Table 2.

Summary of treatment toxicity and response

Age at diagnosis (y)/sexHistologyBRAF statusOther relevant molecular alterationsInvolvement (sites of biopsies in bold)Trametinib line of treatmentClinically significant treatment-related toxicityBest response † Trametinib starting dosageTrametinib ending dosageComments
25/F ECD/RDD Wild-type ‡  MAP2K1K57N, ASXL1R965∗  Skin, bone, heart valve, periaortic 1  CR 0.5 mg daily 0.5 mg daily  
66/M ECD/RDD Wild-type ‡  NRASQ61R Bone, skin, lymph nodes, lung, dura, and orbit 3 Congestive heart failure CR 1.5 mg daily 1 mg daily  
36/M ECD/RDD Wild-type ‡  ANP32A-BRAF fusion Bone, omentum, mesentery, and retroperitoneum 3  SD 1.5 mg daily 0.5 mg daily  
53/M ECD/RDD Wild-type ‡  MAP2K1F53L Bone, pleura, and retroperitoneum 1 Fatigue PR 0.5 mg daily 0.5 mg daily  
69/M ∗  ECD/LCH Wild-type ‡  MAP2K1C121S Brain, bones, retroperitoneum, and periaortic 2 Fatigue PR 1.5 mg daily 0.5 mg daily  
49/M ∗  ECD Wild-type ‡  MAP2K1Q56P Heart, retroperitoneum, pituitary, bones, and skin 4 Rash SD 1 mg daily 0.5 mg daily  
55/M ECD BRAFV600E None identified CNS, adrenal gland, aorta, and perinephric 2 Facial acne (rash), chills, rigors, and drug-induced hepatitis PR 2 mg daily 2 mg daily  
38/F ECD BRAFV600E§,‡  BRAFV471F-NF1 splice site mutations, MCL1 amplification CNS, soft tissue, and bone 4 Paronychia and xerosis SD 2 mg daily 2 mg daily  
44/M ECD/RDD BRAFV600E§,‖  MAP2K1 Eye, vocal cord, periaortic, bone, and sinuses 3 Facial acne (rash) IE 2 mg daily 2 mg daily IE for response because of treatment discontinuation before the first on-treatment assessment 
59/M ECD Wild-type None identified Perinephric, bone, and aorta 3 Rash and diarrhea IE 2 mg daily 2 mg daily IE because of treatment discontinuation before the first on-treatment assessment 
36/M ECD Wild-type None identified Bone and skin 3  IE 1 mg daily 1 mg daily IE for response because of lack of measurable disease 
41/M ECD Wild-type None identified Eyelid 3  IE 2 mg daily 1.5 mg daily IE for response because of lack of measurable disease 
60/M ECD BRAFV600E‡,‖  ASXL1E635fs∗ 15 and CCNE1P396L Pericardial, perinephric, bone, retroperitoneal, and lymph node 1  PR 1 mg daily 1 mg daily  
49/M ECD BRAFV600E‡,‖  ASXL1G646fs∗ 12, BRAFL485W, and ERBB2 amplification Bone, kidney, abdomen, and lung From 1 to 5 (varied with and without dabrafenib and anakinra) Pneumonia PR 1 mg daily 1 mg daily  
40/F ECD Wild-type No additional molecular testing performed Bone and brain 1 Nausea PR 1 mg daily 1.5 mg daily  
23/F RDD CAPZA2-BRAF fusion ‡,‖  IDH2A47V and
RAF1 amplification 		Brain 1 Mucositis and rash IE 2 mg every other day 2 mg daily IE for response because of loss to follow-up 
28/F RDD Wild-type ‖  APCE1157fs Breast and thigh 1 Facial acne (rash) IE 1 mg daily 1 mg daily IE for response because of loss to follow-up 
69/F RDD Wild-type ‖  GNASR201C Ear and eye 1  SD 1 mg daily 1.5 mg daily  
66/M ECD Wild-type ‖  STK11 (splice site SNV) Bone, aorta, and peritoneum 3  IE 1 mg daily  IE for response because of loss follow-up 
