MAP2K1 P124

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

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.

The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib...With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib...The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option.

We have established a novel, straightforward protocol to detect mutation directly from CTC without preamplification at the single cell level. We expect that this workflow will facilitate the exploration of genetic content of CTC, thereby increasing its potential use in the clinic

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

Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.

Briefly, patients with (n=9) or without (n=5) co-occurring TP53 mutations had a median OS of 12.0 months and not up to now respectively (P=0.41); patients with (n=3) or without (n=11) co-occurring KRAS mutations had a median OS of not up to now and 12.0 months respectively (P=0.33); patients with (n=4) or without (n=10) co-occurring KRAS mutations had a median OS of 14.5 months and 12.0 months respectively (P=0.57); patients with (n=4) or without (n=23) co-occurring STK11 mutations had a median OS of 11.5 months and 12.0 months respectively (P=0.70). Conclusion MAP2K1 genetic alter occurs in a subset of NSCLC, and improved understanding of the implications of MAP2K1 aberrations is critical for the identification of therapeutic target candidates.