Mutant Solid Tumors Research Articles

Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives.

The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Abstract 6156: Deciphering the genomic landscape of Chilean cancer: Unveiling driver pathway divergence, and novel germline and actionable somatic variants

Abstract Advances in understanding the genetic landscape of cancer have paved the way for more precise molecular profiling and the development of more efficacious therapeutic options. However, underrepresentation in clinical research endeavors has left the Latin American population uncharacterized, which may prevent them from reaping the benefits of these advancements. This study sought to identify the genetic drivers and actionable mutations in solid tumors from Chilean patients, enhancing our understanding of the mutational landscape in a population with a genetically diverse background shaped by admixture.Methods: 468 biopsy tissues from gastric (171), gallbladder (91), breast (72), Ovarian (69), and colorectal (65) Chilean cancer patients were collected in several pathology services and biobank at Universidad de Chile. Target-sequencing was performed using Oncomine Comprehensive Assay v.1 and v.3; and TumorSec cancer panel. Data from TCGA, MSK-IMPACT, and ACCR GENIE cohorts was accessed through cBioportal and used for comparison with non-Hispanic populations. Variants were annotated with CGI, CancerVar, OncoKB, and ClinVar tools.Results: Overall, tumors have mutations mainly in TP53 (42.4%), PIK3CA (12.5%), KRAS (9.6%), PTEN (4.7%), BRCA1/2 (9%). Driver mutations were present in TP53 (42%), PIK3CA (16%), KRAS (10%), ERBB2 (7%), PTEN (7%), BRCA1/2 (8%), ATM (7%), among others. Accionable mutations were found primarily in PIK3CA (17%), KRAS (10%), ERBB2 (9%), and NTRK1/2/3 (4.8%). Besides already-known mutations, many “novel” mutations were also found in all tumor types. About 5-15% of novel variants were predicted drivers, including variants in CDH1, NOTCH1, BRCA1/2, MTOR, TSC2, and MSH2 genes. Significantly, key driver mutations identified in non-Hispanic patients from international cohorts are also prevalent in admixed Chilean patients. However, variations at the driver pathway level were also observed. Notably, the PI3K and MTOR pathways were more frequently affected in Chilean CRC and GBC, respectively. Furthermore, mutations in specific genes, such as TP53 in GBC, were associated with Amerindian genetic ancestry.The observed differences could be attributed to the abundance of newly identified driver-predicted variants, though the possibility of the admixed genetic background influencing the oncogenic process in various tissue types cannot be excluded. Citation Format: Evelin González, Jessica Toro, Alejandro Blanco, Camilo Tapia, Solange Rivas, José Erices, Felipe Osorio, Gonzalo Sepúlveda-Hermosilla, Matias Freire, Valentina Gárate, Javier Cáceres-Molina, Iván Gallegos, Olga Barajas, Mónica Ahumada, Eva Bustamante, Jaime González, Carolina Ibañez, Alejandro Corvalan, Gareth Owen, Marcelo Garrido, Ricardo Armisen, Katherine Marcelain. Deciphering the genomic landscape of Chilean cancer: Unveiling driver pathway divergence, and novel germline and actionable somatic variants [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 6156.

Abstract 1658: CFT1946, a potent, selective BRAF V600X mutant-specific degrader demonstrates superior activity as a single agent to clinically approved BRAF inhibitors and standard of care combinations in preclinical models of BRAF V600X melanoma, CRC, NSCLC, and brain metastasis

