Induction vemurafenib followed by consolidative radiation therapy for surgically incurable melanoma.
Approximately half of melanomas are driven by a point mutation in the BRAF kinase gene, targetable with vemurafenib. However, the chief limitation of continuous BRAF inhibition is that the majority of patients develop resistance within 8 months, including those with surgically unresectable stage III melanoma. Researchers retrospectively reviewed medical records of all patients at our institution with surgically incurable BRAF V600E mutated stage III or limited stage IV melanoma treated with induction vemurafenib, stopped electively during ongoing response, followed by consolidative radiation therapy with or without intervening surgery to debulk nodal metastases. In our six-patient cohort, the median duration of vemurafenib was 5.8 months and the median radiation dose was 57 Gy using conventional fractionation. This algorithm produced 100% locoregional control at 29+ months following radiation and a median progression-free survival of 32.5+ months. Three of six patients remained progression free, and three relapsed in a single organ and achieved ongoing complete response to subsequent therapy. Outcomes greatly exceeding those reported with either BRAF inhibition or radiation alone suggest unanticipated synergies with this therapeutic sequence for both in-field and distant melanoma control, which may be mediated by radiosensitization and immune activation, respectively. In patients with surgically incurable melanoma encompassed within a radiation field, induction vemurafenib and consolidative radiation therapy, rather than continuing vemurafenib until progression, also limit the duration of vemurafenib toxicity and preserve sensitivity to future BRAF inhibition.
aSchool of Medicine bDepartment of Radiation Oncology cDepartment of Medicine, Division of Hematology Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Ashlyn R
AR
Seeley
Jennifer F
JF
De Los Santos
Robert M
RM
Conry
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D003131:Combined Modality Therapy / Q000009:adverse effects; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D060828:Induction Chemotherapy / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D008875:Middle Aged; D009367:Neoplasm Staging; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D000077484:Vemurafenib; D055815:Young Adult
D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf