News - NRAS G12D - LARVOL VERI

Case report: MEK inhibitor as treatment for multi-lineage mosaic KRAS G12D-associated epidermal nevus syndrome in a pediatric patient. (PubMed, Front Neurol)

While the effectiveness of MEK inhibitors such as selumetinib is established in NF1-associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS-driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling.

1 month ago

Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)

KRAS G12D • RAS mutation • KRAS G12 • NRAS G12D

Koselugo (selumetinib)

BDTX-4933-101: A Study of BDTX-4933 in Patients With KRAS, BRAF and Select RAS/MAPK Mutation-Positive Cancers (clinicaltrials.gov)

P1, N=100, Active, not recruiting, Black Diamond Therapeutics, Inc. | Recruiting --> Active, not recruiting

1 month ago

Enrollment closed

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12V • KRAS G12 • NRAS G12D

BDTX-4933

2ms

Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia. (PubMed, Hemasphere)

Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels...Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • STAT5A (Signal Transducer And Activator Of Transcription 5A) • NKG2D (killer cell lectin like receptor K1)

RAS mutation • KMT2A rearrangement • MLL rearrangement • NRAS G12D • NRAS G12 • FLT3 N676K • MLL mutation • KMT2A expression

Farydak (panobinostat)

2ms

Integrated molecular profiling of RAS, BRAF mutations, and mismatch repair status in advanced colorectal carcinoma: insights from gender and tumor laterality. (PubMed, J Gastrointest Oncol)

In our case series, more than 60% of patients had at least one mutation in KRAS, NRAS, or BRAF. The presence of mutations in these genes is closely related to CRC prognosis and helps define the best therapeutic approach in patients with metastatic CRC.

2 months ago

Journal • Mismatch repair • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

BRAF V600E • KRAS mutation • BRAF mutation • NRAS mutation • BRAF V600 • KRAS G12D • RAS mutation • NRAS G12D

7ms

KRAS Allelic Variants in Biliary Tract Cancers. (PubMed, JAMA Netw Open)

This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.

7 months ago

Retrospective data • Journal • Tumor mutational burden • MSi-H Biomarker

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IFNG (Interferon, gamma)

KRAS mutation • MSI-H/dMMR • NRAS mutation • KRAS G12D • KRAS G12V • TMB-L • KRAS G12 • NRAS Q61 • KRAS Q61H • NRAS G12D

7ms

Exploring the Relationship Between KRAS, NRAS, and BRAF Mutations and Clinical Characteristics in Iranian Colorectal Cancer Patients. (PubMed, J Gastrointest Cancer)

The study's findings indicate a rising frequency of mutations in these genes in Iran, highlighting the need to screening mutations in the main exons of all three genes for effective colorectal cancer treatment strategies.

7 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS Q61 • KRAS Q61H • KRAS exon 2 mutation • NRAS G12D • BRAF amplification • BRAF exon 15 mutation

7ms

Clinical and genomic landscape of RAS mutations in gynecologic cancers. (PubMed, Clin Cancer Res)

RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

7 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • RAS (Rat Sarcoma Virus)

TP53 mutation • KRAS mutation • NRAS mutation • PIK3CA mutation • KRAS G12D • PTEN mutation • ARID1A mutation • KRAS G12V • RAS mutation • KRAS G12 • NRAS G12D • NRAS G12

7ms

Efficacy of Regorafenib and Trifluridine/Tipiracil According to Extended RAS Evaluation in Advanced Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Analysis. (PubMed, Target Oncol)

Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded.

7 months ago

Retrospective data • Journal • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • KRAS G12D • KRAS wild-type • RAS mutation • RAS wild-type • KRAS G12 • KRAS exon 2 mutation • NRAS G12D • NRAS G12

Stivarga (regorafenib) • Lonsurf (trifluridine/tipiracil)

9ms

Association of KRAS G12C Status with Age at Onset of Metastatic Colorectal Cancer. (PubMed, Curr Issues Mol Biol)

Our data suggest that KRAS G12C mutations are more frequent in early-onset metastatic CRC. To the best of our knowledge, this is the largest cohort in the Latin American population with metastatic CRC reporting RAS, BRAF and MSI/MMR status.

