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| Ref Type | Journal Article | ||||||||||||
| PMID | (37403699) | ||||||||||||
| Authors | Sun W, Xu Y, Yan W, Wang C, Hu T, Luo Z, Zhang X, Liu X, Chen Y | ||||||||||||
| Title | A real-world study of adjuvant anti-PD -1 immunotherapy on stage III melanoma with BRAF, NRAS, and KIT mutations. | ||||||||||||
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| Abstract Text | Melanoma frequently harbors BRAF, NRAS, or KIT mutations which influence both tumor development and treatment strategies. For example, it is still controversial whether adjuvant anti-PD-1 monotherapy or BRAF/MEK inhibitors may better improve the survival for resected BRAF-mutant melanoma. Furthermore, outcomes for melanoma with NRAS and KIT mutation receiving adjuvant immunotherapy remain unclear.One hundred seventy-four stage III melanoma patients who underwent radical surgery in Fudan University Shanghai Cancer Center (FUSCC) during January 2017 to December 2021 were included in this real-world study. Patients were followed up until death or May 30th, 2022. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different category groups. Log-rank analysis was used to identify the prognostic factors for disease-free survival (DFS).There were 41 (23.6%) patients with BRAF mutation, 31 (17.8%) with NRAS mutation, 17 (9.8%) with KIT mutation, and 85 (48.9%) wild-type patients without either genomic alteration of those three genes. Most ( n = 118, 67.8%) of them were acral melanoma, while 45 (25.9%) were cutaneous subtype, and 11 were (6.3%) primary unknown. Among them, 115 (66.1%) patients received pembrolizumab or toripalimab monotherapy as adjuvant therapy; 22 (12.6%) patients received high-dose interferon (IFN), and 37 (21.3%) patients were just for observation. There was no statistical difference in clinicopathologic factors between anti-PD-1 group and IFN/OBS group. Of all the enrolled patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.039). In anti-PD-1 group, patients with BRAF or NRAS mutations had poorer DFS than wild-type group. No survival difference was found among patients harboring different gene mutations in IFN/OBS group. In wild-type patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.003), while no survival benefits were found for patients with BRAF, NRAS, or KIT mutations.Although anti-PD-1 adjuvant therapy provides a better DFS in the general population and in wild-type patients, patients with BRAF, KIT or, especially, NRAS mutation may not benefit further from immunotherapy than conventional IFN treatment or observation. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| KIT | Y553D | missense | unknown | KIT Y553D lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). Y553D has been identified in sequencing studies (PMID: 37125020, PMID: 30923944, PMID: 37403699), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Apr 2024). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| KIT exon11 | melanoma | not predictive | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| KIT exon17 | melanoma | not predictive | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| NRAS act mut | melanoma | decreased response | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 9 months in melanoma patients harboring activating NRAS mutations in either G12 (29%) or Q61 (67.1%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p<0.0001) (PMID: 37403699). | 37403699 |
| NRAS act mut | melanoma | decreased response | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 9 months in melanoma patients harboring activating NRAS mutations in either G12 (29%) or Q61 (67.1%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p<0.0001) (PMID: 37403699). | 37403699 |
| BRAF V600E | melanoma | decreased response | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 17 months in melanoma patients harboring BRAF V600E compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.022) (PMID: 37403699). | 37403699 |
| KIT exon13 | melanoma | not predictive | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| KIT exon11 | melanoma | not predictive | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| KIT exon17 | melanoma | not predictive | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| KIT exon13 | melanoma | not predictive | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 33 months in melanoma patients harboring KIT mutations in either exon 11 (64.8%), exon 13 (17.6%), or exon 17 (17.6%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.200) (PMID: 37403699). | 37403699 |
| BRAF V600E | melanoma | decreased response | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 17 months in melanoma patients harboring BRAF V600E compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p=0.022) (PMID: 37403699). | 37403699 |