BRAF mutation + MET amplification

ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.

described a small series of pediatric oligodendroglioma-like tumors with BRAF V600E mutations (3). Interestingly, they exhibited molecular changes usually associated with adult high grade gliomas: chromosome instability, chromosome 7 gains and chromosome 10 loss, but had an indolent natural history.

P2 | "Background: In the ongoing, single-arm, Phase II VISION study (NCT02864992), tepotinib (a highly selective MET inhibitor) showed durable clinical activity in NSCLC patients with MET exon 14 skipping... MET exon 14 skipping can be successfully detected through non-invasive liquid biopsy analysis using next-generation sequencing. The rate of MET exon 14 skipping and the genomic profile and demographics of patients were similar to previously reported data. This abstract and presentation was previously presented at AACR 2020."

NGS offered a less expensive and more reliable model of diagnosis respect to sequential one for patients affected by NSCLC-A.

The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.

In the study, cytological specimens and biopsy samples have a very high coincidence rate of gene detection. EGFR, ALK and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma.We speculate that EGFR and ALK are more prone to concomitant mutations respectively and the treatment of advanced lung adenocarcinoma patients with concomitant mutations deserves further study. The rate of KRAS, NRAS, BRAF, PIK3CA, RET and MET exon14 skipping mutation were low but may had a significant impact on the targeted therapy of patients with advanced lung adenocarcinoma.

Funding: This study was supported by CB16/12/00350 and P118/00226 from ISCIII and Asociación de Mujeres de Apoyo al Cáncer de Mama (AMACMA). AM is recipient of PhD scholarship from Asociación Española Contra el Cáncer (AECC) Valencia Scientific Foundation.

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC)...Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

The treatment of lung cancer is increasingly biomarker-driven, as patients are selected for targeted agents based on the identification of genetic alterations amenable to inhibition. Our ability to further improve patient outcomes with this precision medicine approach will require continued efforts to identify, characterize, and target lesions driving lung cancer tumorigenesis and progression.

Routine testing for extended RAS, BRAF, dmmr or high msi, and NTRK fusions is necessary to determine the best sequencing of chemotherapy and biologic agents for patients with mcrc. Although next-generation sequencing and ctdna are increasingly being adopted, other techniques such as immunohistochemistry retain their relevance in detection of her2 amplification, NTRK fusions, and dmmr.

Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma.

In patients with NSCLC, the cytological material obtained by ultrasound-guided needle aspiration is sufficient for individual and partial molecular analysis in the vast majority of cases. Membrane slides such as cell blocks are valid samples for molecular analysis.

Purpose: In the ongoing, single-arm, Phase 2 VISION study (NCT02864992), tepotinib (a highly selective MET inhibitor) has shown durable clinical activity in NSCLC patients (pts) with METex14 skipping... In this population, METex14 skipping can be successfully detected through non-invasive LBx analysis using a next-generation sequencing panel. The rate of METex14 skipping and the genomic profile and demographics of pts were similar to previously reported data.

Experimental procedures: The combination efficacy and synergy of TNO155 with EGF816 (a 3rd generation EGFR inhibitor), dabrafenib+trametinib or a tool KRAS G12C inhibitor (G12Ci) were respectively assessed in a number of EGFR mutant lung cancer models, BRAFV600E colorectal cancer models and KRASG12C lung and colorectal cancer models. Our findings suggest that SHP2 inhibition is an effective strategy to block the feedback activation of wild type and G12C KRAS, as well as NRAS and HRAS, by a variety of RTKs, in response to ERK inhibition. Given the mutant selective properties of those inhibitors we studied, the tolerability of their combinations with TNO155 is highly expected. Our data provide pre-clinical rationale to explore those TNO155 combinations in the corresponding cancer indications in clinic.

MSI-high or POLE mutant mCRC patients were enrolled in KM-01 (Avelumab)...In addition, there were potentially actionable variants outside of approved label in Korea; translocation of NTRK3 (n=4), RET (n=3), ALK/EML4 (n=2).Promising drugs could be possible to incorporate in clinical trials using PIK3CA (14.5%) with PIK3CA/Akt/mTOR pathway inhibitor, DNA damage response (DDR) genes such as BRCA2 (19.2%), ATM (14.2%), FANCA (6.6%), POLE (5.8%), BRIP1(4.8%), RAD50 (4.5%), BRCA(4.0%), PALB2 (4.0%), PARP2 (3.7%), CDK12 (3.4%), MUTYH (2.7%), RAD54L (2.5%) with immune checkpoint inhibitor and/or PARP inhibitor, KRAS G12C (n=18) with AMG 510 (KRAS inhibitor), amplification of FGFR1 (n=4) and MET (n=1). There are 2 clinical trials which mCRC patients can participate in early 2020; MET alteration in KM-08 (Tepotinib), high tumor mutation burden in KM-12 (Ipilimumab and nivolumab).In conclusion, this project is efficient to detect actionable variations in mCRC...By help of regulatory approval of innovative drugs and off-label use, biomarker-driven early phase clinical trials, it could be a huge therapeutic opportunity for refractory mCRC patients. (This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206).

"Background In the TRIBE2 study, molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD...Legal entity responsible for the study The author. Funding GONO Foundation."

Four samples harbored crizotinib-sensitive mutations (2 MET amplifications and 2 MET exon 14 skipping mutations)... We identified 92/511 samples (18%) with clinically actionable mutations; distributed in 32% early stage and 18% advanced stage disease, indicating that actionable mutations are present at an increased frequency in early stage solid malignancies in our data set and trials to investigate targeted therapy in such settings should be considered. Furthermore, we show that a community-based hospital can be a site for future clinical trials of small molecule inhibitors and bring precision-guided medicine to additional patients. Research Funding: None

A 66 yr old pt with neoplasm of rectosigmoid junction tumor was found to be KRAS wildtype and was treated with cetuximab plus FOLFIRI...A 52 year-old male met Stage IV PC, was treated with rucaparib and irinotecan based on prior sequencing data. Upon relapse, the pt went on ATR inhibitor (BAY1895344) and progressed very quickly...Upon disease progression pt was sequenced and based on presence of BRAF V600E, pt was treated with trametinib and dabrafenib... Our study highlights the utility of comprehensive testing integrating genomic and transcriptomic data, in identifying targeted therapy options for cancer patients. Research Funding: Ashion Analytics

"Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD... TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs."