MAP2K1 K57N

P1b, N=6, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2027 --> Oct 2023 | Trial primary completion date: Sep 2027 --> Oct 2023

P1b, N=6, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=150 --> 6

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027

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.

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center

We also found two MAP2K1 activating mutations (K57E and K57N) which can be targeted by trametinib...We also observed two activating PIK3CA mutations (R108H and G364R) which may be sensitive to PIK3CA inhibitor alpelisib... The mutational landscape of our SBA cohort provided compelling evidence that multiple signaling pathways play a role in the pathogenesis of SBA and many driver mutations in these pathways are targetable. Our findings indicated that SBA patients should participate in matched clinical trials for better management of this disease.

In early phase clinical trials of patients with KRASG12C-mutant cancers, promising antitumor activity has been reported with drugs such as adagrasib (MRTX849) and sotorasib (AMG510) which are direct inhibitors of KRASG12C. Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors in patients with cancer. Acquired genomic mutations, amplifications, and rearrangements may be potentially targetable by combining KRASG12C inhibition with available kinase inhibitors or SHP2 inhibitors.

Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.