Dataset Information

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

ABSTRACT:

Background

Imatinib is an active agent for some patients with melanoma harbouring c-KIT alterations. However, the genetic and clinical features that correlate with imatinib sensitivity are not well-defined.

Methods

We retrospectively evaluated 38 KIT-altered melanoma patients from five medical centres who received imatinib, and pooled data from prospective studies of imatinib in 92 KIT-altered melanoma patients. Baseline patient and disease characteristics, and clinical outcomes were assessed.

Results

In the pooled analysis (N = 130), alterations in exons 11/13 had the highest response rates (38% and 33%); L576P (N = 23) and K642E (N = 12) mutations had ORR of 52% and 42%, respectively. ORR was 38% (mucosal), 25% (acral), and 8% (unknown-primary). PFS appeared longer in exon 11/13 vs. exon 17 alterations (median 4.3 and 4.5 vs. 1.1 months; p = 0.19), with similar superiority in OS (median 19.7 and 15.4 vs. 12.1 months; p = 0.20). By histology, median PFS was 4.5 months (mucosal), 2.7 (acral), and 5.0 (unknown-primary) [p = 0.36]. Median OS was 18.0 months (mucosal), 21.8 (acral), 11.5 (unknown-primary) [p = 0.26]. In multivariate analyses, mucosal melanoma was associated with higher PFS and exon 17 mutations were associated with reduced PFS.

Conclusion

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

SUBMITTER: Jung S

PROVIDER: S-EPMC9596433 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

Jung Seungyeon S Armstrong Emma E Wei Alexander Z AZ Ye Fei F Lee Aaron A Carlino Matteo S MS Sullivan Ryan J RJ Carvajal Richard D RD Shoushtari Alexander N AN Johnson Douglas B DB

British journal of cancer 20220823 9

<h4>Background</h4>Imatinib is an active agent for some patients with melanoma harbouring c-KIT alterations. However, the genetic and clinical features that correlate with imatinib sensitivity are not well-defined.<h4>Methods</h4>We retrospectively evaluated 38 KIT-altered melanoma patients from five medical centres who received imatinib, and pooled data from prospective studies of imatinib in 92 KIT-altered melanoma patients. Baseline patient and disease characteristics, and clinical outcomes w ...[more]

PMID: 35999272

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Project description:BackgroundMast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.MethodsWe conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy.ResultsAmong the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.ConclusionsIn patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694 .).

Project description:Rationale: Mutations in KIT, a major cancer driver gene, are now considered as important drug targets for the treatment of melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for KIT-mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with KIT mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of KIT-mutation-bearing melanomas are urgently needed. Methods: A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring KIT mutations (KIT V560D, KIT K642E and KIT D816V) were established, characterized, and then used to test the in vitro and, subsequently, in vivo inhibitory effects of a panel of known KIT inhibitors. Results: Ponatinib was more potent than imatinib against cells bearing KIT mutations. In vivo drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of KIT-mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the KIT D816V mutant protein than does imatinib. Conclusions: Our study of KIT-mutation-and KIT WT-bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-mutation-bearing melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have KIT mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.

Dataset Information

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

Background

Methods

Results

Conclusion

Publications

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

Similar Datasets

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