Abstract Activating mutations in BRAF at residue V600 (typically V600E) lead to dysregulation of the MAPK pathway and occur in approximately 8% of all human cancers including 60% of melanoma, up to 12% of colorectal cancer (CRC), and 4% of NSCLC. Currently approved BRAF inhibitors (BRAFi) are selective for BRAF V600X mutant proteins and are typically used in combination with MEK inhibitors (MEKi) in melanoma and NSCLC, or anti-EGFR antibodies such as cetuximab in CRC. However, their activity is limited by primary or acquired resistance often mediated by RAF dimer-inducing mechanisms. Furthermore, progression of BRAF V600X melanoma after BRAFi/MEKi treatment frequently involves brain metastasis, and currently approved BRAFi have relatively poor brain penetration. CFT1946 is a potent, orally bioavailable, cereblon-based BiDACTM degrader that selectively degrades BRAF V600X mutant protein and is currently under investigation in a Phase I clinical trial. CFT1946 has the potential to overcome limitations of clinically approved BRAFi, as degradation of BRAF V600X should abrogate RAF dimer-driven resistance and paradoxical activation. Indeed, we have previously demonstrated that CFT1946 is efficacious in an A375 BRAF V600E/NRAS Q61K xenograft model of BRAFi resistant melanoma. Here we substantially expand our preclinical characterization of CFT1946 across multiple models of BRAF V600X-driven cancers including BRAF V600X-driven CRC and NSCLC, additional BRAFi-resistant melanoma models, and a brain metastatic melanoma model. Single agent CFT1946 outperformed the SOC encorafenib + cetuximab combination in a panel of BRAF-V600X CRC xenograft models. Pathway analysis in BRAF V600X CRC models revealed that CFT1946 suppresses EGFR-mediated MAPK pathway reactivation, a mechanism known to diminish the impact of approved BRAF inhibitors in this indication. CFT1946 also demonstrated regression in a BRAF-V600X NSCLC PDX model where the SOC dabrafenib + trametinib showed only modest tumor growth inhibition. Consistent with our previous results in the A375 melanoma model, single agent CFT1946 showed superior activity versus the SOC dabrafenib + trametinib combination in all additional melanoma models tested, with complete regression achieved using a CFT1946 + trametinib combination in a PDX model bearing a BRAF-V600E kinase duplication that showed minimal response to dabrafenib + trametinib. Finally, using an A375 intracranial model, treatment with CFT1946 gave robust, dose dependent efficacy and survival advantage over encorafenib. The promising activity of CFT1946 in a broad range of BRAF V600X preclinical models supports its ongoing clinical investigation in BRAF V600 mutant solid tumors (NCT05668585). Citation Format: Bridget Kreger, Jacob R. Stephenson, Mathew E. Sowa, Samantha A. Perino, Laura L. Poling, Eunju Hurh, Michael J. Thomenius, Yanke Liang, Stewart L. Fisher, Roy M. Pollock. CFT1946, a potent, selective BRAF V600X mutant-specific degrader demonstrates superior activity as a single agent to clinically approved BRAF inhibitors and standard of care combinations in preclinical models of BRAF V600X melanoma, CRC, NSCLC, and brain metastasis [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 1658.

Targeting KRAS and SHP2 signaling pathways for immunomodulation and improving treatment outcomes in solid tumors.

Historically, KRAS has been considered 'undruggable' inspite of being one of the most frequently altered oncogenic proteins in solid tumors, primarily due to the paucity of pharmacologically 'druggable' pockets within the mutant isoforms. However, pioneering developments in drug design capable of targeting the mutant KRAS isoforms especially KRASG12C-mutant cancers, have opened the doors for emergence of combination therapies comprising of a plethora of inhibitors targeting different signaling pathways. SHP2 signaling pathway, primarily known for activation of intracellular signaling pathways such as KRAS has come up as a potential target for such combination therapies as it emerged to be the signaling protein connecting KRAS and the immune signaling pathways and providing the link for understanding the overlapping regions of RAS/ERK/MAPK signaling cascade. Thus, SHP2 inhibitors having potent tumoricidal activity as well as role in immunomodulation have generated keen interest in researchers to explore its potential as combination therapy in KRAS mutant solid tumors. However, the excitement with these combination therapies need to overcome challenges thrown up by drug resistance and enhanced toxicity. In this review, we will discuss KRAS and SHP2 signaling pathways and their roles in immunomodulation and regulation of tumor microenvironment and also analyze the positive effects and drawbacks of the different combination therapies targeted at these signaling pathways along with their present and future potential to treat solid tumors.

