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Abstract
Background Less than 20% of advanced melanoma patients achieve radiographic Complete Response (CR) with anti-PD1 therapy.1 The Overall Response Rate (ORR) for patients treated with Ipilimumab and Nivolumab is 60%.2 Progression-free Survival (PFS) for combination anti- PD1 and anti-CTLA4 therapy is 11.4 months3 NF1 (Neurofibromatosis 1) mutations occur in 14% of cutaneous melanoma.4 We present data on clinical responses to Immune Checkpoint Inhibitor (ICI) therapy in advanced melanoma patients with tumors harboring pathogenic NF1 mutations compared to NFI wild-type (WT) tumors.
Methods Metastatic or unresectable cutaneous melanoma patients who received ICI therapy were stratified into two groups: (1) NF1-mutated group; (2) NF1-WT group. The latter group included patients whose tumors had non-pathologic NF1 variants, or no NF1 mutations. Mutation status was identified via Next Generation Sequencing (NGS) and variant pathogenicity status was determined using Association of Molecular Pathology (AMP)/American society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for interpretation and classification of somatic variants.5 All patients received ICI therapy. RECIST 1.1 was used to assess treatment responses with CT scans. CR on PET was defined as disappearance of all metabolically active lesions.
Results 71 patients met criteria for inclusion. 25 (35.2%) patients had pathogenic NF1-mutated melanoma. Patients received ICI therapy as follows: Pembrolizumab (n=34), Ipilimumab and Nivolumab (n=22), Relatlimab and Nivolumab (n=12), and Nivolumab (n=3). Median PFS was 30 months in the NF1-mutated group as compared to 15.4 months in the NF1-WT group (HR 0.40; CI 0.19–0.87; p-value 0.02) (table 1, figure 1). Median OS was 48.5 months in the NF1-mutated group as compared to 29.2 months in the NF1-WT group (HR 0.26; 95% CI 0.09 – 78; p-value 0.02) (table 1, figure 2).On univariate analysis, pathogenic NF1 mutation status was associated with an increased likelihood patients achieving radiographic CR with ICI therapy; however, on multivariate analysis, the association between pathogenic NF1 status and CR only approached significance in the setting of concurrent BRAF V600 mutation (HR 2.04; 95% CI 0.93 – 4.46; p-value 0.07).
Conclusions ICI therapy in NF1-mutated advanced cutaneous melanoma appears to have higher rates of PFS and OS, as compared to NF1-WT melanoma. The finding warrants prospective validation. NF1 mutation status could be used as a predictor of response to ICI therapy in advanced melanoma.
Acknowledgements Dr. Asad Javed - for his guidance and leadership throughout this project. Dr. Anthony Snow - for his insights in designing this project. Bradley Loeffler - for helping guide the analysis. Dr. Mohammed Milhem - for his mentorship and encouragement.
References
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Ethics Approval Approval UIHC IRB board Brian Bishop, CIP, MA on 11/07/23. DHHS Registration IRB00000099. IRB ID 202310133. Project met criteria to be granted a full waiver of HIPAA Authorization - 1. The use or disclosure of the requested information involves no more than a minimal risk to the privacy of individuals based on, at least, the presence of the following elements: (a) An adequate plan to protect the identifiers from improper use and disclosure (b) An adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the research, unless there is a health or research justification for retaining the identifiers or such retention is otherwise required by law; and (c) Adequate written assurances that the requested information will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research study, or for other research for which the use or disclosure of the requested information would be permitted by the Privacy Rule; 2. The research could not practicably be conducted without the waiver or alteration 3. The research could not practicably be conducted without access to and use of the requested information.
Progression free survival and overall survival with ICI therapy in NF1-mutated vs. NF1-WT melanoma
Progression free survival in NF1-mutated melanoma compared to NF1-WT melanoma patients
Overall survival in NF1-mutated melanoma compared to NF1-WT melanoma patients
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