DOI: 10.5061/dryad.m0cfxpp0g
title: Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations

description: Background: Somatic CDKN2A and TP53 mutations are recurrent events in
 melanoma, occurring in 13.3% and 15.1% of cases respectively and are
 associated with poorer outcomes. It is unclear what effect somatic CDKN2A
 and TP53 mutations have on the clinical outcomes of patients treated with
 checkpoint inhibitors. Methods: All patients with cutaneous melanoma or
 melanoma of unknown primary who received checkpoint inhibitor therapy and
 underwent genomic profiling with the 50-gene Mayo Clinic solid tumor
 targeted cancer gene panel were included. Patients were stratified
 according to the presence or absence of mutations in BRAF, NRAS, CDKN2A,
 and TP53. Patients without mutations in any of these genes were termed
 quadruple wild type (Quad WT ). Clinical outcomes including median time to
 progression (TTP), median overall survival (OS), 6-month and 12-month OS,
 6-month and 12-month without progression, ORR and disease control rate
 (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and
 Quad WT . Results: A total of 102 patients were included in this trial of
 which 14 had somatic mutations of CDKN2A (CDKN2A mut ), 21 had TP53
 mutations (TP53 mut ), and 12 were Quad WT . TP53 mut , CDKN2A mut and
 Quad WT mutational status did not impact clinical outcomes including
 median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month
 without progression, ORR and DCR. There was a trend towards improved
 median TTP and DCR in CDKN2A mut cohort and a trend towards worsened
 median TTP in the Quad WT cohort. Conclusion: Cell cycle regulators such
 as TP53 and CDKN2A do not appear to significantly alter clinical outcomes
 when immune checkpoint inhibitors are used.
description: <i>Study Population/Study
 Design</i>: This is a
 retrospective study which was approved by Mayo Clinic IRB(16-005168). No
 consent was needed as information was obtain anonymously. This study was
 conducted in accordance with principles for human experimentation as
 defined in the Declaration of Helsinki and International Conference on
 Harmonization Good Clinical Practice guidelines. No participating
 physicians have conflicts of interest to declare.  The Mayo Clinic IRB
 waived the requirement for informed consent since the data was analyzed
 anonymously. Patients were identified from all three Mayo Clinic campuses
 (Minnesota, Arizona and Florida). Patients with a diagnosis of metastatic
 or unresectable cutaneous melanoma or melanoma of unknown primary whose
 tumors were analyzed with our 50 gene Solid Tumor Targeted Cancer Gene
 Panel were included. Patients who received an immune checkpoint inhibitor
 at any point during their treatment course were included. However, data
 associated with the first immunotherapy regimen and overall patient
 outcomes were evaluated for this analysis. Response to targeted therapy,
 chemotherapy and subsequent lines of immunotherapy treatments were
 collected but are not the focus of this study. This study allowed for
 treatment with cytotoxic T-lymphocyte associated protein 4 (CTLA-4)
 inhibitors, PD-1 inhibitors, or combinations that included either a PD-1
 inhibitor or CTLA-4 inhibitor. 
 The objective of this study is to investigate the
 impact of the presence of <i>CDKN2A</i> mutations
 (<i>CDKN2A<sup>mut</sup></i>),
 <i>TP53</i> mutations
 (<i>TP53<sup>mut</sup></i>) and quadruple wild
 type (<i>Quad<sup>WT</sup></i>) mutational status
 on clinical outcomes in patients who received immune checkpoint
 inhibitors. Patients who did not carry <i>TP53</i>,
 <i>CDKN2A</i>, <i>NRAS</i> or
 <i>BRAF<sup>v600</sup></i> mutations were termed
 <i>Quad<sup>WT</sup></i>. The primary endpoint
 measured was median time-to-progression (TTP) with secondary endpoints
 including the percentage of participants without progression at 6 and 12
 months, median overall survival (OS), OS at 6 and 12 months, disease
 control rate (DCR) and overall response rate (ORR) to immunotherapy.
 Response rates were assessed using available CT or MRI imaging and their
 associated reports. Calculations were based on the best overall response
 using the immune related response criteria (irRC) and were categorized as
 complete response (CR), partial response (PR), stable disease (SD) and
 progressive disease (PD). Pathologic tumor characteristics, patient
 demographic and clinical details were also collected by chart review.
