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Immunosuppressive therapy is standard for the treatment of inflammatory diseases and for minimizing rejection in transplant patients. However, immunosuppressant drugs are associated with an increased risk of certain cancers. In particular, melanoma is an immunogenic tumor and as such, is strongly influenced by the immune system. We performed this literature review to summarize the effects of commonly used immunomodulating agents on melanoma development, recurrence and progression. We outline the mechanism of action of each drug and discuss the available evidence on its influence on melanoma. Based on existing literature, we recommend avoiding the following agents in patients with a history of invasive melanoma: cyclosporine, sirolimus, natalizumab, IL-6 inhibitors, cyclophosphamide, methotrexate and the tumor necrosis factor-alpha inhibitors infliximab and etanercept. If there are no viable alternative agents, we recommend for these patients to see a dermatologist every 6 months for a thorough skin examination.

Immunotherapy; Pembrolizumab; Thyroid neoplasms Inmunoterapia; Pembrolizumab; Neoplasias de tiroides Immunoteràpia; Pembrolizumab; Neoplàsies de tiroides Background The authors report results from the thyroid carcinoma cohort of the multicohort phase 2 KEYNOTE-158 study (NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated cancers. Methods Eligible patients had histologically and/or cytologically confirmed papillary or follicular thyroid carcinoma, failure of or intolerance to prior therapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients received pembrolizumab (200 mg) every 3 weeks for up to 35 cycles. The primary end point was objective response rate (ORR) per RECIST v1.1 by independent central review. Results A total of 103 patients were enrolled and received pembrolizumab. Median duration from first dose to data cutoff (October 5, 2020) was 49.4 (range, 43.9–54.9) months. ORR was 6.8% (95% confidence interval [CI], 2.8%–13.5%), and median duration of response was 18.4 (range, 4.2‒47.2+) months. ORR was 8.7% (95% CI, 2.4%‒20.8%) among patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 (n = 46) and 5.7% (95% CI, 1.2%‒15.7%) among patients with PD-L1 CPS

Supplementary Data from Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101)

Supplementary Table S1. Representativeness of Study Participants Supplementary Table S2. Disease response as assessed by RECIST v1.1 by PD-L1 tumor cell expression (response-evaluable population). Supplementary Table S3. Disease response as assessed by RECIST v1.1 in prior line of therapy subgroups (response-evaluable population) and survival (as-treated population).

Purpose:Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors.Patients and Methods:Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses.Results:Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease.Conclusions:Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment.See related commentary by Punekar and Weber, p. 5007

Supplementary Figure S1. Patient disposition. Supplementary Figure S2. Association of PD-L1 expression and HPV status with best antitumor response. Supplementary Figure S3. Kaplan-Meier distribution curves for (A) PFS and (B) OS in the as-treated population according to line of treatment and platinum-refractory status, including estimates of medians. Supplementary Figure S4. Peripheral HPV-18-specific T-cells on IFNγ ELISpot assay of PMBCs. Supplementary Figure S5. Peripheral HPV-16 (A, C) E6-specific and (B, D) E7-specific T-cell responses on IFNγ ELISpot assay of PMBCs. Supplementary Figure S6. Peripheral HPV-18 (A, C) E6-specific and (B, D) E7-specific T-cell responses on IFNγ ELISpot assay of PMBCs. Supplementary Figure S7. Baseline peripheral (A) HPV-16-specific and HPV-16 (B) E6-specific and (C) E7-specific T-cell counts on IFNγ ELISpot assay of PMBCs according to best response to treatment. Supplementary Figure S8. Baseline peripheral (A) HPV-18-specific and HPV-18 (B) E6-specific and (C) E7-specific T-cell counts on IFNγ ELISpot assay of PMBCs according to best response to treatment. Supplementary Figure S9. (A) HPV-16-specific and (B) HPV-18-specific T-cell count measured by IFNγ ELISpot assay of PMBCs over time per individual patient (n = 34), color-coded by best response, plotted on a log10 y-axis.

Purpose:Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC.Patients and Methods:In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS).Results:Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. 2-fold increase in tumor-infiltrating CD8+ T cells.Conclusions:MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.

Supplementary Figure from Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study

Supplementary Data from Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study

Purpose:Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti–PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.Patients and Methods:Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.Results:Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3–4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4–6.8] months in the combination arm and 1.7 (95% CI, 1.4–4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.Conclusions:Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.

Purpose: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC. Patients and Methods: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). Results: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. 2-fold increase in tumor-infiltrating CD8+ T cells. Conclusions: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.