9 months ago

Clinical • Journal • MSi-H Biomarker • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

BRAF V600E • KRAS mutation • MSI-H/dMMR • KRAS G12C • NRAS mutation • KRAS G12D • KRAS G12V • KRAS G12 • NRAS G12D

9ms

Elusive and Aggressive: Unraveling SMARCB1/INI1-Deficient Undifferentiated Carcinoma With Rhabdoid Features Arising From the Colon: A Case Report and Comprehensive Literature Review. (PubMed, Int J Surg Pathol)

The diagnosis of SWI/SNF-deficient undifferentiated carcinoma can be challenging. Correlation with clinical findings, in conjunction with IHC work-up and molecular analysis, is of utmost importance to arrive at the appropriate diagnosis and exclude potential mimics.

9 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1)

KRAS mutation • BRAF mutation • KRAS G12D • BRAF wild-type • RAS wild-type • KRAS G12 • NRAS wild-type • NRAS G12D

11ms

Transcriptome analysis of primary adult B-cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis. (PubMed, Eur J Haematol)

We demonstrate that RNA-seq is an effective tool for precision medicine in B-ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.

11 months ago

Preclinical • Journal

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CRLF2 (Cytokine Receptor Like Factor 2) • PDE4DIP (Phosphodiesterase 4D Interacting Protein) • PDE4D (Phosphodiesterase 4D) • DUX4 (Double Homeobox 4)

KRAS mutation • KRAS G12D • KRAS G13D • KRAS G12 • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • NRAS G13D

11ms

AMPLIFY-201: A Study of ELI-002 in Subjects With KRAS Mutated Pancreatic Ductal Adenocarcinoma (PDAC) and Other Solid Tumors (clinicaltrials.gov)

P1, N=25, Active, not recruiting, Elicio Therapeutics

11 months ago

Trial completion date

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS G12D • NRAS G12

ELI-002 7P

11ms

Schimmelpenning-Feuerstein-Mims syndrome with orbital choristoma and KRAS mutation: a current review and novel case report. (PubMed, Ophthalmic Genet)

This is the first case description of a KRAS mutation identified in an orbital choristoma in SFMS. The disease is described under various names in the literature, and we propose that all syndromic cases with mosaic RAS mutations be reported under the eponym, SFMS.

11 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)

KRAS mutation • NRAS mutation • KRAS G12D • RAS mutation • HRAS mutation • KRAS G12 • NRAS G12D

12ms

Association of KRAS G12C status with age at onset of metastatic colorectal cancer in the Brazilian population: A multicenter analysis of a molecular profile database (RAS, BRAF and MSI status). (ASCO-GI 2024)

In our Brazilian cohort of mCRC patients, frequencies of RAS and BRAF mutations were similar to worldwide data. However, we found lower than expected frequency of MSI-high tumors. KRAS G12C mutation was associated with early-onset mCRC, an emergent population in which KRAS G12C inhibitors might be particulary useful.

12 months ago

Clinical • MSi-H Biomarker • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability)

BRAF V600E • KRAS mutation • MSI-H/dMMR • KRAS G12C • NRAS mutation • KRAS G12D • KRAS G12V • KRAS wild-type • RAS mutation • RAS wild-type • NRAS Q61K • KRAS G12 • NRAS Q61 • NRAS G12D • NRAS G12 • KRAS Q61K

1year

Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma. (PubMed, J Hepatol)

These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.

1 year ago

Preclinical • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR2 (Fibroblast growth factor receptor 2) • BICC1 (BicC Family RNA Binding Protein 1)

BRAF V600E • KRAS mutation • BRAF V600 • KRAS G12D • FGFR2 mutation • FGFR2 fusion • FGFR fusion • KRAS G12 • NRAS Q61 • FGFR2-BICC1 fusion • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • KRAS Q61 • NRAS G13D • NRAS G12C

Lytgobi (futibatinib)

1year

Deciphering the Role of RAS Pathway Mutations in the Biology of Human Acute Myeloid Leukemia Using In Vivo Models (ASH 2023)

Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias.

