BRAF amplification

These two fusion genes may be detected in resembling tumors, which contain giant cells, apart from malignant GCTB. The real-world data used herein provide a unique perspective on genomic alterations in clinicopathologically diagnosed malignant GCTB.

Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.

P1/2, N=65, Active, not recruiting, Sanofi | Trial completion date: Jul 2024 --> Mar 2024 | Trial primary completion date: Jul 2024 --> Mar 2024

The study provided insights into MAPK-altered gliomas in Kuwait highlighting the differences among paediatric and adult patients and providing a framework for planning therapeutic polices.

P2, N=425, Recruiting, Centre Leon Berard

In this highly selected cohort of pts with resected, early stage, non-metastatic CCA, the majority underwent molecular profiling before or at the time of surgery. As expected, FGFR2 fusion/rearrangement and IDH1 mutations were only present in iCCA. An FGFR2 fusion/rearrangement was seen in young, female pts and may have a favorable prognostic value as suggested by a trend in increased RFS.

The present study showed that anal AD had a different profile of GAs compared with advanced rectal AD. CGP tests are useful tool for identifying druggable GAs in advanced anal AD for expanding therapeutic opportunities.

HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.

P1, N=36, Not yet recruiting, Jonathan Riess

Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + T + modified FOLFOX) or the SOC arm (modified FOLFOX alone or in combination with either bevacizumab or cetuximab)...Enrollment is ongoing in Europe, with global sites planned. This abstract was previously presented at ESMO 2022, FPN (Final Publication Number): 1037, by Thierry Andre (reused with permission).

PRESSING-HER2 panel and HER2 non-amplified status by NGS warrant validation as potential predictive markers in this setting.

CNAs, CDKN2A genomic alterations, and MET amplifications have a poor prognosis, while MSS-TMB≥10/Mb cases have a better prognosis, like MSI-TMB≥10/Mb cases. Our findings are remarkable because of the possible importance of ARID1A and CDKN2A in the right colon and some differences in the left colon regarding other agnostic biomarkers, especially amplifications of the rectosigmoid region and rectum.

Twenty-one patients received prior osimertinib, n=5 with erlotinib and n=2 with afatinib before detection of acquired BRAF alteration...The most common EGFR TKI with RAF and/or MEK inhibitors were osimertinib+trametinib+vemurafenib (n=1), osimertinib+trametinib (n=5), osimertinib+dabrafenib (n=2), osimertinib+selumetinib (n=3) and erlotinib+trametinib (n=4)... Our study of patients with EGFR-mutant NSCLC with acquired BRAF alteration patients provides insight into the clinical and treatment outcomes. Further exploration of drug combinations is warranted to investigate the tolerability of treatment for patients with EGFR-mutant with acquired BRAF alteration.

Alternating lorlatinib and crizotinib is safe, preserves QOL, with similar survival to historical data. Expanded exploration of this novel treatment approach is supported.

Based on NGS and PD-L1 IHC, gene mutation, TMB and PD-L1 expression are analyzed. Cox single factor and PFS are used to verify that these molecular markers are independent of TMB and PD-L1 for targeted therapy of lung cancer.

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.

The development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In depth description about different heterocyclic scaffolds (quinoline, imidazole, pyridine, triazole, pyrrole etc.) as BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies.

Combined NGS-based script and ddPCR method is reliable and easily feasible for the detection of gene amplifications, providing useful data for guided therapy in cancer.

P1/2, N=113, Completed, Revolution Medicines, Inc. | Phase classification: P1b/2 --> P1/2

Finally, the platform was applied to quantify IDH1 R132H and BRAF V600E in the serum of subcutaneous-tumor‑bearing nude mice, and the results obtained by SERS were consistent with those from quantitative real-time polymerase chain reaction (qRT-PCR). The present study showed that the dual-signal amplification method is a simple and ultrasensitive strategy for gliomas-associated ctDNAs detection, which is crucial for early diagnosis and dynamic monitoring.

High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7-11% of patients.

He received 4 cycles of 3 weekly Inj cisplatin and Inj pemetrexed followed by adjuvant radiotherapy...He then received multiple lines of chemotherapy with pemetrexed + carboplatin followed by maintenance pemetrexed...He was then managed with Nab paclitaxel with atezolizumab for 7 months. At further progression we resent comprehensive genomic profiling which was positive for MET amplification along with BRAF D594E. Patient was started on Tab capmatinib and had a rapid response that has shown radiological reduction in disease volume in the PET CT done recently. This is a case which illustrates that MET amplification could also be an escape mechanism for non-targetable mutations even while the patient is undergoing standard chemotherapy and immunotherapy. This is a case which illustrates that MET amplification could also be an escape mechanism for non-targetable mutations even while the patient is undergoing standard chemotherapy and immunotherapy. This is in contrast to previous belief that MET amplification is an escape phenomenon only when a known driver mutation is targeted with a receptor blocking agent. We thus propose repeating comprehensive genomic profile at progression in all patients known to have a driver mutation at inception and irrespective of the treatment given.

