally, MAP2K1, CTNNB1, and MYC were mutated in three patients (2.4%). Two mutations (1.1%) were observed in ERBB3, RAF1, MTOR, JAK1, and FGFR2. No significant survival differences were observed based on number of mutations. In total, 40% of patients had druggable molecular alterations, but only 1.1% received genomically guided treatment, suggesting limited application in standard practice. Despite this, expanded gene panel testing can identify actionable mutations, aiding personalized treatment strategies in metastatic CRC, although current eligibility for biomarker-guided trials remains limited.

Molecular Profiling of Low-Grade Appendiceal Mucinous Neoplasms (LAMN).

Low-grade appendiceal mucinous neoplasia (LAMN) represents a relatively rare tumor of the appendix typically diagnosed incidentally through appendectomy for acute appendicitis. In cases where perforation occurs, mucinous content may disseminate into the abdominal cavity, leading to the development of pseudomyxoma peritonei (PMP). The primary objective of this study was to elucidate the molecular characteristics associated with various stages of LAMN and PMP. DNA was extracted from LAMN, primary PMPs, recurrent PMPs, and adenocarcinomas originating from LAMN. The subsequent analysis involved the examination of mutational hotspot regions within 50 cancer-related genes, covering over 2800 COSMIC mutations, utilizing amplicon-based next-generation sequencing (NGS). Our findings revealed activating somatic mutations within the MAPK-signaling pathway across all tumors examined. Specifically, 98.1% of cases showed mutations in KRAS, while one tumor harbored a BRAF mutation. Additionally, GNAS mutations were identified in 55.8% of tumors, with no significant difference observed between LAMN and PMP. While LAMN rarely displayed additional mutations, 42% of primary PMPs and 60% of recurrent PMPs showed additional mutations. Notably, both adenocarcinomas originating from LAMN showed mutations within TP53. Furthermore, 7.7% (4/52) of cases exhibited a potentially targetable KRAS G12C mutation. In four patients, NGS analysis was performed on both primary PMP and recurrent PMP/adenocarcinoma samples. While mutations in KRAS and GNAS were detected in almost all samples, 50% of recurrent cases displayed an additional SMAD4 mutation, suggesting a notable alteration during disease progression. Our findings indicate two key points: First, mutations within the MAPK pathway, particularly in KRAS, are evident across all tumors, along with a high frequency of GNAS mutations. Second, progression toward PMP or adenocarcinoma is associated with an accumulation of additional mutations within common oncogenic pathways.

Clinical utility of upfront liquid biopsy in non-small cell lung cancer in the community setting.

316 Background: Molecular diagnosis of advanced non-small cell lung cancer (NSCLC) is critical to guide therapeutic decisions. Blood next generation sequencing (NGS) allows for non-invasive screening for targetable genetic abnormalities. Many studies have validated using the liquid biopsies to screen for resistant mutations at the emergence of treatment failure. However, the clinical utility of liquid biopsy for newly diagnosed NSCLC, as part of a comprehensive molecular profiling, is an area of active research. Methods: Retrospective analysis of the molecular landscape and clinical outcomes in NSCLC patients who had liquid biopsy done between December of 2017 to February of 2022. Patients had EGFR, ALK, ROS-1, and BRAF tested in the tissue, and underwent liquid biopsy for broad molecular profiling. The plasma genotyping was conducted using a 73-gene panel by Guardant 360 test. Actionable mutations were stratified accordingly to the OncoKB database based on the level of preclinical and clinical evidence of drug targetability. Survival analysis was conducted by August of 2023. Results: We enrolled 122 NSCLC patients who 84% were treatment-naïve and 78% had the liquid biopsy performed at the initial diagnosis. We found that 86 patients had oncogenic mutations and 43 (35%) had actionable mutations, with 37 (29%) falling under level 1 of evidence mutations. EGFR and KRAS G12C mutations were the two most common level 1 genetic abnormalities (23% and 11% of all actionable mutations, respectively). We identified two germline BRCA carriers who were referred for genetic counselling. 25 patients (20%) received treatment based on the liquid biopsy results, with 15 (12%) achieving partial response. Six patients had liquid biopsy done at progression of EGFR or MET therapies, which identified a resistance mechanism in three of them. Conclusions: Upfront liquid biopsy identified a significant proportion of patients with targetable mutations. Here, we reported actionable mutations in 35% of our patients who 84% had no prior systemic treatment. Our results complement prior literature and shows that blood next generation sequencing can be a useful tool to guide upfront therapeutical options at the community healthcare setting.