Background In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. Methods Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). Results Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. Conclusions Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Purpose: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti–PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC. Patients and Methods: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival. Results: Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3–4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4–6.8] months in the combination arm and 1.7 (95% CI, 1.4–4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size. Conclusions: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.

Purpose: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors. Patients and Methods: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses. Results: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. Conclusions: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007

Summary Background Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov , NCT02320058 . Findings Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding Bristol Myers Squibb.

BACKGROUND Head and neck squamous cell carcinoma of unknown primary site (HNSCCUP) is a diagnostic challenge. Identification of an ultraviolet (UV) light-related DNA damage signature using next-generation sequencing (NGS) can classify the primary site of origin as cutaneous. METHODS A 62-year-old male was seen with 2 months of left neck swelling. He was a lifetime nonsmoker but had a history of cutaneous squamous cell carcinoma (SCC) of the left helix. He was also found to have left hilar adenopathy. He had a p16-negative HNSCCUP on fine needle aspiration (FNA) biopsy of the left neck. RESULTS NGS of the FNA specimen revealed a high number of somatic mutations that were mostly C to T transitions, indicating a UV mutation signature and confirming the diagnosis of cutaneous SCC. CONCLUSIONS Identification of a UV DNA damage signature with NGS distinguishes HNSCCUP of cutaneous vs mucosal or other squamous cell carcinoma origin.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma., Immune checkpoints inhibitors or MAPK inhibitors are currently used as standard of care therapies for patients with advanced melanoma. Here the authors report a phase 1 clinical trial testing the anti-PD-L1 antibody durvalumab in combination with the BRAF inhibitor dafrafenib and the MEK inhibitor trametinib in patients with BRAFV600-mutant melanoma.

Background A recent phase III study (Keynote-048) demonstrated survival benefit of platinum, 5-FU and pembrolizumab in 1st line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC).1 However, administration of 5-FU has been a challenge for logistics and toxicities. As platinum, paclitaxel and pembrolizumab has been shown to be an effective and safe treatment for non-small cell lung cancer,2 we hypothesized that carboplatin, paclitaxel and pembrolizumab would be safe and effective for 1st line treatment of RM-HNSCC. Methods We performed a retrospective study of RM-HNSCC patients who received carboplatin, paclitaxel and pembrolizumab for first line systemic therapy, treated between December 2015 and January 2020 at the University of California, San Francisco. Patients who received at least 1 cycle of treatment with pre-treatment and post-treatment images were included in the analyses. Response to the treatment was assessed using RECIST criteria version 1.1. We also estimated overall survival and progression free survival using Kaplan-Meier method. Results Nine patients who received carboplatin, paclitaxel and pembrolizumab as first line systemic therapy for RM-HNSCC were identified. Two patients had HPV positive oropharyngeal SCC, the other patients unknown primary SCC in head and neck (2), oral cavity SCC (2), laryngeal SCC (1), hypopharyngeal SCC (1) and SCC of orbit (1). There were 1 complete response (CR, 11%), 6 partial responses (PR, 55%), 1 stable disease (SD, 11%) and 1 progressive disease (PD, 11%). Overall response rate (ORR) was 78%, and median progression free survival and median overall survival have not reached with median follow-ups of 6 months and 8 months, respectively. Two patients discontinued chemotherapy after 1 cycle for grade 4 acute kidney injury and grade 4 anaphylaxis, yet achieved CR and PR, respectively. Conclusions The retrospective analysis suggests that first line carboplatin, paclitaxel and pembrolizumab for RM-HNSCC is an active regimen and can be considered in place of platinum, 5-FU and pembrolizumab, which merits further investigation. Ethics Approval The study was approved by UCSF’s Institutional Review Board, approval number 19-29365. References Burtness B, Harrington K, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915–1928. Paz-Ares L, Luft A, Vincente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. New Engl J Med 2018; 379:2040–2051.

Background Efficacy of anti-PD-1 therapy is attributed to the presence of infiltrating antigen-specific CD8+ T-cells. Despite the success of anti-PD-1 therapy, many patients with SCCHN present with immune desert or immune excluded tumors and only 13–18% of patients achieve tumor reductions. Given this low response rate, it is imperative to combine agents that generate or expand anti-tumor T cells, such as vaccines, with anti-PD-1 therapies. SNS-301 is a first-in-class, bacteriophage-based immune activating agent targeting human aspartate β-hydroxylase (ASPH), a tumor associated antigen overexpressed in multiple tumor types. SNS-301 is a self-adjuvanted vaccine consisting of λ-bacteriophage engineered to express an immunogenic fragment of ASPH fused to the phage gpD coat protein, previously shown to be well tolerated and generate an immune response (Phase 1, NCT03120832). The objectives of this trial are to evaluate safety, immunogenicity and preliminary efficacy of SNS-301 in combination with pembrolizumab in patients that did not achieve tumor reductions on anti-PD-1/PD-L1 therapy alone. Methods The study consists of an initial safety-run-in followed by a two-stage design. SNS-301 is delivered intradermally in addition to pembrolizumab in up to 30 patients with locally advanced unresectable or metastatic/recurrent SCCHN. Patients must have actively received anti-PD-1 therapy for ≥12 weeks, with a best response of stable disease (SD) or unconfirmed progressive disease (PD) per iRECIST. Patients provide pre, on-treatment and biopsies at PD (optional) to characterize the tumor microenvironment using NanostringTM, multiplex immunohistochemistry, and correlate with clinical outcomes. Blood samples are collected to evaluate T cell responses using flow cytometry, ELISA, ELISPOT. Results As of July 23, 2020, 9 patients were enrolled. Median duration of ongoing anti-PD therapy was 37 weeks (range 20–101). The combination was well-tolerated with no DLTs and mostly Grade 1–2 unrelated adverse events. Two Grade 3 events were reported: hypertension (not related) and dehydration (related), the later reported as serious adverse event. Of seven patients eligible for efficacy analysis, one patient with PD-L1 negative disease had a partial response with a reduction of 29% at week 6 with deepening of the response to 43% at week 12 and one patient with progressive disease at study entry had stabilization of disease at week 6 and 12. Another two patients had stable disease for 30+ weeks and three patients had PD. Additional efficacy and immunological analyses are ongoing. Conclusions Early data show that the combination of SNS-301 and pembrolizumab has manageable toxicity and capacity to achieve long-term disease stability and objective tumor responses. Trial Registration NCT04034225 Ethics Approval This study has been approved by WIRB (20190628) as well as several institutional IRBs.

Background Electroporated plasmid IL-12 (TAVO or tavokinogene telseplasmid) is a novel pro-inflammatory intratumoral therapy with substantial single agent activity in melanoma, which has been shown to synergize with anti-PD-1 antibodies in patients predicted as non-responders to anti-PD-1.1 2 Interim data from patients with stage III/IV melanoma actively progressing on anti-PD-1 antibody are presented herein. Methods Patients with confirmed disease progression by RECIST v1.1 after at least 12 weeks of treatment on pembrolizumab or nivolumab (or combination checkpoint blockade) and within 12 weeks of last dose (with no intervening therapies) were enrolled. There was no limit on the number of prior lines of therapy. At least one accessible lesion was electroporated with plasmid IL-12 (pIL-12-EP) on days 1, 5 and 8 every 6 weeks and pembrolizumab was administered every 3 weeks. Tumor response in treated and untreated lesions was assessed by RECIST v1.1 every 12 weeks. Endpoints include ORR, safety, PFS, OS, and DOR. Results The first 56 patients treated of 100 planned were included in this interim analysis. Of these, 84% had Stage IV disease, 30% had M1c or M1d disease, and 27% had prior exposure to ipilimumab. In 54 efficacy evaluable patients the investigator-assessed ORR was 30% (3 CR/13 PR), 5 patients had 100% reduction of target lesions. All responses have been confirmed, only two responding patient progressed while on study, 2 patients completed the study with ongoing responses (figures 1 and 2). In patients with M1c/M1d disease, the ORR was 35.2% (n=6/17). Tumor reduction was observed in untreated lesions in 12 of 12 patients who had unaccessible lesions or accessible untreated lesions. The median overall survival (mOS) and duration of response (mDOR) has not been reached, with a median follow-up time of 13 months. Grade 3 treatment-related adverse events (TRAEs) were seen in 5.4% of patients, and there were no grade 4/5 TRAEs. The rate of grade 3 treatment-emergent (TEAEs) regardless of cause was 23.2%. The median time for pIL-12-EP treatment was 10 minutes (range 2,46). Consistent with prior studies of single-agent pIL-12-EP, tumor IHC, and transcriptomic assessments revealed hallmarks of antigen-specific antitumor immunity in this study. Additional analyses including microbiome, TCR clonality, and peripheral blood biomarker assays will be presented. Conclusions In this rigorously defined PD-1 antibody refractory patient population, the addition of pIL-12-EP to PD-1 antibody therapy induced deep, durable, systemic response in local treated and distant visceral metastatic untreated lesions with nominal systemic toxicity. Trial Registration Trial Registration: NCT#03132675 Ethics Approval The study was approved by a central IRB and/or local institutional IRBs/Ethics Committees as required for each participating institution. Consent Written informed consent was obtained from the patients participating within the trial, the current abstract does not contain sensitive or identifiable information requiring an additional consent from patients. References Algazi A, Bhatia S, Agarwala S, et al. Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients. Annals of Oncology 2019;31:532–540. Algazi A, Twitty C, Tsai K, et al. Phase II trial for IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. Clinical Cancer Research 2020;26:2827-2837.