1 year ago

Preclinical

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTCH1 (Patched 1) • CD34 (CD34 molecule)

KRAS mutation • NRAS mutation • KRAS G12D • KRAS wild-type • NF1 mutation • KRAS G13D • RAS mutation • RAS wild-type • KRAS G12 • MLL rearrangement • PTCH1 mutation • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • MLL mutation • NRAS G13D • KMT2A expression • KRAS overexpression • KRAS expression

cytarabine • Daurismo (glasdegib)

1year

N/KRAS-Mutant AML LSCs Originate from Committed Myelomonocytic Progenitors and Drive Clinical Resistance to Venetoclax (ASH 2023)

We reanalyzed data from a cohort of 118 older/unfit newly diagnosed AML patients treated on a prospective clinical trial with VEN and decitabine (DEC) (NCT03404193). It shows for the first time that interaction between an oncogenic driver and the non-genetic developmental hematopoietic hierarchy imposes a specific LSC cell-of-origin restriction and in turn shapes the hierarchical structure of the resulting AML and critically determines therapeutic outcomes in patients. Importantly, our results have direct implications for clinical practice, as they support that RAS MT LSCs drive clinical resistance to VEN and that treatment with VEN in patients with RAS mutations can accelerate disease progression by selection of RAS MT LSCs (Figure).

1 year ago

Clinical • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • CD34 (CD34 molecule) • CD14 (CD14 Molecule) • CD68 (CD68 Molecule) • ITGAM (Integrin, alpha M)

KRAS mutation • NRAS mutation • KRAS G12D • RAS mutation • RAS wild-type • KRAS G12 • NRAS G12D • NRAS G12

Venclexta (venetoclax) • decitabine

1year

Clonal Targeting of DNA Damage Response Pathways Eradicates Myeloproliferative Neoplasms (ASH 2023)

The "clonal attack" by DDR inhibitors shifts the paradigm of genotoxic therapies from those using non-discriminative cytotoxic drugs to those selectively attacking DDR vulnerabilities in MPN clones with minimal harm to normal cells. Since clonal heterogeneity and DNA damage are hallmarks of cancer, the "clonal attack" may be broadly applicable to the quest for cancer cure.

1 year ago

PARP Biomarker

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • RAD51 (RAD51 Homolog A) • CD34 (CD34 molecule) • SETBP1 (SET Binding Protein 1) • RAD52 (RAD52 Homolog DNA Repair Protein)

DNMT3A mutation • NRAS G12D • NRAS G12 • JAK2 V617F • IDH1 R132

1year

Characterizing Intraprimary Tumor Genetic Heterogeneity in Colorectal Carcinoma with Multiple Driver Alterations (AMP 2023)

These data support that the tumor likely arose from three separate clonal populations, the BRAF V600E population and the KRAS G12G and KRAS G12C populations, each having distinct molecular pathways to tumorigenesis. Future directions include measuring spatial gene expression patterns of the tumor to correlate with the tumor mapping described above and to further characterize the multiple populations of tumor cells harboring different driver alterations and molecular pathways to tumorigenesis.

1 year ago

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)

BRAF V600E • KRAS mutation • KRAS G12C • BRAF V600 • KRAS G12D • BRAF V600K • KRAS G12 • KRAS exon 2 mutation • NRAS G12D • HRAS G12C • BRAF V600E + KRAS G12D

Cologuard®

1year

Molecular Pattern and Clinical Implications of KRAS/NRAS and BRAF Mutations in Colorectal Cancer. (PubMed, Curr Issues Mol Biol)

NRAS and BRAF mutations were significantly more frequent in the right colon. BRAF mutation was more common in women and in the right colon.

