Faculty Bibliography

AIM:To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. METHODS:mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p < 0.01 in one pembrolizumab arm. RESULTS:A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p = 0.117) and 10 mg/kg (0.74, 0.57-0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. CONCLUSION:Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.

Background gpNMB is an internalizable transmembrane glycoprotein expressed in multiple tumor types. The ADC GV delivers the potent cytotoxin MMAE to gpNMB+ cells and showed promising activity as monotherapy in advanced melanoma refractory to checkpoint inhibitors (CPI). Preclinical results showed synergistic antitumor activity between ADC with CPI [1, 2], via dendritic cell (DC) activation; ADC-MMAE augmented the immune response induced by V, an agonist monoclonal antibody against the T cell costimulatory molecule CD27. This Phase 2 study was conducted to evaluate the activity and safety of the GV/ V combination in advanced melanoma. Methods Patients with advanced melanoma, progressive after <=1 chemotherapy, >=1 checkpoint inhibitor (CPI), and if BRAF mutation >=1 BRAF or MEK + BRAF inhibitor, were treated with GV (1.9 mg/kg q3w until progression/ intolerance) in combination with V (3.0 mg/kg) on day 1 of weeks 1, 3, 9, 15, 21, and 27. Retrospective analysis on pre-study tumors and skin biopsies include gpNMB expression and infiltrating lymphocytes by immunohistochemistry plus gene expression profiling. Primary objective is to evaluate objective response rate (ORR) (RECIST 1.1). Results Thirty-four patients enrolled: median age of 61 years; 59% male; 18% BRAFV600 mutated; 59% >=3 lines prior therapy; 76% prior anti-CTLA-4; 100% prior anti-PD-1/PD-L1 inhibitor; 97% Stage IV; 71% M1c. Of 30 response evaluable patients, emerging tumor response data shows 2 confirmed partial responses (PR) (ORR = 7%, CI: 0.8, 22.1), and 1 single time point PR before patient withdrew consent. 48% patients had tumor shrinkage. Median PFS = 2.6 months and median OS = 4.4 months; 3 patients remain on treatment and 18 patients in survival follow up. Most common treatment related toxicities include alopecia, rash, fatigue, neuropathy, nausea, and vomiting. Tumor cells in 84% of patients with samples (n=25) tested to date are 100% gpNMB+. Conclusions The GV/V combination was well tolerated without evidence of additive toxicity. There was no apparent enhanced clinical benefit of GV/V over GV alone in this patient population, perhaps because immune checkpoint molecules remained unblocked and/or of a dearth of antigen presenting cells in tumors. Correlative biomarker analyses are ongoing and will be presented. For further insights into the synergy of ADC and immunotherapy, a cohort evaluating GV with anti-PD-1 in CPI-refractory melanoma is enrolling and a cohort investigating GV with the DC growth factor FLT3L (CDX-301) is planned

BACKGROUND: Metastatic melanoma of unknown primary (MUP) is uncommon, biologically ill defined, and clinically understudied. MUP outcomes are seldom reported in clinical trials. In this study, we analyze responses of MUP patients treated with systemic therapy in an attempt to inform treatment guidelines for this unique population. METHODS: New York University (NYU)'s prospective melanoma database was searched for MUP patients treated with systemic therapy. PubMed and Google Scholar were searched for MUP patients treated with immunotherapy or targeted therapy reported in the literature, and their response and survival data were compared to the MUP patient data from NYU. Both groups' response data were compared to those reported for melanoma of known primary (MKP). RESULTS: The MUP patients treated at NYU had better outcomes on immunotherapy but worse on targeted therapy than the MUP patients in the literature. The NYU MUP patients and those in the literature had worse outcomes than the majority-MKP populations in 10 clinical trial reports. CONCLUSIONS: Our study suggests that MUP patients might have poorer outcomes on systemic therapy as compared to MKP patients. Our cohort was small and limited data were available, highlighting the need for increased reporting of MUP outcomes and multi-institutional efforts to understand the mechanism behind the observed differences.