BACKGROUND. The frequency of "exhausted" or check-point-positive (PD-1(+)CTLA-4(+)) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade. METHODS. Pretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan–Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. RESULTS. Of the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis. CONCLUSION. The results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups. The randomized phase 2 trial S1320 comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF-mutated advanced melanoma shows intermittent therapy does not result in superior progression-free survival in patients.

Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.

Author(s): Cohen, Roger B; Delord, Jean-Pierre; Doi, Toshihiko; Piha-Paul, Sarina A; Liu, Stephen V; Gilbert, Jill; Algazi, Alain P; Damian, Silvia; Hong, Ruey-Long; Le Tourneau, Christophe; Day, Daphne; Varga, Andrea; Elez, Elena; Wallmark, John; Saraf, Sanatan; Thanigaimani, Pradeep; Cheng, Jonathan; Keam, Bhumsuk | Abstract: ObjectivesTreatment options for patients with unresectable or metastatic salivary gland carcinoma (SGC) are limited. Safety and efficacy of pembrolizumab for SGC expressing programmed death ligand 1 (PD-L1) were explored.Materials and methodsA cohort of patients with advanced, PD-L1-positive SGC was enrolled in the nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (KEYNOTE-028; NCT02054806). Key inclusion criteria included recurrent or metastatic disease, failure of prior systemic therapy, and PD-L1 expression on ≥1% of tumor or stroma cells (per a prototype immunohistochemistry assay). Patients received pembrolizumab 10 mg/kg every 2 weeks for ≥2 years or until confirmed disease progression or unacceptable toxicity. Primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review.ResultsTwenty-six patients with PD-L1-positive SGC were enrolled and treated; median age was 57 years, 88% were men, and 74% had received prior therapy for recurrent/metastatic disease. Confirmed objective response rate after median follow-up of 20 months was 12% (95% confidence interval, 2%-30%), with 3 patients achieving partial response; there were no complete responses. Median duration of response was 4 months (range, 4 to 21 mo). Treatment-related adverse events occurred in 22 patients (85%), resulting in discontinuation in 2 patients and death in 1 (interstitial lung disease); those occurring in ≥15% of patients were diarrhea, decreased appetite, pruritus, and fatigue.ConclusionsPembrolizumab demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, PD-L1-positive SGC.

Background The purpose of this study was to assess changes resulting from the American Joint Committee on Cancer (AJCC) eighth edition for cutaneous squamous cell carcinoma (SCC) and evaluate pertinent excluded factors. Methods In 101 patients receiving surgery and postoperative radiation, recurrence and survival were estimated by cumulative incidence and Kaplan-Meier method. Time-to-event analysis was performed using Cox proportional hazards and Fine-Gray competing risks regression models. Results The 2-year locoregional recurrence, overall survival (OS), and cause-specific mortality rates were 25%, 72%, and 13%, respectively. The AJCC eighth edition upstaged T classification in 50% of patients and overall stage in 39%. In multivariate analysis, immunosuppression and in-transit metastasis were associated with locoregional recurrence. Older age and in-transit metastasis were associated with worse OS. In univariate analysis (limited by number of events), cause-specific mortality was associated with positive margin, in-transit metastasis, and the seventh edition dichotomized T classification and overall stage. Conclusion In-transit metastasis was significantly associated with locoregional recurrence, OS, and cause-specific mortality. Efforts should be made to define in-transit metastasis in the staging system.

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) Tcells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust Tcell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

Purpose To establish the safety profile and antitumor activity of the anti–programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.

We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis− group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417–24. ©2017 AACR.

Background Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT 01502293). Patients and methods Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Results The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. Conclusions Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Skin cancer, as the most physically accessible malignancy, allows for the greatest variety in treatment innovation. The last 2 decades have seen striking increases in the life expectancies of those diagnosed with malignant melanoma. However, many cases remain in which disease prevails against standard treatment, and those patients rely on continuing ingenuity. Drugs that can be injected directly into patients’ tumors have become increasingly promising, not least for the reduction in side effects observed. Intratumoral therapy encompasses a wide array of agents, from chemotherapeutic drugs to cancer vaccines. While each show some efficacy, those agents which regulate the immune system likely have the greatest potential for preventing disease progression or recurrence. Recent research has highlighted the importance of the presence of cytotoxic T cells and of keeping regulatory T cells in check. Thus, manipulating the tumor microenvironment is a need in skin cancer therapy, which intratumoral delivery can potentially address. In order to find the best approach to each person’s disease, more studies are needed to test intralesional agents in combination with currently approved therapies and with each other.