Potent covalent irreversible inhibitor of KRAS G12C IBI351 in patients with advanced solid tumors: First-in-human phase I study

BackgroundIBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation. MethodsIn phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated. ResultsAs of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months. ConclusionsIBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation.

Abstract C027: Efficacy advantages of a novel pan-RAS inhibitor, ADT-1004, over mutant- specific KRAS inhibitors for suppressing pancreatic tumor growth in murine models

Abstract Background/Objective: Prognosis remains grim for localized or metastasized pancreatic ductal adenocarcinoma (PDAC) with 5-year survival rates of 3-16%. More than 90% of PDAC cases harbor KRAS mutations. KRASG12C inhibitors recently developed have limited use for PDAC because only 3% of cases express this mutation. We developed a novel pan-RAS inhibitor, ADT-1004 and evaluated antitumor activity in tumor models established from murine or human PDAC cell lines or patient-derived xenografts (PDX). ADT-1004 is an orally bioavailable prodrug of ADT-007, a highly potent and selective pan-RAS inhibitor (doi.org/10.1101/2023.05.17.541233). Methods: Murine PDAC cells harboring the KRASG12D mutation (KPC-Luc or 2838C3-Luc) were orthotopically implanted into the pancreas of C57BL/6J mice. Four PDX PDAC tumors harboring KRAS mutations were implanted orthotopically in NSG mice. To assess potential to overcome RAS inhibitor resistance, parental KRASG12C MIA PaCa-2 PDAC cells and a resistant derivative of MIA PaCa-2 cells were implanted subcutaneously. To assess selectivity, mice were implanted with RASWT BxPC-3 cells SC. Mice were treated orally with ADT-1004 (40mg/kg) 5x/week for 4 weeks. Sotorasib and adagrasib KRASG12C inhibitors were administered at the same dose, route, and schedule as ADT-1004. Results: ADT-007 potently and selectively inhibited the growth of human and mouse PDAC cell lines in vitro. For example, the IC50 value of ADT-007 for KRASG12C MIA PaCa-2 PDAC cells was 2 nM compared to 2500 nM for RASWT BxPC-3 PDAC cells. Growth inhibition by ADT-007 was dependent on activated RAS and associated with reduced GTP-RAS levels and MAPK/AKT signaling. ADT-1004 was well tolerated in mice at doses up to 175 mg/kg bid orally with sustained plasma levels of ADT-007 exceeding growth IC50 values. ADT-1004 displayed robust antitumor activity in mouse tumor models using human- or mouse-derived PDAC cell lines with G12D, G12V, G12C, or G13Q KRAS mutations, causing selective inhibitory effects on ERK phosphorylation in tumors but not in normal tissues. ADT-1004 also inhibited growth of KRASG12C mutant MIA PaCa-2 tumors to a comparable extent as sotorasib and adagrasib. Sotorasib and adagrasib were ineffective against xenografted tumors of resistant cells derived from MIA PaCa-2 cells, while ADT-1004 strongly inhibited tumor growth. Target selectivity of ADT-1004 was confirmed in vivo, as ADT-1004 did not affect the growth of RASWT BxPC-3 tumors. Conclusions: ADT-1004 inhibited tumor growth of KRAS mutant PDAC tumors by blocking activated RAS to disrupt downstream MAPK/AKT signaling. Side-by-side comparisons reveal antitumor efficacy advantages of ADT-1004 over mutant-specific KRAS inhibitors. These results highlight the promise of ADT-1004 for treatment of PDAC and other RAS-driven cancers by addressing the complex genetic landscape of many cancers and limitations from resistance to mutant specific KRAS inhibitions. Citation Format: Dhana Sekhar Reddy Bandi, Ganji P Nagaraju, Jeremy B Foote, Adam B Keeton, Xi Chen, Kristy L Berry, Yulia Y Maxuitenko, Upender Manne, Donald J Buchsbaum, Gary A Piazza, Bassel F El-Rayes. Efficacy advantages of a novel pan-RAS inhibitor, ADT-1004, over mutant- specific KRAS inhibitors for suppressing pancreatic tumor growth in murine models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C027.