1 year ago

Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

BRAF V600E • KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12D • RAS mutation • KRAS G12 • KRAS exon 2 mutation • NRAS G12D • KRAS exon 3 mutation • KRAS exon 4 mutation

1year

AMPLIFY-201: A Study of ELI-002 in Subjects With KRAS Mutated Pancreatic Ductal Adenocarcinoma (PDAC) and Other Solid Tumors (clinicaltrials.gov)

P1, N=25, Active, not recruiting, Elicio Therapeutics | Trial completion date: Jul 2025 --> Mar 2026

1 year ago

Trial completion date • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS G12D • NRAS G12

ELI-002 7P

over1year

Molecular Characterization of Non-small Cell Lung Cancer in People Living with HIV or Solid Organ Transplants (IASLC-WCLC 2023)

The identification of targetable genomic alterations in tumors from individuals living with HIV and solid organ transplant recipients underscores the importance of comprehensive molecular testing in these patient populations. While important markers of immunotherapy response (PD-L1, TMB) were similar, different immune characteristics were identified. Further research is necessary to fully understand the molecular profiles of lung cancer in individuals with HIV and solid organ transplant.

over 1 year ago

Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • LAG3 (Lymphocyte Activating 3) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • KDM5C (Lysine Demethylase 5C)

PD-L1 expression • TP53 mutation • KRAS mutation • TMB-H • KRAS G12C • NRAS mutation • PIK3CA mutation • HER-2 mutation • KRAS G12D • PTEN mutation • KRAS G12V • MET exon 14 mutation • STK11 mutation • KRAS G12 • KRAS G13 • NRAS G12D • LAG3 expression • NRAS G13 • KRAS G13C

PD-L1 IHC 22C3 pharmDx • MI Tumor Seek™

over1year

Exploring switch II pocket conformation of KRAS(G12D) with mutant-selective monobody inhibitors. (PubMed, Proc Natl Acad Sci U S A)

When expressed in cells as genetically encoded reagents, these monobodies engaged selectively with KRAS(G12D) and inhibited KRAS(G12D)-mediated signaling and tumorigenesis. These results further illustrate the plasticity of the S-II pocket, which may be exploited for the design of next-generation KRAS(G12D)-selective inhibitors.

over 1 year ago

Journal

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)

KRAS mutation • NRAS mutation • KRAS G12D • KRAS wild-type • RAS wild-type • HRAS mutation • KRAS G12 • NRAS G12D • NRAS G12

over1year

Trial redesign for the phase II/III DETECTION trial: circulating tumour DNA-guided therapy for stage IIB/C melanoma after surgical resection (BAD 2023)

Those with ctDNA detected were randomized 1 : 1 in a double-blind fashion to continue routine follow-up with the investigators’ choice of treatment if they developed disease recurrence or were unblinded and treated with nivolumab...CtDNA is a useful tool to monitor for MRD/molecular relapse. The DETECTION trial will assess whether it can be used to safely monitor patients and systemically treat only those at highest risk of melanoma progression.

over 1 year ago

P2/3 data • PD(L)-1 Biomarker • Circulating tumor DNA

BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • TERT (Telomerase Reverse Transcriptase)

BRAF V600E • BRAF V600 • BRAF V600K • NRAS Q61K • NRAS Q61 • NRAS G12D • NRAS G12 • TERT mutation

Opdivo (nivolumab)

over1year

Detection of RAS gene mutations in patients with metastatic colorectal cancer during cetuximab-based first-line treatment and survival of the patients in relation to changes in RAS gene status (ESMO-GI 2023)

The first-line therapy consisted of anti-EGFR cetuximab in combination with irinotecan or oxaliplatin-based chemotherapy. PFS2 was statistically significantly shorter for RAS MT patients resulting in statistically non-significantly shorter OS in RAS MT patients. Our findings indicate that a change in RAS status is a negative prognostic factor for the second-line treatment, but this needs to be confirmed in large-scale studies. Testing RAS status analysing ctDNA might help to stratify patients during the metastatic treatment and to personalize the ongoing therapy.

over 1 year ago

Clinical • Metastases

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

KRAS mutation • NRAS mutation • KRAS G12D • RAS mutation • RAS wild-type • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS Q61H • NRAS G12D • NRAS G12 • KRAS exon 3 mutation

Idylla™ KRAS Mutation Test

Erbitux (cetuximab) • oxaliplatin • irinotecan

over1year

Efficacy of regorafenib according to extended RAS evaluation: A multicenter retrospective analysis (ESMO-GI 2023)