Non-response to anti-PD-1 antibodies is characterized by a “cold” tumor microenvironment lacking “exhausted” CD8+ T cells. We report on the first prospective Phase 2 trial of intratumoral plasmid IL-12 and pembrolizumab in advanced melanoma with “exhausted” T-cell (peCTL) poor tumors that had a low pre-test probability of response to anti-PD-1 Ab monotherapy. Patients had a 43% objective response rate (n=23, RECIST 1.1) with 38% complete responses. Interrogation of samples demonstrated that, while intratumoral IL-12 triggered a rapid increase in immune signaling and licensing of the tumor microenvironment, the compensatory adaptive resistance blunted clinical responses. However, by disrupting the PD-1/PD-L1 axis with pembrolizumab, the IL-12/IFN-γ feed-forward cycle was sustained, driving intratumoral cross-presenting DC subsets with increased TIL and TCR clonality and, ultimately, systemic cellular immune responses. Thus, combination of intratumoral plasmid IL-12 with pembrolizumab transformed poorly immunogenic lesions into effective in situ vaccines, attaining clinical activity in low peCTL tumors.

6029 Background: The absence of infiltrating antigen-specific CD8+ T-cells at baseline is associated with low response rates to PD-1 blockade. SCCHN tumors often exclude effector T cells, and 2nd line response rates are low (13-18%). Highly immunogenic, antigen specific antitumor vaccines may expand intratumoral CD8+ T cells, potentially increasing durable response rates to PD-1 blockade. SNS-301 is a first-in-class, bacteriophage-based immune activating agent targeting human aspartate β-hydroxylase (ASPH), a tumor associated antigen overexpressed in multiple tumor types. SNS-301 is a self-adjuvanted vaccine consisting of λ-bacteriophage engineered to express an immunogenic fragment of ASPH fused to the phage gpD coat protein. The study objectives are to evaluate safety, immunogenicity and preliminary efficacy of SNS-301 added to pembrolizumab in patients (pts) not achieving tumor reductions on PD-1 blockade alone. Methods: Intradermal SNS-301 was combined with pembrolizumab in pts with locally advanced unresectable (LA) or metastatic/recurrent (met) SCCHN with a best response of stable disease (SD) or unconfirmed progressive disease (uPD) on ongoing PD-1 blockade > 12 weeks. Pts provided pre and on-treatment biopsies to characterize the tumor microenvironment using Nanostring and multiplex immunohistochemistry (mIHC). Blood samples were collected to evaluate B and T cell responses using ELISA/ELISPOT assays. Results: As of February 4, 2021, 13 pts were enrolled. Median duration of PD-1 blockade was 48 weeks (range 14-114) at study entry. There were no DLTs & mostly Grade 1-2 unrelated adverse events. Only two related Grade 3 events were reported: rash & dehydration (also a serious adverse event). Ten pts were evaluable for efficacy: 1 pt with PD-L1 negative (neg) disease & SD on pembrolizumab monotherapy achieved a partial response (PR; -52% at 8 months), 4 pts achieved SD & 5 pts had progressive disease. Two of the pts with SD had long-lasting duration (8 & 10 months) of which the latter had PD-L1 neg disease. One pt with uPD at enrollment achieved SD for 4 months. Analyses of pre- & on-treatment biopsies from the PR pt demonstrated an increase in infiltrating CD8+ T cells, PD-L1 expression & PD-1/PD-L1 proximity measures. Nanostring analysis demonstrated increased gene expression signatures for immune cells in the PR pt that was concordant with the mIHC & clinical outcome. Conclusions: The combination of SNS-301 and pembrolizumab was well-tolerated and resulted in encouraging clinical efficacy in pts not expected to respond to PD-1 blockade alone. Translational data suggest cellular response to SNS-301 and transformation of a poorly inflamed tumor to an immunologically active tumor in a responding pt (PR). Based on these data, an additional cohort will start enrolling PD-1 blockade naïve pts with LA/met SCHNN in the front-line setting. Clinical trial information: NCT04034225.

BACKGROUND Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method. RESULTS Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354–3362. © 2016 American Cancer Society.

BACKGROUND Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined. RESULTS Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity. CONCLUSIONS PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344–3353. © 2016 American Cancer Society.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.