Abstract PR010: Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001

Abstract Background: RMC-6236 is an oral RASMULTI(ON) tri-complex inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. RMC-6236 binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that potently binds to RAS(ON) to form a tri-complex, blocking downstream signaling. Preclinical studies with RMC-6236 demonstrated deep and sustained regressions across multiple RASMUT tumor types at well tolerated doses, particularly tumors harboring KRAS glycine-12 substitutions (KRASG12X). Methods: Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses of single agent RMC-6236 administered once daily (QD). Results: As of May 11, 2023, 54 patients received RMC-6236 at dose levels from 10 to 220 mg QD. The majority of patients had pancreatic cancer (26 [48%]), non-small cell lung cancer (13 [24%]), or colorectal cancer (10 [19%]). The most common (≥10% of patients) treatment-related adverse events (TRAEs) were rash and gastrointestinal (GI)-related toxicities that were all Grade 1 or 2 in severity. Most rashes were acneiform (35%) or maculopapular (13%), consistent with known on-target rash presentation from other RAS pathway inhibitors. Rash frequency, but not severity, was dose-dependent. One patient required a dose reduction due to Grade 2 acneiform rash. The most common GI-related toxicities were nausea (32%), diarrhea (19%), and vomiting (15%) that were manageable with standard supportive care. There were two Grade ≥3 TRAEs in patients with pancreatic cancer: Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment, and Grade 3 pancreatitis reported at the time of disease progression. Thirty-one patients (57%) remain on treatment, and 23 (43%) discontinued, including 17 (31%) due to progressive disease (PD) per RECIST v1.1, 2 (4%) due to clinical progression, and other reasons due to adverse event (Grade 4 large intestine perforation), death (due to PD), investigator’s decision, or patient withdrawal (1 patient each). RMC-6236 exhibited dose-dependent increases in exposure in patients with no apparent accumulation in the blood following repeated daily dosing. At 220 mg QD, exposure to RMC-6236 was within range of the preclinical exposures in mice that demonstrated significant tumor regressions. Preliminary evidence of anti-tumor activity, including partial responses per RECIST v1.1, was observed in patients across several tumor types and dose levels. Molecular responses were observed with reduction in circulating tumor DNA of the KRAS-mutated allele and other somatic mutations consistent with inhibition of mutant RAS by RMC-6236. Conclusions: RMC-6236 is safe and well tolerated at doses that induce anti-tumor activity in patients with tumors harboring KRASG12X mutations and has favorable pharmacokinetics with oral dosing. A recommended phase 2 dose has not yet been determined and dose escalation is ongoing. Citation Format: Alexander I Spira, Alexander N Starodub, Kathryn C Arbour, David Sommerhalder, Brian M Wolpin, Minal Barve, Ignacio Garrido-Laguna, Salman Punekar, Meredith Pelster, Sumit Kar, Jamie Wong, Tong Lin, Rakesh Raman, Lin Tao, Zeena Salman, Xiaolin Wang, W. Clay Gustafson, David S Hong. Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR010.

The pharmacologic and toxicologic characterization of the potent and selective KRAS G12D inhibitors ERAS-4693 and ERAS-5024

Two potent and selective KRASG12D inhibitors, ERAS-4693 and ERAS-5024, were generated as possible clinical candidates to treat patients harboring G12D mutations in solid tumors. Both molecules exhibited strong anti-tumor activity in the KRASG12D mutant PDAC xenograft mouse models while ERAS-5024 also showed tumor growth inhibition when administered on an intermittent dosing regimen. Acute dose-limiting toxicity consistent with an allergic reaction was observed for both molecules shortly after administration at doses just above those which demonstrated anti-tumor activity, indicative of a narrow therapeutic index. A series of studies were subsequently conducted to identify a common underlying mechanism for the observed toxicity, including CETSA® (Cellular Thermal Shift Assay) as well as several functional off-target screens. Both ERAS-4693 and ERAS-5024 were identified to agonize MRGPRX2 which has been linked to pseudo-allergic reactions. In vivo toxicologic characterization of both molecules included repeat-dose studies in the rat and dog. Dose-limiting toxicities were observed in both species with ERAS-4693 and ERAS-5024 and plasma exposure levels at the maximum tolerated doses were generally below that which caused strong anti-tumor activity, supporting the initial observation of a narrow therapeutic index. Additional overlapping toxicities included a reduction in reticulocytes and clinical pathological changes suggestive of an inflammatory response. Furthermore, increases in plasma histamine were observed in dogs administered ERAS-5024, supporting the hypothesis that MRGPRX2 agonism may be the cause of the pseudo-allergic reaction. This work highlights the importance of balancing both the safety and efficacy of KRASG12D inhibitors as this class of molecules begins to enter clinical development.

Analysis of ATM germline mutations in solid tumors from Chinese patients.

10586 Background: Ataxia-telangiectasia mutated (ATM) is a tumor suppressor genes and plays an important role in the repair of DNA double-strand breaks (DSBs). Germ-line mutations of ATM gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Novel therapies are in development that may improve the response to therapy of patients with ATM-deficient cancers including targeted therapy and immunotherapy. Nevertheless, the knowledge of incidence of ATM germline mutations in solid tumor remains poorly understood. Methods: We identified 19248 malignant solid tumors patients without selecting age or family history in a retrospective cohort. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines.The patients were divided into two groups, P/ LP group (with pathogenic or likely-pathogenic mutations), and Non-P/LP group (neither pathogenic nor likely-pathogenic mutation). Results: In 19248 patients with pan-cancer, 76 patients were found 76 heterozygous pathogenic or likely pathogenic germline mutations in ATM gene and the mutation frequency was 0.39%.Among these 76 carriers, 71 (93.4%) carried frameshift, nonsense or splice mutations (33 for frameshift,21 for missense and 17 for splice mutations). 4 carried missense mutations and 1 carried intron mutations. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained cancers were pancreatic cancer (1.0%,7/692), breast cancer (0.71%,3/423), gastric cancer (0.6%,7/1094), The median age of group P/LP and non-P/LP group was 64 and 63 in pancreatic cancer，62 and 53 in breast cancer and 62 and 61 in gastric cancer. The three genes with the most somatic mutations were TP53, MUC16 and KRAS in P/LP group and were TP53, MUC16 and EGFR in non-P/LP group. There was no significant difference in mutation frequency of the four genes. The media TMB in P/LP group and non-P/LP group were 3.55 and 2.84 respectively and there was no statistical difference. In P/LP group，only one patients is high microsatellite instability who carryied a MLH1 and a ATM pathogenic mutation. Conclusions: This was the first report of the incidence of ATM germline mutations in Chinese solid tumors which expanded the understanding of ATM and provided a direction for clinical trial design of novel therapies. The relationship between germline mutations and cancer susceptibility will be studied in the future.

