KRAS G12A

This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.

In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

Actionable alterations were identified in 53.4% of the patients, and KRAS was the most common oncogenic driver alteration. Our study revealed a lower prevalence of patients whose tumor harbors ALK, ROS1, and RET fusions, compared with similar data sets.

Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

P1, N=12, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2024 --> Apr 2025

Furthermore, this phenotype was confirmed by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. These findings show novel insight into the relationship between PFOS, PFOA, and CRC.

We did not confirm the negative predictive value of KRAS G12 mutation in patients treated with T/T, however, OS depends on the specific G12 mutation. In contrast, patients with KRAS G13 mutation had worse survival.

The circulating VAF of RAS genes enables to split RAS mutant-Low (favorable prognosis similar to RAS/BRAF wild-type) from RAS mutant-High (poorer prognosis similar to BRAF mutant) metastatic colorectal cancer. These results provide further insights into prognostication and therapeutic strategies in patients with RAS mutant metastatic colorectal cancer.

ELI-002 2P is a lymph node targeted immunotherapy comprised of Amphiphile (Amph)-modified G12D, G12R, G12V, G12C, G12A, G12S and G13D mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant...Subsequent patients will receive up to 10 doses of Amph-peptides 7P 700 mcg each (4.9 mg total), together with Amph-CpG-7909 (10.0 mg) administered over a five-month treatment period...An interim analysis is planned using group sequential design for control of overall alpha 0.10. Clinical trial information: NCT05726864.

Our study reveals that KRAS mutations exhibit considerable variability in predicting outcomes for LUAD patients undergoing ICI treatment. Thus, the evaluation of KRAS as a biomarker for ICIs necessitates recognizing the potential diversity inherent in KRAS mutations.

Because of a specific p.G12C-KRAS somatic mutation, only the minority of MLA (7.9% with uterine and 6.2% with ovarian primary) are potentially targetable by sotarasib in that rare but aggressive subtype of adenocarcinoma of the female genital tract. Until now, the different location of a somatic KRAS-mutation is of no prognostic impact.

dSTORM imaging of cell line models carrying patient-derived secondary genetic alterations revealed a distinct pattern linked to each mutation respectively. In KRASG12A, we observed a reduction in BCMA density by 2-fold as compared to wild type cells (5.9 ± 0.3 vs. 10.8 ± 1.2 localization clusters/µm2, p=0005).

The rapid demise of these two patients with BRAF V600E-mutant AML highlights their poor prognosis. Few cases of BRAF V600E-mutant AML have been described in the literature, all of which reported poor survival. Intriguingly, most cases exhibited monocytic morphology and concurrent KMT2A rearrangements, as was observed in case 2.

These findings imply the genetic basis of KRAS with immunotherapeutic target molecules based on a real-time platform. This study also suggests the highly heterogeneous nature of cancer cells, which may facilitate the assessment of clonal dynamics across a single patient's disease.

"Recently, sotorasib was developed as a molecular targeted drug for KRAS mutations...By the PNA-LNA PCR clamp method, G12C mutation of surgical specimens was detected successfully. The PNA-LNA PCR clamp method is expected to be applied to the detection of druggable G12C mutations."

Conclusions Chinese KRAS mutant lung cancers are highly heterogeneous in terms of both KRAS mutations and co-altered genes and varied in inflammatory status in tumor microenvironment as well. Molecular and immune characteristics in KRASm NSCLC may influence the clinical outcome of adjuvant therapy.

In our cohort of molecularly profiled KRAS-mutant lung adenocarcinoma BM patients treated with SRS, we found that co-occurring KEAP1 and STK11 were significantly associated with worse iPFS. We also observed that CDKN2A co-altered tumors had an increased incidence of LMD. These findings have implications for future efforts to personalize brain metastasis management based on comprehensive genomic profiling.

We report a case of CCSCC of the oral cavity with PIK3CA and HRAS mutations. The identification of PIK3CA and/or HRAS mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.

These findings argue against the development of 'early' resistance mechanisms after neratinib and pemetrexed exposure. Future studies will be required to understand how NSCLC cells become resistant to neratinib and pemetrexed.

In our cohort of molecularly profiled KRAS -mutant lung adenocarcinoma BM patients treated with SRS, we found that co-occurring KEAP1 and STK11 were significantly associated with worse iPFS . We also observed that CDKN2A co-altered tumors had an increased incidence of LMD. These findings have implications for future efforts to personalize brain metastasis management based on comprehensive genomic profiling.