Our data demonstrate that RAS mutations do not affect outcome in regorafenib-treated patients, although a trend toward a better efficacy in RAS mutated patients has been observed. Patients receiving TAS102 in addition to regorafenib (before or after) show a better Regorafenib-related survival, probably because of a less aggressive disease; the benefit of the combination is significantly higher in WT patients and not significant in RAS mutated subgroups. These data, even bearing in mind that less than 50% of patients will receive both drugs, might advise regorafenib anticipation (compared to TAS 102) in RAS mutated patients.

over 1 year ago

Retrospective data

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

KRAS mutation • KRAS G12C • NRAS mutation • KRAS G12D • KRAS wild-type • RAS mutation • RAS wild-type • KRAS G12 • NRAS G12D • NRAS G12

Stivarga (regorafenib) • Lonsurf (trifluridine/tipiracil)

over1year

RAS-mutations in population-based and real-life metastatic colorectal cancer cohorts (ESMO-GI 2023)

In this cohort with population-based and real-world patients, no differences in patient characteristics or treatment modalities were seen between different RAS mt, except a higher frequency of right-colon primaries among KRAS mt compared with NRAS mt. KRAS -G12S conferred a worse OS compared with some other KRAS mt, whereas no other differences in OS were seen. It therefore seems as if different RAS mt behave quite similar.

over 1 year ago

Clinical • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

BRAF V600E • KRAS mutation • KRAS G12C • NRAS mutation • BRAF V600 • KRAS G12D • KRAS G12V • RAS mutation • NRAS Q61K • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS G12S • NRAS Q61R • KRAS G13 • KRAS Q61H • NRAS G12D • NRAS G12 • NRAS G13 • KRAS A146T • NRAS A146T • NRAS A146 • KRAS G12C + KRAS G12V • KRAS Q61K • NRAS G12S

over1year

RAS/ BRAF molecular profile in metastatic versus non-metastatic colorectal cancer (ESMO-GI 2023)

Our results highlighted a difference in the molecular profile of KRAS, NRAS,and BRAF mutations' distribution between metastatic colorectal cancer and non-metastatic ones: NRAS and BRAF mutations were associated with metastasis advent; moreover, the G13D mutation of KRAS was correlated to a better prognosis than mutations in codon 12 of KRAS: G12A and G12S alleles gave the worst prognosis.

over 1 year ago

Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12V • RAS mutation • KRAS G12A • KRAS G12 • KRAS G12S • KRAS G13 • NRAS G12D • NRAS G13 • NRAS G12S

Idylla™ KRAS Mutation Test • Idylla™ NRAS-BRAF Mutation Test

over1year

Efficacacy of trifluridine/tipiracil according to extended RAS evaluation: A multicenter retrospective analysis (ESMO-GI 2023)

Our data demonstrate that RAS mutations do not affect outcome in TAS102-treated patients, although a trend toward a better efficacy in WT patients has been observed. Patients receiving regorafenib in addition to TAS102 (before or after) show a better TAS-related survival, probably because of a less aggressive disease; the benefit of the combination is higher in WT patients but even present in mutated ones subgroups (Codon 12 and rare RAS mutations). These data, even bearing in mind that less than 50% of patients will receive both drugs, might advise regorafenib anticipation (compared to TAS 102) in RAS mutated patients.

over 1 year ago

Retrospective data

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

KRAS mutation • KRAS G12C • NRAS mutation • KRAS G12D • KRAS wild-type • RAS mutation • RAS wild-type • KRAS G12 • NRAS G12D • NRAS G12

Stivarga (regorafenib) • Lonsurf (trifluridine/tipiracil)

over1year

AMPLIFY-201, a first-in-human safety and efficacy trial of adjuvant ELI-002 2P immunotherapy for patients with high-relapse risk with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer. (ASCO 2023)

In a 3+3 dose escalation, n=22 received a subcutaneous course of 6 prime and 4 booster injections of fixed dose Amph-peptides (1.4 mg), admixed with escalating Amph-CpG-7909 (Table). ELI-002 2P, evaluated in a novel MRD+ trial, was safe with ctDNA and serum tumor biomarker reduction and clearance and notable immune responses. The RP2D is the start dose for a phase 1/randomized phase 2 study evaluating a new seven peptide formulation for G12 D, R, V, S, A, C, and G13D mutated solid tumors (NCT05726864). Clinical trial information: NCT04853017.