Phase I Beamion Lung 1 trial of BI 1810631, a HER2 tyrosine kinase inhibitor (TKI), as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations: Updated data.

8545 Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, especially NSCLC. BI 1810631 is a highly potent and selective HER2 TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions (ex20ins), while sparing EGFR. Beamion Lung 1 is an ongoing Phase Ia/Ib study to determine the safety, MTD, PK, PD, and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804). Preliminary results from Phase Ia are presented. Methods: In Phase Ia, pts with advanced/unresectable/metastatic solid tumors who were refractory or unsuitable for standard treatment (Tx) and had HER2 aberrations (e.g. overexpression, gene amplification, somatic mutation, or gene rearrangements) were enrolled. Pts received escalating doses of BI 1810631 BID starting from 15 mg or BI 1810631 QD starting from 60 mg via a Bayesian model. Phase Ib will initially include 30 pts with advanced HER2 tyrosine kinase domain mutation-positive, pre-treated NSCLC. Additional cohorts may be included. Primary endpoints: MTD based on DLTs; pts with DLTs (Phase Ia); ORR (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire Tx period and PK parameters (Phase Ia/Ib); DoR, DCR, duration of disease control, and PFS (Phase Ib). Results: As of 23 January 2023, 36 pts had been treated in the US, The Netherlands, Japan, and China. Pts had NSCLC (n = 22), colorectal cancer (n = 3), or other tumors (n = 11). Most pts (n = 26; ex20ins: n = 23) had a pathological HER2 mutation. Median (range) lines of prior systemic Tx: 2.5 (1–8). Prior HER2-targeted Tx: 12 (33%). Pts received BI 1810631 at 15, 30, 60, 100, 150 mg BID (n = 3/3/4/4/3) or 60, 120, 180, 240, 300 mg QD (n = 5/4/5/4/1). Median number of cycles was 4 (range 1–14). Tx is ongoing in 20 pts. To date, 3 DLTs have been observed (grade 2 edema [60 mg BID], grade 3 anemia [60 mg QD], grade 3 elevated ALT [180 mg QD]). The MTD has not been reached with either schedule. Tx-related adverse events (TRAEs) were reported in 25 pts (69%). The most common TRAEs were diarrhea (n = 10), anemia (n = 5), increased alkaline phosphatase, increased creatinine, increased ALT, hypoalbuminemia (all n = 4), hypocalcemia, increased AST, dry skin, increased GGT (all n = 3). Three pts had grade 3 TRAEs (anemia/increased GGT [n = 1], increased ALT [n = 2]). Strong preliminary efficacy signals were observed across all dose levels. Of 22 evaluable NSCLC patients, 10 responded (all PRs; all ex20ins) and 11 had SD. Two patients with other tumors (esophagus; cholangiocarcinoma) also achieved PR. Conclusions: These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Updated data, including durability endpoints, will be presented. Clinical trial information: NCT04886804 .

Clinical activity of mitogen-activated protein kinase (MAPK) inhibitors in patients with MAP2K1 (MEK1)-mutated metastatic cancers: A systematic review and meta-analysis.

