Faculty Bibliography

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Melanoma in the head and neck is known to metastasize to cranial nerves. Prompt treatment is critical for preventing progression and reducing neuropathy. We report a patient who presented with cranial neuropathy related to a malignant skull base lesion that originated as lentigo maligna. The diagnosis was challenging, requiring two surgeries to obtain tissue and neither biopsy leading to a definitive diagnosis. Pathological analyses demonstrated positive immunoreactivity for SOX10 and S100, preservation of H3K27me3, and PTEN and STK11 mutations. The patient was managed with Gamma Knife Radiosurgery and combination immunotherapy. Imaging at 9 months post-SRS showed resolution of the mass lesion. Clinically, the patient has occasional left-sided facial pain requiring no medication and denies facial numbness. We favor a diagnosis of desmoplastic neurotropic melanoma due to the neurotropic spread and response to melanoma-targeted immunotherapy.

BACKGROUND:Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community. METHODS:In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression. RESULTS:Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up (p = 0.002). Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis. CONCLUSIONS:This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

Background: Cemiplimab-rwlc is the only US FDA-approved treatment for patients (pts) with advanced CSCC. The primary analysis of a weight-based regimen of cemiplimab 3 mg/kg IV dosed every 2 weeks (Q2W) in mCSCC has been published; follow-up data are reported here. The primary analysis for the approved fixed-dosing regimen of cemiplimab 350 mg IV dosed every 3 weeks (Q3W) in mCSCC, which displays comparable pharmacokinetics to weight-based dosing, is also reported.
Method(s): In a phase II study (NCT02760498), pts with mCSCC received IV cemiplimab as a weight-based regimen for up to 96 weeks (Group [Gp] 1, n=59) or a fixed regimen for up to 54 weeks (Gp 3, n=56). The primary objective was objective response rate (ORR) per independent central review (ICR; RECIST 1.1 for scans, modifiedWHOcriteria for photos).
Result(s): Baseline characteristics were similar in both gps (Table). Median (range) duration of follow-up was 16.5 (1.1-26.6) months (mos) for the Gp 1 update and 8.1 (0.6-14.1) mos for the Gp 3 primary analysis. ORR (95% confidence interval [CI]) by ICR was 49.2% (35.9-62.5%) in Gp 1, 39.3% (26.5-53.2%) in Gp 3, and 44.3% (35.1-53.9%) for both gps combined. ORR by investigator assessment was 49.2% (35.9-62.5%) in Gp 1, 51.8% (38.0-65.3%) in Gp 3, and 50.4% (41.0-59.9%) combined. Median duration of response (DOR) per ICR has not been reached (range: Gp 1, 2.8-21.6 mos; Gp 3, 2.1-11.1 mos). Estimated 12-month DOR (95% CI) per ICR was 88.9% (69.3-96.3%) in Gp 1 and not evaluable in Gp 3. Similar proportions of pts in both gps experienced an adverse event (AE), most commonly diarrhea, fatigue, and nausea (Table). Grade >=3 AEs were reported in 45.2% (52/115) of pts in both gps combined, most commonly anemia (6.1%, 7/115).
Conclusion(s): The primary analysis of Gp 3 confirms that the approved dose of cemiplimab 350 mg IV Q3W confers comparable efficacy and safety to the weight-based regimen (Gp 1) in mCSCC. Responses in both mCSCC cohorts were durable

Despite major improvements in combatting metastatic melanoma since the advent of immunotherapy, the overall survival for patients with advanced disease remains low. Recently, there is a growing number of reports supporting an "obesity paradox," in which patients who are overweight or mildly obese may exhibit a survival benefit in patients who received immune checkpoint inhibitors. We studied the relationship between body mass index and progression-free survival and overall survival in a cohort of 423 metastatic melanoma patients receiving immunotherapy, enrolled and prospectively followed up in the NYU Interdisciplinary Melanoma Cooperative Group database. We analyzed this association stratified by first vs. second or greater-line of treatment and treatment type adjusting for age, gender, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, number of metastatic sites, and body mass index classification changes. In our cohort, the patients who were overweight or obese did not have different progression-free survival than patients with normal body mass index. Stratifying this cohort by first vs. non-first line immunotherapy revealed a moderate but insignificant association between being overweight or obese and better progression-free survival in patients who received first line. Conversely, an association with worse progression-free survival was observed in patients who received non-first line immune checkpoint inhibitors. Specifically, overweight and obese patients receiving combination immunotherapy had a statistically significant survival benefit, whereas patients receiving the other treatment types showed heterogeneous trends. We caution the scientific community to consider several important points prior to drawing conclusions that could potentially influence patient care, including preclinical data associating obesity with aggressive tumor biology, the lack of congruence amongst several investigations, and the limited reproduced comprehensiveness of these studies.

Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MPM risk reduction (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57-7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MPM survival. The study suggests that inherited host immunity may play an important role in MPM development.

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

Patients diagnosed with metastatic melanoma have varied clinical courses, even in patients with similar disease characteristics. We examine the impact of initial stage of melanoma diagnosis, BRAF status of primary melanoma, and receiving adjuvant therapy on postmetastatic overall survival (pmOS). We studied melanoma patients presenting to Perlmutter Cancer Center at New York University and prospectively enrolled in New York University melanoma biospecimen database and followed up on protocol-driven schedule. Patients were stratified by stage at initial melanoma diagnosis as per AJCC 7th ed. guidelines. pmOS was determined using the Kaplan-Meier method and Cox's proportional hazards models were used to assess hazard ratios (HRs). Three hundred and four out of 3204 patients developed metastatic disease over the time of follow-up (median follow-up 2.2 years, range: 0.08-35.2 years). Patients diagnosed with stage I (n=96) melanoma had longer pmOS (29.5 months) than those diagnosed with stage II (n=99, pmOS 14.9 months) or stage III (n=109, pmOS 15.1 months) melanoma (P=0.036). Initial stage of diagnosis remained significant in multivariate analysis when controlling for lactate dehydrogenase and site of metastases [primary diagnosis stage II (HR 1.44, P=0.046), stage III (HR 1.5, P=0.019)]. Adjuvant treatment was associated with better survival but BRAF mutation status did not show an association. Our data challenge the general assumption that primary melanomas converge upon diagnosis of metastatic disease and behave uniformly. Primary stage of melanoma at the time of diagnosis may be prognostic of outcome, similar to lactate dehydrogenase and metastatic disease sites.

PURPOSE:/UNASSIGNED:To report that metastatic choroidal melanoma (systemic and intraocular) can respond to systemic immunotherapy. METHODS:/UNASSIGNED:In 2010, a 64-year-old woman with a choroidal melanoma was treated with palladium-103 plaque brachytherapy. Developing 2.5 years later, radiation maculopathy was suppressed with periodic intravitreal anti-vascular endothelial growth factor injections for five additional years. Development of a new, discrete choroidal melanoma in the same eye prompted radiographic imaging of the orbits, abdomen/pelvis, and chest. Multi-organ metastasis in the eye, the liver, and nodes was treated with systemic combination immunotherapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) intravenous every 3 weeks for four cycles followed by nivolumab (3 mg/kg) intravenous every 4 weeks as maintenance. Subsequent ophthalmic and systemic surveillance were performed. RESULTS:/UNASSIGNED:All sites of metastases were found to regress on systemic immunotherapy. For example, ophthalmic ultrasound imaging revealed that the intraocular metastasis was reduced from 6.6 to 1.5 mm in thickness. Synchronously, serial radiographic imaging revealed progressive shrinkage and disappearance of hepatic and nodal metastasis (except for one gastrohepatic node). However, combination stereotactic body radiation therapy (30 Gy) with nivolumab maintenance was found to induce a significant reduction in this remaining node. Continued periodic intraocular anti-vascular endothelial growth factor therapy has suppressed her radiation maculopathy resulting in 20/25 vision, now 8 ½ years after initial plaque therapy. CONCLUSION:/UNASSIGNED:This case shows that metastatic choroidal melanoma can present in the same eye as the primary tumor. It also shows that systemic immunotherapy can control both ocular and systemic metastases as well as prolong both life and sight.

BACKGROUND:Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS:This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS:In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS:Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.