Abstract IA-08: Syndecan 1 is a therapeutic target for KRAS-driven pancreatic cancer

Abstract KRAS inhibitors targeting G12C mutation have been approved by FDA for the treatment of non-small cell lung cancers and have shown promising clinical responses in pancreatic ductal adenocarcinoma (PDAC). RAS inhibitors targeting additional KRAS mutations or multiple RAS isoforms are under clinical development. Although targeting KRAS exhibits anti-tumor effect in PDAC, majority of tumors inevitably develop resistant disease, as is the case for most targeted therapies. In this new era of targeting KRAS driven cancer, understanding mechanisms driving this resistance to RAS targeted therapies and further devising combination strategies to overcome it have become a necessary, though challenging, task to achieve long term disease control. To tackle this problem, we employed various in vitro and in vivo preclinical model systems to explore the development of resistance to both genetic and pharmacological KRAS blockade. Our previous work identified the membrane proteoglycan Syndecan 1 (SDC1) as a KRAS downstream surrogate whose cell surface localization is tightly controlled by oncogenic KRAS signaling and is critical for KRAS-driven tumor development. Here, our analysis of KRAS driven genetically engineered PDAC mouse model and human pancreatic or colorectal cancer (CRC) cells with KRASG12C mutation discovered that, while cell surface SDC1 is reduced upon acute genetic or pharmacological inhibition of oncogenic KRAS, plasma membrane SDC1 is recovered in tumor cells that become resistant to KRAS inhibition (KRAS-bypass cells). Surface localization of SDC1 leads to the activation of multiple receptor tyrosine kinases (RTKs) and macropinocytosis, resulting in the resistance to KRAS blockade. We further identified that the recovery of plasma membrane SDC1 in KRAS-bypass cells is driven by YAP1 oncogene, which induces the downregulation of ARF6 GAPs, leading to the activation of ARF6, a small GTPase required for SDC1 membrane recycling. To therapeutically targeting SDC1, we have successfully developed a monoclonal antibody (22B mAb), which exhibits remarkable sensitivity and specificity for human SDC1. Our results indicate that 22B mAb exerts substantial inhibition of PDAC cell growth in vitro and desirable tumor inhibitory effects in vivo in murine PDAC tumors and human PDAC cell-derived xenograft tumors. Importantly, our 22B mAb synergizes with KRAS inhibitors, chemotherapy, or immunotherapy, resulting in significantly enhanced therapeutic effects. Taken together, our study identified SDC1 as a functional driver for the bypass of KRAS-dependence and therapeutically targeting SDC1 with a novel mAb will overcome the acquired resistance to KRAS targeted therapy. As such, our research yields important new insights in the fields of cancer biology regarding mechanisms of resistance employed by human cancers, and identifies new actionable therapeutic targets and approaches to overcome resistance to KRAS inhibition. Citation Format: Mitsunobu Takeda, Zecheng Yang, Madeline S Theardy, Alexey Sorokin, Oluwadara Coker, Shuaitong Chen, Long T Vien, Laura Bover, Haoqiang Ying, Scott Kopetz, Wantong Yao. Syndecan 1 is a therapeutic target for KRAS-driven pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-08.