Background: Unlike other solid tumors, the impact of primary HS on melanoma survival and response to systemic therapy is not well studied. Nodular melanoma (NM) has a worse prognosis than superficial spreading melanoma (SSM), which is usually attributed to thicker primary tumors. Herein, we examine the hypothesis that HS might have an impact on MSS independent of thickness and that NM and SSM exhibit different mutational landscapes that associate with response to checkpoint inhibitor immunotherapy (IT) and BRAF targeted therapy (TT) in the metastatic setting. Methods: Primary NM and SSM patients prospectively enrolled at NYU (2002 - 2016) were compared to the most recent SEER cohort (1973 - 2012) and analyzed with respect to MSS. Next-Generation Sequencing (NGS) was performed on a subset of matched tumor-germline pairs, allowing a comparison of the mutational landscape between NM and SSM. In the metastatic setting, survival analyses were used to compare outcomes and responses to treatment across HS. Results: The NYU cohort of 1,621 patients with either NM (n = 510) or SSM (n = 1,111) was representative of the analogous SEER cohort (21,339 NM, 97,169 SSM), with NM presenting as thicker, more ulcerated, and later stage (all p < 0.001). Among the NYU cohort, NM was found to have lower rates of TIL (p = 0.047), higher mitotic index (p < 0.001), and higher rates of NRAS mutation (p < 0.001). In multivariate Cox models, NM was a significant predictor of worse MSS, independent of thickness and stage (p = 0.01). NM had a significantly lower mutational burden across the exome (p < 0.001). Some of the most under-mutated genes noted in NM were NOTCH4, BCL2L12 and RPS6KA6 (all p < 0.01). Among patients treated with TT (n = 56), NM remained a significant predictor of worse MSS (p = 0.004). However, there was no difference in response to IT. Conclusions: NM and SSM show divergent mutational patterns which may contribute to their different clinical behaviors and responses to BRAF targeted therapy. More studies are needed to better understand the key molecular and cellular processes driving such differences. Integration of HS data into prospective clinical trial reporting is needed to better assess its impact on response to treatment

Background: There are no predictive biomarkers of ipilimumab (IPI) toxicity. Of metastatic melanoma (MM) patients (pts) receiving IPI (3mg/kg), 35% require systemic therapies to treat immune-related adverse events (irAEs) and 20% must terminate treatment (Horvat et al., JCO 2015). Here we tested the hypothesis that a pre-existing autoantibody (autoAb) profile is predictive of IPI irAEs. Methods: We measured autoAb levels in pre- and post-treatment sera from mm pts who received IPI (3mg/kg) monotherapy on a proteome microarray containing ~20,000 unique full-length human proteins (HuProt array, CDI Laboratories). Clinical data were prospectively collected with protocol-driven follow-up. IrAEs were categorized by CTCAE guidelines as none (grade 0), mild (grade 1-2), or severe (grade 3-4). AutoAb levels were standardized using median quantile normalization and considered positive hits if > 2-SD above the peak array signal and differed by >=2 fold with p < 0.05 between toxicity groups (Non-parametric Analysis/Wilcox test). Results: Seventy-eight sera from 37 mm pts were analyzed. Antibodies against CTLA-4 were significantly elevated post IPI treatment (p < 0.0001), validating the assay. The pre-treatment levels of 190 IgG autoAbs were significantly diferent in pts who experienced irAEs (n = 28) compared to those with no irAEs (n = 9). Comparison of severe irAE (n = 9) and no irAE (n = 9) groups revealed 129 IgG autoAbs that significantly differed in pre-treatment sera. Localization and pathway analysis (UniProt, KEGG, Reactome) showed 81/190 (43%) of the autoAbs targeted nuclear and mitochondrial antigens and were enriched in metabolic pathways (p = 0.015). AutoAbs associated with irAEs did not correlate with treatment response. Conclusions: AutoAbs to antigens enriched in metabolic pathways prior to treatment may predict IPI-induced toxicity in MM. The subcellular localization of targeted antigens could explain the autoimmune toxicities associated with IPI. Studies in larger cohorts and in pts receiving other checkpoint inhibitors and/or combination therapies are essential to determine the validity of the data. If validated, our results would support the discovery of the first toxicity predictor in cancer immunotherapy