 <i>Genomic
 Profiling</i>: The Solid
 Tumor Targeted Cancer Gene Panel is a 50 gene panel that evaluated the
 following genes: <i>ABL1</i>, <i>AKT1</i>,
 <i>ALK</i>, <i>APC</i>, <i>ATM</i>,
 <i>BRAF</i>, <i>CDH11</i>,
 <i>CKDN2A</i>, <i>CSF1R</i>,
 <i>CTNNB1</i>, <i>EGFR</i>,
 <i>ERBB2</i>, <i>ERBB4</i>,
 <i>EZH2</i>, <i>FBXW7</i>,
 <i>FGFR1</i>, <i>FGFR2</i>,
 <i>FGFR3</i>, <i>FLT3</i>,
 <i>GNA11</i>, <i>GNAQ</i>,
 <i>GNAS</i>, <i>HNF1A</i>,
 <i>HRAS</i>, <i>IDH1</i>, <i>IDH2</i>,
 <i>JAK2</i>, <i>JAK3</i>, <i>KDR</i>,
 <i>KIT</i>, <i>KRAS</i>, <i>MET</i>,
 <i>MLH1</i>, <i>MPL</i>,
 <i>NOTCH1</i>, <i>NPM1</i>,
 <i>NRAS</i>, <i>PDGFRA</i>,
 <i>PIK3CA</i>, <i>PTEN</i>,
 <i>PTPN11</i>, <i>RB1</i>, <i>RET</i>,
 <i>SMAD4</i>, <i>SMARCB1</i>,
 <i>SMO</i>, <i>SRC</i>, <i>STK11</i>,
 <i>TP53</i> and <i>VHL</i>. This is a
 laboratory-developed  test using Research Use Only reagents.  Extracted
 DNA from the clinical specimen is fragmented, adapter ligated, and a
 sequence library of fragments is prepared using a custom capture
 hybridization method. Individual patient samples are indexed for
 identification and the library is sequenced on an Illumina platform.
 Sequence data are processed through the Mayo Clinic Clinical Genome
 Sequencing Lab bioinformatics pipeline and a variant call file is
 generated for final analysis and reporting(Unpublished Mayo method). This
 testing is clinically available through Mayo Clinic.
description: The Solid Tumor Targeted Cancer Gene Panel is a 50
 gene panel that evaluated the following genes: <i>ABL1</i>,
 <i>AKT1</i>, <i>ALK</i>, <i>APC</i>,
 <i>ATM</i>, <i>BRAF</i>, <i>CDH11</i>,
 <i>CKDN2A</i>, <i>CSF1R</i>,
 <i>CTNNB1</i>, <i>EGFR</i>,
 <i>ERBB2</i>, <i>ERBB4</i>,
 <i>EZH2</i>, <i>FBXW7</i>,
 <i>FGFR1</i>, <i>FGFR2</i>,
 <i>FGFR3</i>, <i>FLT3</i>,
 <i>GNA11</i>, <i>GNAQ</i>,
 <i>GNAS</i>, <i>HNF1A</i>,
 <i>HRAS</i>, <i>IDH1</i>, <i>IDH2</i>,
 <i>JAK2</i>, <i>JAK3</i>, <i>KDR</i>,
 <i>KIT</i>, <i>KRAS</i>, <i>MET</i>,
 <i>MLH1</i>, <i>MPL</i>,
 <i>NOTCH1</i>, <i>NPM1</i>,
 <i>NRAS</i>, <i>PDGFRA</i>,
 <i>PIK3CA</i>, <i>PTEN</i>,
 <i>PTPN11</i>, <i>RB1</i>, <i>RET</i>,
 <i>SMAD4</i>, <i>SMARCB1</i>,
 <i>SMO</i>, <i>SRC</i>, <i>STK11</i>,
 <i>TP53</i> and <i>VHL</i>. This is a
 laboratory-developed  test using Research Use Only reagents.  Extracted
 DNA from the clinical specimen is fragmented, adapter ligated, and a
 sequence library of fragments is prepared using a custom capture
 hybridization method. Individual patient samples are indexed for
 identification and the library is sequenced on an Illumina platform.
 Sequence data are processed through the Mayo Clinic Clinical Genome
 Sequencing Lab bioinformatics pipeline and a variant call file is
 generated for final analysis and reporting(Unpublished Mayo method). This
 testing is clinically available through Mayo Clinic.