3125 Background: MAP2K1 (MEK1) mutations are potentially actionable driver mutations in cancer. MAP2K1 mutations can be classified into 3 classes according to molecular characteristics. The efficacy of MAPK inhibitors (MAPKi) for the treatment of MAP2K1 mutant tumors is not well understood. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors, and to evaluate the relationship between MAP2K1 mutation class and clinical activity of MAPKi in patients with MAP2K1 mutant metastatic solid tumors. Methods: We interrogated AACR GENIE (v13) to identify all tumors with Class 1/2/3 MAP2K1 mutant solid tumors. We performed a systematic review and meta-analysis of individual patient data from patients with MAP2K1 mutant cancer published between 2010-22. Key inclusion criteria were: MAP2K1 mutation, solid tumor, metastatic disease, treatment with MAPKi and available treatment response data. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall response rate (RR) and duration of response (DOR). Chi-squared and Log-Rank tests were used to evaluate statistical significance of differences between groups. Results: MAP2K1 driver mutations were present in 917/167,423 (0.5%) tumors in the AACR GENIE dataset. MAP2K1 mutants were most commonly identified in melanoma, colorectal (CRC) and non-small cell lung cancer (NSCLC). In solid tumors, Class 2 mutations were the most prevalent (n=310, 63%) followed by Class 1 (n=119, 24%) and Class 3 (n=66, 13%). Co-occurring MAPK pathway activating mutations (KRAS, NRAS, HRAS, NF1, BRAF, RAF1, or EGFR) were significantly more likely (P&lt;0.0001) to occur in Class 1 (82.3%), versus Class 2 (30.9%) or Class 3 (10.6%) MAP2K1 mutant tumors. We identified 55 patients with MAP2K1 mutant tumors who received MAPKi (n=16/30/6/3 for Class 1/2/3/unclassified, respectively). Of these, (n=22, 18, 12, 3) had melanoma, CRC, NSCLC, or other cancers, respectively. Patients were treated with BRAFi (n=12), MEKi (n=24), BRAF+MEKi (n=2), ERKi (n=1) or EGFRi (n=16). Co-occurring MAPK pathway mutations were present in 51% of tumors. In the entire cohort, the RR was 24% and median PFS was 3.3 months. The RR did not differ according to mutation class, cancer type or MAPKi regimen. However, patients with Class 2 mutations experienced longer PFS (4.0 months) and DOR (23.8 months) compared to patients with Class 1, 3 or unclassified MAP2K1 mutations (PFS 3.0 months, P=0.035; DOR 4.2 months, P=0.04). Conclusions: Class 2 MAP2K1 mutations are RAF-regulated oncogenic mutations with a relatively low incidence of co-occurring MAPK pathway activating mutations. Some patients with Class 2 MAP2K1 mutations may derive durable therapeutic benefit from MAPKi. Prospective clinical studies with MAPK inhibitors are warranted in patients with MAP2K1-mutated metastatic cancer.

A phase 1/2 study of CFT1946, a novel, bifunctional degradation activating compound (BIDAC) degrader, of mutant BRAF V600 as monotherapy and in combination with trametinib, in mutant BRAF V600 solid tumors.

TPS3163 Background: BRAF is a protein kinase that acts as a signal transducer in the MAPK pathway. Mutant BRAF V600 is capable of uncontrolled signaling and is constitutively active and signals as a monomer, leading to hyperactivation of MEK, ERK, and dysregulation of cellular proliferation. Mutant BRAF V600 is a clinically-validated target in a variety of cancers including melanoma, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and anaplastic thyroid carcinoma (ATC). Currently approved BRAF inhibitors (BRAFi) result in paradoxical RAF activation as the mutant BRAF protein is still able to dimerize with WT BRAF, resulting in a dimeric signaling complex. CFT1946 is a novel, orally bioavailable BiDAC degrader that inhibits and degrades mutant BRAF V600 protein. Distinct from approved BRAFi, CFT1946 avoids paradoxical RAF activation as the degraded BRAF V600 mutant protein can no longer incorporate into a dimeric signaling complex. CFT1946 is selective for the mutant protein and spares WT BRAF V600. CFT1946 has demonstrated preclinical activity in BRAF V600 mutant in vitro and in vivo models, including models resistant to BRAFi. These preclinical data provide rationale for a first-in-human (FIH) study to evaluate CFT1946 in BRAF V600 mutant solid tumors. Methods: This is a FIH, open-label, multicenter, Phase 1/2 clinical trial to characterize the initial safety, tolerability, and preliminary efficacy of CFT1946 and CFT1946+trametinib in BRAF V600 mutant melanoma, NSCLC, CRC, ATC, and other non-CNS BRAF V600 mutant solid tumors. This study includes 2 phases: dose escalation Phase 1 comprising CFT1946 (Arm A) with a starting oral dose of 20 mg twice daily and CFT1946+trametinib (Arm B) as well as dose expansion Phase 2 comprising CFT1946 (Arm A1) and CFT1946+trametinib (Arms B1 and B2). Arm A1 and B1 will include BRAF V600 mutant melanoma and NSCLC with prior BRAFi therapy while Arm B2 will enroll BRAF V600 mutant NSCLC who are BRAFi-naïve. Phase 2 will be initiated once the RP2D has been identified. Eligible subjects are ≥18yo with documented BRAF V600 mutant cancers who have received ≥1 prior therapy. CFT1946 will be administered orally in 28-day cycles until disease progression or intolerable toxicity. Primary objectives include safety, tolerability, RP2D and preliminary antitumor activity of CFT1946 monotherapy and in combination with trametinib. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics. Key inclusion criteria include documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy; at least 1 prior line of standard-of-care therapy for locally advanced or metastatic disease. The study is anticipated to enroll 101-122 patients across 11 participating US and European sites and is currently open to enrollment (NCT05668585). Clinical trial information: NCT05668585 .