Conclusions Unfortunately, NGS somatic panel seems to have limited role for the PC treatment nowadays, with few pts receiving treatment guided by the panel. The development of new targeted therapy directed to the most frequently molecular alterations, including KRAS-directed therapy other than KRAS G12C, are urgently needed to improve outcomes.

Conclusions In the largest analysis of the association of KRAS exon 2 and BRAFV600E mutations and disease outcome in resected stage III CC, either mutation was associated with significantly shorter DFS, OS and SAR in MSS tumors, but only with shorter SAR in MSI-H tumors. In addition, all KRAS codon 12 and 13 mutations had similar prognostic value.

Conclusions RMC-6236 exhibits promising anti-tumor activity in patients with KRASG12X PDAC and NSCLC at doses that are well tolerated. Dose escalation is ongoing and data from additional patients will be available at the time of the meeting.

This study details the most prevalent KRAS alterations and co-mutations among KRASalt NSCLC. KRAS p.G12C was the most frequently observed alteration and co-mutations were found in TP53, LRP1B, STK11, KEAP1, and CDKN2A. Our findings have therapeutic implications as co-alterations with STK11/KEAP1 are associated with worse outcomes.

The inhibitors AMG 510 and MRTX849 targeting the KRAS G12C mutation had shown promising results in clinical trials. This small sample retrospective study of real-world revealed that tislelizumab combined with nab-paclitaxel and platinum-based chemotherapy has shown a promising trend of anti-tumor efficacy with manageable safety profile for advanced lung cancer harboring KRAS mutations in China.Patients characteristicsCharacteristicsPatients (n=10)Age (median-yr)55 (51-69)<65 yr-no. (%)8 (80%)Male-no. (%)10 (100%)ECOG Performance Status 1-no.

P1/2, N=150, Enrolling by invitation, Shanghai YingLi Pharmaceutical Co. Ltd. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Apr 2023 --> Apr 2024

The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation.

This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes. The authors found that advanced/metastatic, KRAS-positive nonsmall cell lung cancer is characterized by a poor prognosis and that first-line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression-free survival was observed in patients who had p.G12D and p.G12A mutations. These results underline the need for novel treatment options in this population, such as next-generation KRAS inhibitors, which are in clinical and preclinical development.

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.

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.

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.

These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.

PEAC is a disease of genetic heterogeneity. The administration of EGFR and ALK inhibitors was effective in patients with PEAC. PD-L1 expression and KRAS mutation type may be used as predictive biomarkers for immunotherapy in PEAC. This study provided both theoretical basis and clinical evidence for PEAC.

The case documents a rare presentation of carcinosarcoma within the mediastinum with uncommon paraneoplastic syndrome and genetic profile. Awareness of these unusual clinical and pathological manifestations of the tumor will help in reaching correct diagnosis and proper management of such patients.

P1 | "The combination of a pooled SLP mKRAS vaccine and dual checkpoint blockade is tolerable and immunogenic in patients with resected PDAC. Induction of an mKRAS-specific T cell response is associated with improved DFS in this cohort. Ongoing correlative studies will apply multi-omic approaches to identify novel biomarkers of immune response and resistance."

Patients with no evidence of disease on imaging within 6 months of completion of adjuvant chemotherapy were vaccinated with the mKRAS vaccine (0.3mg/peptide and 0.5mg poly-ICLC (Hiltonol: Oncovir)) weekly for 4 doses followed by booster vaccines every 8 weeks. Patients also received ipilimumab (1mg/kg, every 6 weeks for 2 doses) and nivolumab (3mg/kg, every 3 weeks in the priming phase) followed by nivolumab (480mg, flat dose in boost phase)... This study thus far indicates the induction of de novo, high quality mKRAS-specific T cells in the periphery post-vaccine. Ongoing studies will define TCR diversity and clonality of mKRAS-specific T cells to each mKRAS epitope. Overall, our data will be used to identify peripheral T cell-based biomarkers that may be able to predict response to mKRAS-targeted immunotherapy.

The combination of avutometinib and everolimus overcomes the activation of the PI3K/AKT/mTOR pathway which is an adaptive resistance mechanism to MAPK pathway inhibition. We have shown that avutometinib and everolimus induce synergistic anti-tumor effects preclinically, and preliminary data suggest clinically meaningful ORR and PFS in patients with KRAS mt NSCLC including non-G12C variants.