KIT L576P

P2, N=40, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=40, Recruiting, National Cancer Institute (NCI) | Initiation date: Sep 2023 --> Dec 2023

P2, N=40, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

This diagnosis was unexpected and would have been missed without highly sensitive molecular testing; yet it is of clinical importance for the patient. This case raises interesting biology questions regarding the relationship between melanoma and LCH; moreover, it highlights the importance of integrating quantitative information in molecular data interpretation.

P2, N=40, Recruiting, National Cancer Institute (NCI) | Initiation date: Jun 2023 --> Sep 2023

P2, N=40, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Dec 2022 --> Jun 2023

NGS analysis of TETs revealed several somatic variants in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. TCs showed greater genetic dysregulation than TMs. KIT alterations in TCs have potential as therapeutic targets.

In liquid, 58% (39/67) of samples with a KIT-driver mutation had a co-occurring imatinib-resistant KIT alteration... Known driver and TKI-resistant mutations of both somatic and potential germline origin are identified in peripheral blood ctDNA of GIST patients. Liquid biopsy shows high concordance to tissue in identifying driver mutations in the presence of elevated TF and may exhibit TKI-resistant specific alterations. This study indicates that liquid biopsy may be useful in the molecular classification of GIST during the medical management of advanced GIST patients.

This multicenter study highlights KIT-alterations sensitive to imatinib and augments evidence for imatinib in subsets of KIT-altered melanoma.

The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

The patient is currently receiving 400mg of imatinib daily with surveillance CT scans of her abdomen and pelvis as well as chest X-rays every 3 months. The patient is currently 7 months from her tumor resection without evidence of local recurrence, pulmonary chondroma, or paraganglioma. This case report represents the first, known, published description of a pediatric patient with a combined SDH-deficient and KIT-mutated GIST.

The 3rd patient, who was treated first-line with ipilimumab (Ipi) and Nivo, had to discontinue therapy due to autoimmune (AI) colitis grade 3 according to CTCAE. The 4th patient received multiple previous therapies (pembrolizumab (Pembro) + IDO ‐ 1 inhibitor, Ipi + Nivo, paclitaxel + nintedanib, imatinib, Nivo + LAG 3 inhibitor, imatinib)...showed a full remission with good tolerability after 6 months with pembro + nilotinib, the 2nd patient showed stable results after 2 doses of Ipi + Nivo in combination with nilotinib, but developed grade 3 AI gastritis... C ‐ KIT inhibitors alone or in combination with ICI can represent an effective treatment option with good tolerability for c ‐ KIT mutated MM after failure of standard ICI therapy and exhaustion of study therapy options.

In conclusion, in addition to KIT, TP53, and ATRX mutations, which have been previously reported, our cases harbor NF2 mutation and multiple gene copy alterations that have not previously been documented in vaginal melanomas. These findings highlight the potential role of targeted therapy in this rare melanoma subtype.