A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors.

9111 Background: RET gene fusions have been identified as oncogenic drivers in 1-2% of non-small-cell lung cancer (NSCLC) and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancer (MTC). Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 is a highly potent RET inhibitor that selectively targets RET fusions and mutations. This study is to investigate the safety, PK characteristics and preliminary efficacy of SY-5007 in Chinese patients with advanced RET-altered solid tumors. Methods: In this first-in-human phase I study, eligible patients previously treated and with positive RET were enrolled. In the dose escalation phase, following 3+3 design, the patients were administered orally with SY-5007 20 mg once daily, or 20, 40, 80, 120, 160, 200 mg twice daily in a 28-day cycle. The expansion doses (160 and 200 mg twice daily) were executed in a dose expansion phase to determine a recommended phase II dose (RP2D). Then three cohorts ( RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC) at RP2D were expanded in eligible patients. Primary endpoints included safety, tolerability, MTD, DLTs. Secondary endpoints included PK and preliminary antitumor activity of SY-5007 per RECIST v1.1. Results: As of Feb.06, 2023, a total of 60 patients including 55 RET fusion NSCLC and 5 RET mutant solid tumors were enrolled into dose escalation cohorts (n = 17) and dose expansion cohorts (n = 43).Totally, 55 (91.7%) patients experienced treatment-related adverse events (TRAEs) including increased aspartate aminotransferase (50.0%), increased alanine aminotransferase (41.7%), diarrhea (41.7%), etc. Grade ≥3 TRAEs were observed in 22 (36.7%) patients including hypertension (15%), diarrhea (5%), increased alanine aminotransferase (3.3%), etc. PK study showed SY-5007 was absorbed rapidly, exposure of SY-5007 increased in a dose-dependent manner at doses between 20 and 160 mg twice daily, and it was saturated at 160 mg twice daily. In 50 evaluable patients, the overall ORR and DCR was 62.0% (95% CI, 47.2-75.4) and 94.0 % (95% CI, 83.5-98.8), respectively. 29 patients (24 NSCLC, 4 MTC) received SY-5007 at 160 mg twice daily, 27 of 28 (96.4%) evaluable patients showed tumor regression, ORR and DCR was 72.4% (95% CI, 52.8-87.3) and 89.7% (95% CI, 72.7-97.8), respectively. For NSCLC patients, the ORR and DCR was 75.0% (95% CI, 53.3-90.2) and 91.7% (95% CI, 73.0-99.0), respectively. Conclusions: SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing. Research Sponsor: Shouyao Holdings (Beijing) Co., Ltd. Clinical trial information: NCT05278364 .

Abstract ND05: The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers

Abstract The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated in ~8% of all human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), which is found in &amp;gt;70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because nearly all patients progress, due to either primary or acquired resistance. A bifunctional degradation activating compound (or BiDACTM degrader) may address the liabilities of approved drugs by overcoming, or preventing the emergence of, resistance to BRAF inhibitors. Here we describe CFT1946, an orally bioavailable cereblon-based BiDAC degrader of BRAF V600 mutant proteins, and provide an overview of the medicinal chemistry path leading to its discovery. CFT1946 degrades BRAF V600 mutant proteins, while maintaining exquisite selectivity against the proteome, sparing wild type BRAF (BRAF-WT), ARAF, and CRAF. In A375 cells, CFT1946 potently degraded BRAF V600E and inhibited ERK phosphorylation and cell growth while having no effect in the mutant KRAS, BRAF-WT driven cell line HCT116. In the A375 xenograft model, oral delivery of CFT1946 at 10 mg/kg PO BID resulted in deeper and more durable tumor regression compared to a clinically relevant dose of encorafenib. Further evaluation of CFT1946 in an engineered, clinically relevant BRAFi-resistant A375 cell line (endogenous BRAF V600E + engineered expression of NRAS Q61K) demonstrated that CFT1946 both degraded BRAF V600E and caused a loss of viability in these cells, while treatment with encorafenib had no effect. In xenografts derived from this BRAFi-resistant cell line, oral dosing of CFT1946 as a single agent led to tumor growth inhibition, while treatment with a clinically relevant dose of encorafenib had no effect on tumor growth. Furthermore, dosing CFT1946 in combination with the MEK inhibitor, trametinib, resulted in significant tumor regression, whereas combining encorafenib with the same dose of trametinib had no effect. The medicinal chemistry campaign resulting in CFT1946 focused on the improvement of in vivo pharmacokinetics and rational linker design to achieve high oral bioavailability in a beyond Rule of 5 heterobifunctional degrader. The preclinical data presented herein support the planned Phase 1/2 clinical trial of CFT1946 for the treatment of BRAF-V600 mutant solid tumors. Citation Format: Yanke Liang, Mathew E. Sowa, Katrina L. Jackson, Jeffrey R. Simard, Bridget Kreger, Ping Li, Laura Poling, Joelle Baddour, Andrew Good, Hongwei Huang, Scott Eron, Christopher G. Nasveschuk, Robert Yu, Mark Fitzgerald, Victoria Garza, Morgan W. O’Shea, Gesine Veits, Jeremy L. Yap, Moses Moustakim, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe S. Patel, Richard Deibler, Kyle S. Cole, David Cocozziello, Fazlur Rahman, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Roy M. Pollock, Stewart L. Fisher. The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND05.