49/F ECD BRAFV600E‡  NF1H1494Y Bone, abdomen, and kidney 3 Rash and dizziness IE 0.5 mg daily (1 week) 1 mg daily IE because of treatment discontinuation before the first on-treatment assessment; trametinib used with dabrafenib 
56/M ECD BRAFV600E No additional molecular testing performed Bone and peritoneum 4 Renal toxicity PR 0.5 mg daily 0.5 mg daily Trametinib used with vemurafenib 
52/M ECD BRAFV600E‡  NF1S1407R, NRASG60R, KRASA59T Bone, kidney, abdomen, and lung 2 Uveitis SD 0.5 mg daily 0.5 mg every other day  
29/F ECD Wild-type ‡  MAP2K1Q65P Bone and pericardium 3  PR 0.5 mg daily 0.5 mg daily  
77/M ECD BRAFV600E None identified Bone, aorta, and peritoneum 2 Congestive heart failure IE 2 mg daily 2 mg daily IE because of treatment discontinuation before the first on-treatment assessment; trametinib used with dabrafenib 
53/M ECD Wild-type ‡  GNASR201S Bone and lung 1 Mucositis and infection PR 1 mg daily 0.5 mg daily  
59/M ECD Wild-type ‡  KRASA146P, RB1S249, and GNASQ227E Bone, kidney, abdomen, lung 1  PR 0.5 mg daily 0.5 mg daily  
Age at diagnosis (y)/sexHistologyBRAF statusOther relevant molecular alterationsInvolvement (sites of biopsies in bold)Trametinib line of treatmentClinically significant treatment-related toxicityBest response † Trametinib starting dosageTrametinib ending dosageComments
25/F ECD/RDD Wild-type ‡  MAP2K1K57N, ASXL1R965∗  Skin, bone, heart valve, periaortic 1  CR 0.5 mg daily 0.5 mg daily  
66/M ECD/RDD Wild-type ‡  NRASQ61R Bone, skin, lymph nodes, lung, dura, and orbit 3 Congestive heart failure CR 1.5 mg daily 1 mg daily  
36/M ECD/RDD Wild-type ‡  ANP32A-BRAF fusion Bone, omentum, mesentery, and retroperitoneum 3  SD 1.5 mg daily 0.5 mg daily  
53/M ECD/RDD Wild-type ‡  MAP2K1F53L Bone, pleura, and retroperitoneum 1 Fatigue PR 0.5 mg daily 0.5 mg daily  
69/M ∗  ECD/LCH Wild-type ‡  MAP2K1C121S Brain, bones, retroperitoneum, and periaortic 2 Fatigue PR 1.5 mg daily 0.5 mg daily  
49/M ∗  ECD Wild-type ‡  MAP2K1Q56P Heart, retroperitoneum, pituitary, bones, and skin 4 Rash SD 1 mg daily 0.5 mg daily  
55/M ECD BRAFV600E None identified CNS, adrenal gland, aorta, and perinephric 2 Facial acne (rash), chills, rigors, and drug-induced hepatitis PR 2 mg daily 2 mg daily  
38/F ECD BRAFV600E§,‡  BRAFV471F-NF1 splice site mutations, MCL1 amplification CNS, soft tissue, and bone 4 Paronychia and xerosis SD 2 mg daily 2 mg daily  
44/M ECD/RDD BRAFV600E§,‖  MAP2K1 Eye, vocal cord, periaortic, bone, and sinuses 3 Facial acne (rash) IE 2 mg daily 2 mg daily IE for response because of treatment discontinuation before the first on-treatment assessment 
59/M ECD Wild-type None identified Perinephric, bone, and aorta 3 Rash and diarrhea IE 2 mg daily 2 mg daily IE because of treatment discontinuation before the first on-treatment assessment 
36/M ECD Wild-type None identified Bone and skin 3  IE 1 mg daily 1 mg daily IE for response because of lack of measurable disease 