Abstract IA-05: Targeting KRAS for pancreatic cancer treatment

Abstract The approval of clinically effective inhibitors for KRAS G12C mutant non-small cell lung cancers in 2021 and 2022 marks a significant milestone in anti-KRAS oncogene drug discovery. This success has fueled intense efforts to develop inhibitors targeting additional KRAS mutations. However, primary and treatment-associated acquired resistance limit the depth and duration of efficacy of KRAS G12C selective and likely other KRAS inhibitors. Thus, a major challenge moving forward will be the elucidation of mechanisms of resistance to then guide development of effective combination anti-KRAS therapies. Recent studies have begun to identify mechanisms of acquired resistance, where most involve alterations in components in the RAS signaling network that then cause reactivation of KRAS effector signaling that bypass drug activity. Our studies have established the critical role of reactivation of the RAF-MEK-ERK mitogen activated protein kinase cascade, and the ERK target MYC, in driving resistance in KRAS-mutant pancreatic cancer. To fully understand how aberrant ERK and MYC activation overcomes KRAS inhibitor response, we have established a comprehensive molecular portrait of ERK- and MYC-dependent activities. We have also identified YAP/TAZ-TEAD activation as a mechanism of acquired resistance and have characterized KEAP1 loss as a mechanism of primary resistance. Together, these studies have identified drug combination strategies that enhance KRAS inhibitor activity. Progress in these and other studies will be presented. Citation Format: Channing J. Der. Targeting KRAS for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-05.

Abstract IA-04: Targeting the oncogenic state of RAS with tri-complex inhibitors

Abstract KRAS oncogenic driver mutations occur in approximately 30% of all human cancers, and in particular, in over 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Small molecule inhibitors that selectively target the inactive, GDP-bound state of KRAS G12C mutant proteins have demonstrated clinical efficacy in non-small cell lung cancer (NSCLC) as monotherapies, and in the small subset of PDAC patients that harbor this mutation. However, there are no currently approved RAS-targeted therapy options for the majority of patients with non-G12C RAS mutant PDAC. We have designed a series of tri-complex inhibitors that specifically target the GTP-bound, active state of RAS (RAS(ON)). These small molecule inhibitors bind non-covalently to an abundant intracellular protein, cyclophilin A (CypA). The resulting binary complex selectively engages RAS(ON), forming a tri-complex that sterically inhibits RAS interaction with downstream effectors. We have generated mutant-selective inhibitors that covalently engage RAS(ON) G12C (RMC-6291) or RAS(ON) G12D (RMC-9805). In addition, RMC-6236 is a RAS(ON) multi-selective inhibitor that non-covalently inhibits the active, GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS). Here we will describe the mechanism of action of these investigational agents and the preclinical profiles that support their clinical evaluation in patients with PDAC as monotherapies and in combination therapy regimens with standard-of-care agents or as novel RAS(ON) inhibitor doublets. Citation Format: Mallika Singh. Targeting the oncogenic state of RAS with tri-complex inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-04.

Clinical characteristics of KRAS mutation subtypes in non-small cell lung cancer population in Xinjiang, China, and their impact on the prognosis of immunotherapy

