Faculty Bibliography

Purpose: The TLR 7/8 agonist, Resiquimod has been shown to induce local activation of immune cells, production of cytokines, and antigenpresentation by dendritic cells, features desirable for cancer vaccine adjuvants. In this study, we evaluated the safety and immunogenicity of vaccination with NY-ESO-1 protein emulsified in Montanide ISA-51 VG when given with or without Resiquimod in surgically resected stage IIB-IV melanoma patients. Experimental design: This is a two-part study design. Part I represents an open-label dose-escalation with Resiquimod using 2 cohorts treated with 100mug NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by topical application of 1000mg of the 0.2% Resiquimod gel on days 1 and 3 for cohort-1 (N=3) or days 1, 3, and 5 for cohort-2 (N=3). The cycles were repeated every 3 weeks, total of 4 cycles. For part II of the study, patients were blindly randomized to receive 100mug NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by topical application of placebo gel (Arm-A; N=8) or 1000mg of 0.2% Resiquimod gel (Arm-B; N=12) using the dosing regimen established in Part I. Blood samples were collected at baseline, one week after each cycle of vaccination, and at follow-up visit for the assessment of NY-ESO-1-specific humoral and cellular immune responses. Results: The vaccines were generally well-tolerated, with no grade 4 adverse events or study-related deaths. Most study participants experienced mild adverse reactions reported as Grade 1 or 2 per CTCAE criteria v. 4. One patient experienced a grade 3 syncopal episode that was unrelated to the study drugs and another patient had a grade 3 injection site necrosis that was possibly related to the study drugs. NYESO- 1 specific antibody responses were induced in both study arms although higher mean antibody titers were observed in Arm B. NY-ESO-1 specific CD4+ T cell responses were induced in patients in both study arms. However, significant NY-ESO-1 CD8+ T cell responses were detected only in Arm B. Conclusions: The current study shows that Resiquimod is safe and contributes to the induction of immune responses in patients

Combined BRAF and MEK inhibition can delay the onset of resistance compared with BRAF inhibitor alone in preclinical models. Safety/tolerability of vem + GDC-0973 was evaluated in a phase Ib trial. Eligible pts had BRAFV600-mutated unresectable or metastatic melanoma by cobas BRAF test, ECOG PS 0/1 and were either naive to vem or had disease progression on vem. Pts received vem 720 or 960 mg BID continuously. GDC-0973 was dosed at 60, 80 or 100 mg QD 14 days (d) on/14 d off (14/14); 21 d on/7 d off (21/7); or continuously (28/0) in 10 cohorts. Primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and safety. Of the 70 pts treated as of July 6, 2012, 70% were male, median age 57.5 year (range 19-76), 74.3% M1c, and 54.3% had progressed on prior vem therapy. The median no. of cycles to date was 3. DLTs were observed in 3 pts, as of September 18, 2012: Grade (G) 3 QT prolongation (1 pt) in vem 960 mg BID + GDC-0973 60 mg QD 21/7 cohort; G3 mucositis (1 pt) and G3 arthralgia (1 pt), both in vem 960 mg BID + GDC-0973 60 mg QD 28/0 cohort. Most common adverse events (AEs) regardless of attribution were diarrhea (54.3%), non-acneiform rash (54.3%), fatigue/asthenia (38.6%), nausea (35.7%), photosensitivity/ sunburn (31.4%) and liver function test (LFT) abnormality (25.7%). Most frequent treatment-related G > 3 AEs were rash (7.1%), diarrhea (5.7%) and LFT abnormality (4.3%). One pt developed skin SCC. Dose reduction for AE was required for vem in 3 pts and GDC-0973 in 2 pts. Preliminary efficacy in 25 evaluable vem-naive pts showed that all 25 pts had tumor reduction. GDC-0973+ vem can be combined safely at the respective single-agent MTDs of vem (960 mg BID) and GDC-0973 (60 mg 21/7). This dose level was chosen for further clinical testing in an upcoming phase III study

The oral BRAF inhibitor vemurafenib (VEM) has shown improved overall survival (OS) and high response rates in patients (pts) with BRAFV600-mutant metastatic melanoma with median durations of VEM treatment of up to 5.7 months. Updated data are available from a phase 2 trial (BRIM-2) of VEM in 132 previously treated pts with BRAFV600-mutant metastatic melanoma (median follow-up: 13.4 months, clinical cut-off: February 1, 2012). Confirmed best overall response rate BORR (by IRC) was 53.0% (95% CI 44.2-61.8%). Median OS was 15.9 months and median PFS was 6.8 months. Long-term follow-up of trials with BRAF inhibitors is needed to assess the potential for these agents to induce secondary malignancies. Here we report long-term safety data from BRIM- 2. Safety assessments included incidence of adverse events (AEs), the most common of which were grade 1/2 arthralgia (n = 81; 61.3%), rash (n = 61; 46.2%), photosensitivity (n = 67; 50.8%), fatigue (n = 73; 55.3%), and alopecia (n = 53; 40.1%). Four pts experienced AEs leading to discontinuation of study drug. One drug-related death due to acute renal failure was reported. Secondary cutaneous squamous cell carcinomas (cuSCCs) usually appeared in the first few weeks of treatment and were seen in 36 (27.3%) pts. AEs also observed included two new primary melanomas, but there were no non-cutaneous SCCs or other malignancies and no cases of colonic polyps were reported. Cardiac events occurred in <1% of pts. Other common AEs were similar to those reported previously. Sixty pts required dose reduction below 960 mg BID; nine returned to full dose. After long-term follow-up (median 13.4 months), VEM remains well tolerated, with the majority of AEs being non-severe and manageable. No non-cutaneous malignancy has been observed

ABSTRACT: BACKGROUND: Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. METHODS: We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. RESULTS: A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. CONCLUSION: Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time.