BRAF G469A

In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with TP53 mutations, suggests that high-grade transformation may be a relatively early molecular event.

Despite 4 cycles of gemcitabine and cisplatin chemotherapy and 3 courses of pembrolizumab, the left obturator lymph node enlarged. The disease has remained stable for more than 18 months. The present case indicates the potential of trametinib to treat mBUC patients with the BRAF G469A mutation in this setting.

Our large-scale analysis characterized the prevalence and mutational landscape of BRAF G469V/A-mutant NSCLC and proposed gefitinib as a potential option, providing a basis for further investigations on treating BRAF-mutated NSCLC.

Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

The SH003 and dabrafenib combination can be potentially developed as an effective treatment strategy for addressing lung cancer patients with the BRAF G469A mutation.

Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7). Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to "new drugs" continue to be a challenge in LMICs.

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.

Eight patients received targeted therapy; Dabrafenib/Trametinib (5), Pembrolizumab (2), Entrectinib (1), while radio-chemotherapy was used in the others. Sent abroad NGS testing was feasible, however local capacity building is necessary. In this highly selected tumor cohort, high percentage of targetable alterations were identified. NGS was helpful to characterize tumors more and to offer alternative therapies.

Our results highlight the clinical utility of molecular sequencing in SO, based on this limited number of cases. However, as malignant SO evolve slowly, more extensive molecular studies in SO with more than 10 years' follow-up are required to draw any conclusions on the prognostic value of the associated gene alterations.

The MAPK DM, high TMB and persistent genomic instability suggest roles for MAPK-targeted therapies, immunotherapies and DNA damage repair pathway inhibitors, respectively, in EMD. Recurrent codon 61 mutations in RAS suggest a specific role in EMD progression.

Furthermore, TP53, LRP1B, STK11, SPTA1and MAGI2 were significantly over-mutated in Class II and III (p<0.06) and SETD2 is over-mutated in Class I (p<0.001), might suggesting relatively poor prognosis in NSCLC patients. Conclusions The characteristics of Chinese NSCLC were further explored, including BRAF mutation types, the incidence of related co-mutations and TMB value, which is helpful to formulate targeted therapy strategies to adapt to different types of BRAF mutation functions according to their genomic and clinical characteristics.

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.

Activating BRAF alterations were detected in ~3% of prostate cancers, and most were Class II mutations and rearrangements; BRAF V600 mutations were exceedingly rare. These findings suggest that BRAF activation in prostate cancer is unique from other cancers and supports further clinical investigation of therapeutics targeting the MAPK pathway.

The study highlights the heterogeneity of patients with BRAF class II and class III regarding histology and co-mutational status, with both classes equally frequent. A more granular investigation of non-V600X alterations and their associated clinical outcomes under different treatment approaches is ongoing.

P1/2, N=37, Terminated, Haihe Biopharma Co., Ltd. | N=150 --> 37 | Trial completion date: Dec 2024 --> Mar 2023 | Recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Mar 2023; Sponsor business decision

MAPK DM were frequent in EMD, and detectable in ctDNA, suggesting roles for both MAPK-targeted therapies and for ctDNA as a biomarker in these patients. A high TMB was identified in patients lacking a MAPK driver mutation; immunotherapy should be considered in this subgroup.

P1/2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Feb 2023 --> Feb 2024

Activating BRAF alterations are detected in ~3% of aPC, with frequent BRAF-SND1 fusions. BRAF RE represent almost half of aPC BRAF GA, the highest fraction observed across a pan-tumor dataset. In addition, we detected a higher incidence of concurrent CDK12 GA and a lower relative frequency of concurrent PTEN,APC, and TMPRSS2-ERG GA.

The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.

P1/2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=38 --> 17

This pediatric and young adult BRAF-positive cohort (14% of tested samples) included primarily low-grade CNS tumors, followed by PTC and histiocytosis, indicating that a significant fraction of pediatric tumors may benefit from BRAF inhibitor therapy. The rate of fusion and SNV positivity was nearly equal, though varied by tumor type, demonstrating the utility of a comprehensive panel targeting both DNA and RNA.

All the uncommon mutants displayed higher sensitivity than both the wild type and BRAF-V600E towards PLX 8394 and LSN3074753...Notably, molecular dynamic (MD) simulation revealed that increased number of interactions caused enhanced sensitivity of G469R and N581S towards sorafenib. RAF kinase inhibitors were further classified into two groups as per their selectivity (Group I: BRAF-V600E-selective and Group II: CRAF-selective) based on which potential mutation-wise combinations of RAF kinase inhibitors were proposed to overcome resistance. Based on computational inhibitor sensitivity profiles, appropriate treatment strategies may be devised to prevent or overcome secondary drug resistance in lung cancer patients with uncommon mutations.

This study shows that despite being benign-looking, peritoneal implants of struma ovarii can carry classical mutations of thyroid-type cancer: similar mutation to the initial histologically malignant struma ovarii or a novel one. Still, 2 out of 4 peritoneal implants of our series are not mutated.

No abstract available

The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission.

aBRAF mutations have historically been considered a favorable prognostic marker in mCRC. Co-mutation with RAS is frequent for both classes and portends poor survival in our real-world cohort. Furthermore, early onset aBRAF mCRC is associated with more aggressive disease.

BRAF inhibitors including vemurafenib, dabrafenib and encorafenib have produced impressive responses in V600X patients, however resistance usually emerges within a year, including RAS mutation, BRAFV600E amplification, and BRAFV600E intragenic deletion or splice variants...The combination of encorafenib and trametinib showed no activity in the same model...Based on its activity in preclinical models, including models of BRAF inhibitor resistance, and its drug-like properties we are progressing CFT1946 as a candidate for clinical development in patients with solid tumors bearing BRAF V600X mutations. Further, given CFT1946’s activity on non-V600 BRAF mutations, we are continuing to explore CFT1946 and related BiDAC degraders as therapeutic options for patients bearing Class II or Class III BRAF mutations.

No abstract available

This is a single center experience from an Indian NSCLC cohort and shows higher prevalence of non-V600E than V600E mutation reported in literature. This may be attributed to increased use of NGS testing revealing otherwise missed alterations on sequential single gene testing.

NTRK rearrangements were not detected. The significance of these molecular aberrations is presently unclear and future studies are needed to establish whether these findings carry any clinicopathologic significance.

Other mutations detected were CTNNB1 D32N, KRAS G12V, and PIK3CA E542K Conclusion Resistance development is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs. NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.

BRAF V600E were the most common BRAF mutations, which accounted for 36% of all BRAF mutation. BRAF mutated Chinese NSCLC patients harbored both BRAF mutations and other driver gene mutation, such as EGFR, KRAS, PI3KCA.

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.

One patient with V600E mutation received vemurafenib . The other patient with a nonV600E mutation (V600_601delins, detected on NGS) received combination dabrafenib-trametinib with an ongoing partial response at 6 months... This single centre study depicts distinct clinicopathologic features in Indian patients with BRAF mutant NSCLC . The higher prevalence of non-V600E mutation may be attributed to increased use of broader panel based NGS testing as opposed to sequential single gene testing . One of the patients with a non-V600E mutation responded to targeted therapy, hence clinicians should be aware of this spectrum of potentially targetable BRAF mutations.

Primary and secondary acquired resistance is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs . NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.

No abstract available

In addition, GNF-7 and SIJ1227 suppress more strongly migration/invasion of these cancer cells than vemurafenib and PLX8394. Taken together, both GNF-7 and SIJ1227 are much superior to vemurafenib and PLX8394 in terms of capability to inhibit all classes of BRAF mutants.