over 1 year ago

Clinical • P1 data • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CD8 (cluster of differentiation 8) • RAS (Rat Sarcoma Virus) • CD4 (CD4 Molecule) • CA 19-9 (Cancer antigen 19-9)

KRAS mutation • NRAS mutation • KRAS G12D • RAS mutation • KRAS G12 • NRAS G12D • NRAS G13

ELI-002 7P • Promune (agatolimod)

over1year

A Study of BDTX-4933 in Patients With BRAF and Select RAS/MAPK Mutation-Positive Cancers (clinicaltrials.gov)

P1, N=140, Recruiting, Black Diamond Therapeutics, Inc. | Not yet recruiting --> Recruiting

over 1 year ago

Enrollment open

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12V • KRAS G12 • NRAS G12D

BDTX-4933

over1year

AMPLIFY-201: A Study of ELI-002 in Subjects With KRAS Mutated Pancreatic Ductal Adenocarcinoma (PDAC) and Other Solid Tumors (clinicaltrials.gov)

P1, N=25, Active, not recruiting, Elicio Therapeutics | Recruiting --> Active, not recruiting | N=18 --> 25

over 1 year ago

Enrollment closed • Enrollment change • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS G12D • NRAS G12

ELI-002 7P

over1year

DETECTION: Circulating Tumour DNA guidEd Therapy for Stage IIB/C mElanoma After surgiCal resecTION (clinicaltrials.gov)

P2/3, N=8, Terminated, The Christie NHS Foundation Trust | N=1050 --> 8 | Trial completion date: Oct 2030 --> Jan 2023 | Recruiting --> Terminated | Trial primary completion date: Oct 2030 --> Jan 2023; Closed earlier than expected due to the need for a redesign to reflect the recent change in standard of care guidelines. New design will include these treatments.

over 1 year ago

Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Circulating tumor DNA

BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

BRAF V600E • BRAF V600 • BRAF V600K • NRAS Q61K • NRAS Q61 • NRAS Q61R • NRAS G12D • NRAS G12 • NRAS Q61L • BRAF V600R

Opdivo (nivolumab)

over1year

Identification of novel peptide inhibitors for oncogenic KRAS G12D as therapeutic options using mutagenesis-based remodeling and MD simulations. (PubMed, J Biomol Struct Dyn)

The detailed analysis revealed that newly designed peptides have the potential to inhibit KRAS/Raf interaction and the oncogenic signal of the KRAS G12D mutant. Our findings strongly suggest that these peptides should be tested and clinically validated to combat the oncogenic activity of KRAS.Communicated by Ramaswamy H. Sarma.

over 1 year ago

Journal

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)

KRAS mutation • KRAS G12D • RAS mutation • HRAS mutation • NRAS G12D • KRAS exon 12 mutation

over1year

A Study of BDTX-4933 in Patients With BRAF and Select RAS/MAPK Mutation-Positive Cancers (clinicaltrials.gov)

P1, N=140, Not yet recruiting, Black Diamond Therapeutics, Inc.

over 1 year ago

New P1 trial

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12V • KRAS G12 • NRAS G12D

BDTX-4933

over1year

Exploring the genomic landscape of colorectal cancer for enabling clinical genomics informed and real-world data based clinical development (AACR 2023)

RWD based clinical genomic profiling confirms that the vast majority of RAS-alterations in CRC are SVs in exons 2, 3 and 4. Both TMB-high and MSI-high samples are significantly more abundant in the RAS/BRAF-altered cohort. RWD confirms that PI3K-, ERBB- and FGFR-signaling pathways are frequently altered in CRC.

over 1 year ago

Real-world evidence • Clinical • Tumor mutational burden • PD(L)-1 Biomarker • MSi-H Biomarker • IO biomarker • Real-world

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)

TMB-H • MSI-H/dMMR • KRAS G12C • KRAS G12D • KRAS G12V • BRAF wild-type • KRAS G12 • NRAS G12D

FoundationOne® CDx • FoundationOne® Heme CDx