We describe here the Phase 1 study of PF-07799933 as monotherapy or in combination with binimetinib or cetuximab in participants with BRAF-altered advanced solid tumors. The primary objective of Part 3 is efficacy in defined cohorts (total ~120 participants): Cohort 1-2: BRAF V600 mutant melanoma; Cohort 3: BRAF Class II altered melanoma; Cohorts 4-5: BRAF V600 and Class II altered CRC; Cohort 6: other BRAF V600, Class II/III altered solid tumor not qualifying for Cohorts 1-5. Clinical trial information: NCT05355701.

In conclusion, EGP programmes in patients with advanced CRC are feasible and identify a subset of patients with potentially druggable genomic alterations. However, further efforts must be made to increase the rate of patients treated with genomically guided therapies.

P2 | "According to liquid biopsy before second- and third-line therapies, treatment sequences are: FOLFIRI + cetuximab (first-line), FOLFOX + cetuximab (second-line); irinotecan + cetuximab (third-line) in patients with plasma ctDNA RAS/BRAFV600E WT tumors. In patients with RAS/BRAFV600E mutant tumors, second-line is FOLFOX + bevacizumab, while third-line is regorafenib or trifluridine/tipiracil (investigator's choice)... Both tumor tissue- and liquid biopsy-based comprehensive genomic profiling by NGS identify additional molecular alterations, that could be involved in resistance to anti-EGFR monoclonal antibodies, as compared to PCR-based tumor tissue analysis. CAPRI 2-GOIM trial will determine if NGS would allow better selection of RAS/BRAFV600E WT mCRC patients for the most appropriate treatments through three sequential lines of therapies."

P1/2, N=65, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting | N=133 --> 65 | Trial completion date: Jan 2025 --> Jul 2024 | Trial primary completion date: Jan 2025 --> Jul 2024

To date, treatment has mirrored that of small-cell lung cancer, with platinum-etoposide forming the basis of first-line treatment...However, further prospective investigations are required to elucidate the impact of programmed cell death ligand 1 expression, tumour mutational burden and microsatellite instability on response. This review aims to explore the most recent developments in the treatment of EP-PD-NEC and contribute towards the requirement for clinical guidance founded on prospective evidence.

In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.

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

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.

In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.

High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.

P1/2, N=133, Recruiting, Sanofi | Trial completion date: Dec 2025 --> Dec 2024 | Trial primary completion date: Dec 2025 --> Dec 2024

Approximately 400 pts will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combo w/ either bevacizumab or cetuximab)...Enrollment is ongoing in the US, w/ global sites planned. Clinical trial information: NCT05253651.

Targetable alterations and oncogenic rearrangements are enriched in KRAS wt PDAC compared to KRAS mut. These analyses provide additional therapeutic options and may improve outcomes for KRAS wt patients, warranting blood-based ctDNA genomic profiling in PDAC, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

However, recent significant advances were made with immunotherapy in the first-line treatment of advanced cholangiocarcinoma, with the addition of durvalumab to cisplatin-gemcitabine chemotherapy showing a survival benefit. In the second line setting, only FOLFOX (5FU/folinic acid-oxaliplatin) is validated by a phase 3 trial, yet with a very modest benefit on survival; new options using 5FU with nanoliposomal-irinotecan may emerge in the next few years...This strategy opened the way to personalised medicine for patients which are still fit after first-line treatment and the use of targeted inhibitors in first line constitutes a huge challenge with many ongoing trials to improve patients' care. This review exposes the recent clinical trial findings in non-molecularly selected advanced cholangiocarcinoma, offers a focus on how systematic molecular screening should be structured to allow patients to access to personalised medicine, and details which are the therapeutic options accessible in case of actionable alteration.

P1/2, N=133, Recruiting, Sanofi | Trial completion date: Jul 2025 --> Dec 2025 | Trial primary completion date: Jul 2025 --> Dec 2025

This study suggests a potential role for CDKN2A deletion in glioblastoma-related VTE. Therefore, once independently validated, CDKN2A mutational status may be a promising predictor to identify glioblastoma patients at high risk for VTE, who may benefit from thromboprophylaxis.

Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation...Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.