KRAS amplification

P1, N=388, Recruiting, Shanghai Chest Hospital; CSPC Megalith Biopharmaceutical Co., Ltd

Collectively, our data suggests that CIN and concomitant inflammation are key processes that require correction to allow for fast proliferation in vitro. Finally, we provide evidence that amplification of oncogenic KRAS can promote adaptation.

EGFR p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. MET amplification and TP53 mutations were associated with poorer overall survival.

Our study provides a comprehensive landscape of ancestry-specific patterns in KRAS and EGFR-altered non-Sq NSCLC. These findings can help better understand cancer disparities, aid in the development of new therapeutic strategies and inform more inclusive clinical trials and treatment decisions.

Novel genomic aberrations and molecular subtypes were identified in IGCTs. These findings provide molecular basis for the potential introduction of new treatment strategies in this setting.

Despite accumulating data regarding the genomic landscape of pancreatic ductal adenocarcinoma (PDAC), olaparib is the only biomarker-driven FDA-approved targeted therapy with a PDAC-specific approval...Two were treated with anti-HER2 therapy after their cell-free circulating DNA result, with both benefiting from therapy, including one with a durable response to trastuzumab and no KRAS alteration detected until progression...Our data suggests KRAS mutations as a possible mechanism of primary and acquired resistance to anti-HER2 therapy in pancreatic cancer. Additional studies are needed to clarify the role of KRAS in resistance to anti-HER2 therapy.

P2, N=425, Recruiting, Centre Leon Berard

Among unresectable/recurrent GC population, EOCG has displayed distinct genetic profiles of GAs compared to LOGC. CGP tests may be useful in expanding treatment opportunities for patients with unresectable/recurrent EOGC.

P1, N=146, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively...Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

P1, N=146, Not yet recruiting, Boehringer Ingelheim

P3, N=584, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

We established cell lines with acquired resistance to osimertinib from gefitinib- or erlotinib-resistant NSCLC cells using a dose-escalation method, and found that they had upregulated levels of phosphorylated ERK1/2. Combined treatment with osimertinib and LY3009120 also demonstrated remarkable synergistic anti-tumor activity in mouse xenografts of these cells. This could be a potential new treatment option for KRAS amplification-induced osimertinib failure.

Combined tissue and plasma NGS can increase the detection of AA in patients with newly diagnosed aNSCLC when AA are not detected by one of these assays. Due to discordant data observed, plasma NGS should be considered when AA are not detected by tissue, and viceversa.

Accordingly, the patient continued Osimertinib combined with Carboplatin/Pemetrexed and with additional palliative irradiation due to a new symptomatic spinal cord compression at L3. Acquired EML4-ALK fusion represents an extremely rare (1%) acquired mechanism of Osimertinib-resistance, which enables further effective and feasible therapy by combining EGFR- and ALK-TKI. Rebiopsies, when possible, are of noteworthy value even in heavily pretreated and fragile patients.

The current case report shows that next-generation sequencing can explain why osimertinib is ineffective in EGFR-mutated SCC. The therapeutic strategy for patients with EGFR mutant-positive SCC should include an analysis of coexisting genetic abnormalities by next-generation sequencing. Therapy with EGFR tyrosine kinase inhibitor might be recommended if no additional gene associated with resistance to tyrosine kinase inhibitor is detected.

In the largest on-treatment LBx biomarker dataset for a MET inhibitor in METex14 NSCLC, MR was associated with improved outcomes and TP53 mutation had negative prognostic significance. On-target secondary MET mutations and bypass pathway activation were potential resistance mechanisms.

P3, N=584, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

KRAS amplification defines a novel molecular subset of NSCLC characterized by distinct clinicopathologic and genomic features and worse survival.

These data suggest tumors with high CNA of ERBB2, KRAS and MET represent clinically distinct entities and are significantly less likely to harbour concurrent driver oncogenes. The association between increased copy number and worse OS suggests amplified tumors are an important area for therapeutic development. Overall survival (collection to last contact) for ERBB2, KRAS and MET CNA-High versus CNA-Low tumors, by Driver mutation status.

Instead, sotorasib resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

"Of 21 pts with paired plasma samples, 17 (81%) had ≥1 acquired genomic alteration. RTK alterations and secondary (2°) RAS alterations were most common; each occurred in 57% of pts (Table). KRAS amplification was the most common single alteration (43%)."

Mechanisms of acquired resistance to ICI are heterogenous, including both genomic and immunophenotypic factors. New therapeutic strategies are required to delay and overcome ICI resistance in pts with NSCLC.

In comparison to DMSO-treated and parental controls, the sotorasib-resistant NCI-H358 cells contained an approximately 50-fold increase in KRAS G12C mutant allele copy numbers.Preclinical data generated using a KRASG12C inhibitor-resistant lung cancer cell line is consistent with clinical observations of acquired KRAS amplification following KRASG12C inhibitor treatment as a mechanism of resistance. This model further provides an opportunity to study acquired KRAS amplification and investigate combination treatment options in vitro.

AG is most common in the cerebra of children and adolescents but exceptional cases occur in adults and the acquisition of additional genetic mutations may contribute to high-grade glioma. These cases further demonstrate that molecular characteristics, morphologic features, and clinical context are essential for diagnosis.

SB-PCCs may harbor RHOA mutations, which are reminiscent of the diffuse subtype of gastric cancers or appendiceal GCAs, while KRAS and PIK3CA mutations, commonly involved in colorectal and small bowel adenocarcinomas, are not typical of such cancers.

P2, N=425, Recruiting, Centre Leon Berard | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Feb 2024 --> Feb 2026

Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.

The genomic profiling of Brazilian NSCLC indicated actionable mutations and remarkable genomic amplifications and deletions. Our results may contribute to improve the knowledge about the molecular profile of admixed patients.

"Prevalence of dMMR/MSI-H and TMB-H is very low in HCC. PD-L1 is only expressed in <20%. Even with a finding of strong association of expression of several established IO biomarkers with PD-L1 expression, it’s still not predictive of response to ICI."

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Active, not recruiting --> Recruiting

P1, N=45, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Oct 2023 --> Apr 2026 | Trial primary completion date: Oct 2022 --> Jul 2024

Small molecule KRASG12C inhibitors AZ'1569 and AZ'8037 were employed...ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ'1569...Importantly, KRAS amplification and AZ'1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Taken together, combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients.

Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.

P1, N=133, Active, not recruiting, Revolution Medicines, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Nov 2022 --> May 2023 | Trial primary completion date: Jul 2022 --> Mar 2023

Background In the randomized phase III BEACON study (NCT02928224), encorafenib + cetuximab ± binimetinib regimens improved overall survival and objective response rate vs standard of care (control) in pts with previously treated BRAF V600E-mt mCRC. Conclusions ctDNA analyses revealed that MAPK pathway reactivation is a common mechanism of resistance for BRAF V600E-mt mCRC following inhibition of BRAF and EGFR ± MEK inhibition. Acquired mutations in RAS-MEK signaling were more prevalent in the doublet arm, while enhanced receptor signaling was more prevalent in the triplet arm.

The gene target characteristics of gastric mixed tumors were the existence of multi-gene mutation, including human epidermalgrowth factor receptor-2 (HER2) gene amplification, key result areas (K-ras) and platelet-derived growth factor receptor alpha (PDGFRA). Gastric mixed tumors should be adequately sampled, each piece of tissue should be involved in the morphological proportional division of the tumor, and any independent histological component should be written into the pathological examination report.