41/M ECD Wild-type None identified Eyelid 3  IE 2 mg daily 1.5 mg daily IE for response because of lack of measurable disease 
60/M ECD BRAFV600E‡,‖  ASXL1E635fs∗ 15 and CCNE1P396L Pericardial, perinephric, bone, retroperitoneal, and lymph node 1  PR 1 mg daily 1 mg daily  
49/M ECD BRAFV600E‡,‖  ASXL1G646fs∗ 12, BRAFL485W, and ERBB2 amplification Bone, kidney, abdomen, and lung From 1 to 5 (varied with and without dabrafenib and anakinra) Pneumonia PR 1 mg daily 1 mg daily  
40/F ECD Wild-type No additional molecular testing performed Bone and brain 1 Nausea PR 1 mg daily 1.5 mg daily  
23/F RDD CAPZA2-BRAF fusion ‡,‖  IDH2A47V and
RAF1 amplification 		Brain 1 Mucositis and rash IE 2 mg every other day 2 mg daily IE for response because of loss to follow-up 
28/F RDD Wild-type ‖  APCE1157fs Breast and thigh 1 Facial acne (rash) IE 1 mg daily 1 mg daily IE for response because of loss to follow-up 
69/F RDD Wild-type ‖  GNASR201C Ear and eye 1  SD 1 mg daily 1.5 mg daily  
66/M ECD Wild-type ‖  STK11 (splice site SNV) Bone, aorta, and peritoneum 3  IE 1 mg daily  IE for response because of loss follow-up 
49/F ECD BRAFV600E‡  NF1H1494Y Bone, abdomen, and kidney 3 Rash and dizziness IE 0.5 mg daily (1 week) 1 mg daily IE because of treatment discontinuation before the first on-treatment assessment; trametinib used with dabrafenib 
56/M ECD BRAFV600E No additional molecular testing performed Bone and peritoneum 4 Renal toxicity PR 0.5 mg daily 0.5 mg daily Trametinib used with vemurafenib 
52/M ECD BRAFV600E‡  NF1S1407R, NRASG60R, KRASA59T Bone, kidney, abdomen, and lung 2 Uveitis SD 0.5 mg daily 0.5 mg every other day  
29/F ECD Wild-type ‡  MAP2K1Q65P Bone and pericardium 3  PR 0.5 mg daily 0.5 mg daily  
77/M ECD BRAFV600E None identified Bone, aorta, and peritoneum 2 Congestive heart failure IE 2 mg daily 2 mg daily IE because of treatment discontinuation before the first on-treatment assessment; trametinib used with dabrafenib 
53/M ECD Wild-type ‡  GNASR201S Bone and lung 1 Mucositis and infection PR 1 mg daily 0.5 mg daily  
59/M ECD Wild-type ‡  KRASA146P, RB1S249, and GNASQ227E Bone, kidney, abdomen, lung 1  PR 0.5 mg daily 0.5 mg daily  

CNS, central nervous system; CR, complete response; F, female; IE, inevaluable; M, male; PD, progressive disease; PR, partial response; SD, stable disease; SNV, single nucleotide variant.

∗

Patient deceased.

†

CR indicates resolution of lesions, PR indicates improvement but not resolution, SD indicates no change, PD indicates progressive or new lesions, and IE indicates patients in whom response could not be evaluated, and reasons are listed in “Comments.”

‡

Tissue-targeted NGS in CLIA-certified lab, including MSK-IMPACT, MD Anderson Oncomine, Foundation One and others.

§

Urine cell-free DNA

‖

Plasma-targeted NGS in CLIA-certified lab, including Guardant 360, Foundation Liquid CDx and others. (polymerase chain reaction–based testing for BRAF V600E for others)

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