PurposeNon-small cell lung cancer (NSCLC) is a highly fatal malignancy. The Kirsten rat sarcoma viral oncogene (KRAS) gene profoundly impacts patient prognosis. This study aims to explore the correlation between KRAS mutation subtypes, clinical data, and the impact of these subtypes on immunotherapy.Materials and methodsTumor samples from 269 NSCLC patients at the Affiliated Cancer Hospital of Xinjiang Medical University were analyzed. Patients received first- or second-line therapy without targeted therapy. Molecular and clinical data were used to analysis KRAS mutation subtypes and treatment outcomes.ResultsKRAS mutations predominantly included G12C, G12D, and G12V subtypes. TP53 had the highest mutation frequency among KRAS mutations, followed by MST1, STK11, and KMT2C. Gender differences were noted among KRAS mutation subtypes, with G12C and G12V mutations prevalent in males, while G12D mutations were less common among males. Smokers exhibited varied KRAS mutation subtypes, with G12C and G12V prevalent in smokers and G12D in nonsmokers. KRAS mutations were mainly in lung adenocarcinoma. TTF-1 and PD-L1 expression differed significantly among KRAS mutations. Patients with G12C and G12V mutations showed higher TMB levels and better immunotherapy outcomes compared to those without KRAS mutations. Conversely, patients with G12D mutations had poorer immunotherapy responses.ConclusionsKRAS mutation subtypes exhibit distinct clinical and molecular characteristics and varying responses to immunotherapy. G12C and G12V mutations correlate with better immunotherapy outcomes, while G12D mutations are associated with poorer responses.

Registry of Genetic Alterations of Taiwan Non-Small Cell Lung Cancer by Comprehensive Next-Generation Sequencing: A Real-World Cohort Study-Taiwan Cooperative Oncology Group T1521.

Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis. We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK-negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted. Cohort 1: EGFR TKI-pretreated EGFR-mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK-positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK-negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK-negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients. This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

1392TiP Phase III study of pembrolizumab plus MK-1084 vs pembrolizumab plus placebo as first-line treatment for metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 tumour proportion score (TPS) ≥50%: MK-1084-004

1392TiP Phase III study of pembrolizumab plus MK-1084 vs pembrolizumab plus placebo as first-line treatment for metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 tumour proportion score (TPS) ≥50%: MK-1084-004

622P Safety and efficacy of ifebemtinib (IN10018) combined with D-1553 in solid tumors with KRAS G12C mutation: Results from a phase Ib/II study

622P Safety and efficacy of ifebemtinib (IN10018) combined with D-1553 in solid tumors with KRAS G12C mutation: Results from a phase Ib/II study

615MO Phase I/II study of D3S-001, a second generation KRAS G12C inhibitor in advanced/metastatic solid tumors with KRAS G12C mutations

615MO Phase I/II study of D3S-001, a second generation KRAS G12C inhibitor in advanced/metastatic solid tumors with KRAS G12C mutations

A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell Lung Cancer (CCTG IND.242A): A Substudy of the IND.242 Platform Master Protocol

Molecularly targeted agents are increasingly being studied in the treatment of early-stage non-small cell lung cancer (NSCLC) to try and improve cure. However, phase 3 data on neoadjuvant therapy have largely been conducted in a biomarker agnostic manner with inconsistent exclusion of EGFR and ALK alterations. Our objective was to develop IND.242 as a large-scale neoadjuvant platform trial to introduce novel agents into the preoperative window for molecularly-defined NSCLC patient populations. Given that KRAS G12C mutations are common in the overall NSCLC patient population, ranging from 9.4% to 13% of cases across different cohorts, and may be associated to worse prognosis, the initial IND.242A Substudy was designed to test neoadjuvant JDQ443 (opnurasib), a selective KRAS G12C inhibitor. This current trial report describes the multicenter, Canadian Cancer Trials Group (CCTG)-led IND.242 neoadjuvant phase 2 platform master protocol and its first Substudy (IND.242A) of neoadjuvant opnurasib KRAS G12C inhibitor for patients with surgically resectable NSCLC (AJCC 8th edition stage IA2 to IIIA). In IND.242A, a maximum of 27 patients will be accrued in participating Canadian sites. The primary objective is the rate of major pathological response (MPR) following neoadjuvant opnurasib. Secondary objectives include safety and tolerability of the treatment regimen, objective response rate (ORR) by RECIST 1.1 for the neoadjuvant treatment period, pathological complete response (pCR) rate, event-free survival (EFS) at 2 years, and surgical outcomes. Exploratory objectives are to explore patient related outcomes (PROs) and identify potential predictive biomarkers of response and mechanisms of resistance on tissue and peripheral blood samples.