Abstract B038: Preclinical efficacy of KRASG12C inhibitors in models of pediatric cancer

Abstract Directly targeting RAS is a desirable approach for treating RAS-mutated tumors because direct RAS inhibitors block all RAS effector pathways simultaneously. Recently, several groups have developed agents that directly target KRAS by covalently modifying KRASG12C. KRAS is commonly altered in adult malignancies such as lung, pancreatic, and colorectal adenocarcinoma, but is less commonly altered in pediatric cancer. However, rare pediatric tumors harboring K-, H-, or NRASG12C are observed. The efficacy of KRASG12C inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify H- and NRASG12C has been incompletely characterized. Here we show that the KRASG12C inhibitors AMG 510, MRTX849, and ARS-1620 slow the release of GDP from H-, N-, and KRASG12C in vitro. Using RASless MEFs, we show that the activity of AMG 510 is specific for H-, N- or KRASG12C, while MRTX849 has both G12C and RAS-independent effects on cell viability. The KRASG12C inhibitors decreased cell viability in KRAS-mutant cell lines derived from patients with the pediatric solid tumor neuroblastoma. MRTX849 was more potent than AMG 510 in neuroblastoma cell lines but was less efficacious and less G12C-specific. The KRASG12C inhibitors also decreased cell viability in an NRASG12C-mutant T-cell ALL cell line derived from an adolescent patient but only MTRX849 decreased cell viability in an HRASG12C-mutant rhabdomyosarcoma cell line. These results suggest that KRASG12C inhibitors may be a treatment option for pediatric patients with H-, N- or KRASG12C mutant solid tumors or leukemia. Future studies will be aimed at testing the efficacy of these inhibitors in xenograft models of pediatric cancer and identifying non-RAS targets of MRTX849. Citation Format: Hannah Price, Stacey Stauffer, Katie Powell, Andrew Baker, Andrew Perciaccante, Edjay Ralph Hernandez, Patience Odeniyide, Christine Pratilas, William Burgan, Lisa Jenkins, Kent L. Rossman, Marielle Yohe. Preclinical efficacy of KRASG12C inhibitors in models of pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B038.

Abstract CT203: Updated data from the Phase I Beamion Lung 1 trial of the HER2 tyrosine kinase inhibitor (TKI), BI 1810631, as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations

Abstract Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, particularly in NSCLC. BI 1810631 is a HER2-selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions, whilst sparing EGFR signaling. This ongoing Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804). Here, we present interim results of Phase Ia. Materials and Methods: In Phase Ia, pts with HER2 aberration-positive (overexpression, gene amplification, somatic mutation, or gene rearrangements) advanced/unresectable/metastatic solid tumors refractory/unsuitable for standard therapy were enrolled. Pts received escalating doses of BI 1810631 BID (starting dose: 15 mg) or BI 1810631 QD (starting dose: 60 mg). Phase Ib will initially include 30 pts with advanced HER2 tyrosine kinase domain mutation-positive, pre-treated NSCLC. Additional cohorts may be included in the future. Primary endpoints: MTD based on number of DLTs; number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, disease control, duration of disease control, and PFS (Phase Ib). Results: As of 21 December 2022, 34 pts had been treated in the US, The Netherlands, Japan, and China. Pts had NSCLC (n = 21), colorectal cancer (n = 3), or other tumors (n = 10). Most pts had a pathological HER2 mutation (n = 25). Pts received BI 1810631 15, 30, 60, 100, 150 mg BID (n = 3/3/4/4/3) or 60, 120, 180, 240 mg QD (n = 5/4/5/3). Median number of cycles was 4 (range 1-14). Treatment is ongoing in 23 pts. To date, three DLTs have been observed (grade 2 edema [60 mg BID], grade 3 anemia [60 mg QD], grade 3 elevated ALT [180 mg QD]). The MTD has not been reached with either schedule. Treatment-related adverse events (TRAEs) were reported in 23 pts (68%). The most common TRAEs were diarrhea (n = 9), anemia (n = 5), increased alkaline phosphatase, increased creatinine, increased ALT, hypoalbuminemia (all n = 4), hypocalcemia, elevated AST, dry skin, increased GGT (all n = 3). Three pts had grade 3 TRAEs (anemia/increased GGT [n = 1], increased ALT [n = 2]). In 29 pts evaluable for response the ORR (regardless of confirmation) was 34% (n = 10, all PRs; NSCLC: n = 8; esophagus, cholangiocarcinoma: n = 1). The DCR was 90%. In 19 NSCLC pts evaluable for response, the ORR was 42% and the DCR was 95%. Updated data will be presented at the meeting. Conclusions: These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Citation Format: John Heymach, Frans Opdam, Minal Barve, Hai-Yan Tu, Yi-Long Wu, Neil Gibson, Behbood Sadrolhefazi, Josep Serra, Kiyotaka Yoh, Noboru Yamamoto. Updated data from the Phase I Beamion Lung 1 trial of the HER2 tyrosine kinase inhibitor (TKI), BI 1810631, as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT203.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3+3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N=12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150mg twice daily, oral trametinib 2mg once daily, and intravenous AT13387 260mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Abstract 3425: The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers

Abstract The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated in ~8% of all human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), which is found in &amp;gt;70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because nearly all patients progress, due to either primary or acquired resistance. A bifunctional degradation activating compound (or BiDACTM degrader) may address the liabilities of approved drugs by overcoming, or preventing the emergence of, resistance to BRAF inhibitors. Here we describe CFT1946, an orally bioavailable cereblon-based BiDAC degrader of BRAF V600 mutant proteins, and provide an overview of the medicinal chemistry path leading to its discovery. CFT1946 degrades BRAF V600 mutant proteins, while maintaining exquisite selectivity against the proteome, sparing wild type BRAF (BRAF-WT), ARAF, and CRAF. In A375 cells, CFT1946 potently degraded BRAF V600E and inhibited ERK phosphorylation and cell growth while having no effect in the mutant KRAS, BRAF-WT driven cell line HCT116. In the A375 xenograft model, oral delivery of CFT1946 at 10 mg/kg PO BID resulted in deeper and more durable tumor regression compared to a clinically relevant dose of encorafenib. Further evaluation of CFT1946 in an engineered, clinically relevant BRAFi-resistant A375 cell line (endogenous BRAF V600E + engineered expression of NRAS Q61K) demonstrated that CFT1946 both degraded BRAF V600E and caused a loss of viability in these cells, while treatment with encorafenib had no effect. In xenografts derived from this BRAFi-resistant cell line, oral dosing of CFT1946 as a single agent led to tumor growth inhibition, while treatment with a clinically relevant dose of encorafenib had no effect on tumor growth. Furthermore, dosing CFT1946 in combination with the MEK inhibitor, trametinib, resulted in significant tumor regression, whereas combining encorafenib with the same dose of trametinib had no effect. The medicinal chemistry campaign resulting in CFT1946 focused on the improvement of in vivo pharmacokinetics and rational linker design to achieve high oral bioavailability in a beyond Rule of 5 heterobifunctional degrader. The preclinical data presented herein support the planned Phase 1/2 clinical trial of CFT1946 for the treatment of BRAF-V600 mutant solid tumors. Citation Format: Yanke Liang, Mathew E. Sowa, Katrina L. Jackson, Jeffrey R. Simard, Bridget Kreger, Ping Li, Laura Poling, Joelle Baddour, Andrew Good, Hongwei Huang, Scott Eron, Christopher G. Nasveschuk, Robert Yu, Mark Fitzgerald, Victoria Garza, Morgan W. O’Shea, Gesine Veits, Jeremy Y. Yap, Moses Moustakim, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe S. Patel, Richard Deibler, Kyle S. Cole, David Cocozziello, Fazlur Rahman, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Roy M. Pollock, Stewart L. Fisher. The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3425.

Dabrafenib, alone or in combination with trametinib, in BRAF V600–mutated pediatric Langerhans cell histiocytosis

AbstractLangerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600–mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600–mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600–mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600–mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib.

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration.

Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.

1LBA Late Breaking - A Phase I trial of BI 1810631, a HER2 tyrosine kinase inhibitor (TKI), as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations

Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, particularly in NSCLC. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804).