BRAF D594N

BRAF class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.

Our study provides a novel target sequencing panel suitable for Chinese NSCLC patients, which can effectively identify driver mutations, analyze downstream pathway alterations and predict therapeutic utility. Overall it is promising to further optimize and apply this panel in clinic with convenience and effectiveness.

Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

Patient was put on FOLFIRI/bevacizumab chemotherapy...He completed mFOLFOX6.PET scan was done and showed a right upper lobe mass consistent with metastatic cancer... Identification of genomic signature is key to understanding the molecular mechanism of CRC and the development of novel therapeutics. Figure: Figure 1 (left) shows CT Chest for Case 1 with multiple pulmonary nodules few with cavitation, largest 9mm Figure 2(right) shows Bone Scan for Case 3 in February 2021 with intense uptake in the right distal tibia

Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib...Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib... Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.

Conclusion Our results - on a small number of patients - suggest that patients with rare BRAF mutations may have inferior survival outcomes with first line targeted treatment, compared with patients with classical BRAF mutations. Impact statement Our findings add to the limited clinical knowledge on rare BRAF mutations in melanoma and may help guide treatment decisions on this small subset of patients.

Vemurafenib and dabrafenib have already been approved for the treatment of melanoma, NSCLC and colorectal carcinoma. BRAF gene mutations, especially BRAF non-V600, was extensively mutated in Chinese multiple cancer types. Our revealed the potential targeted therapeutic strategies among non-V600 population with solid tumors should be considered in further study.

Preliminary data confirmed the safety of B+E and demonstrated evidence of anti-tumor activity in advanced cancer pts with non-V600E BRAF mts. Enrolment in the BEAVER trial is ongoing.

Then, most of the cases were diagnosed in the advanced stages of the disease and were represented by high-grade adenocarcinomas. This article demonstrates the feasibility of analysis of the entire exon 15 of BRAF gene in CRC patients regardless of tumor localization.

Preliminary data confirmed the safety of B+E and showed preliminary evidence of anti-tumor activity in advanced cancer pts with non-V600E BRAF mts . This study met the criterion for advancing to stage 2 . Enrolment in the BEAVER trial and correlative biomarker analyses are ongoing.