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Background: Treatment with immune checkpoint inhibitors (ICIs) has been linked to granulomatous and sarcoid-like lesions (GSLs) affecting different organs. This study sought to evaluate GSL incidence in patients with high-risk melanoma treated with cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) blockade adjuvant therapy in two clinical trials: ECOG-ACRIN E1609 and SWOG S1404. Descriptions and GSL severity ratings were recorded. Methods: Data were collected from ECOG-ACRIN E1609 and SWOG S1404. Descriptive statistics along with GSL severity grades were reported. Additionally, a literature review for such cases was summarized. Results: A total of 11 GSL cases were reported among 2878 patients treated with either ICI or with High-Dose Interferon Alfa-2b (HDI) in ECOG-ACRIN E1609 and SWOG S1404 trials. Cases were numerically more commonly reported with ipi10, followed by pembrolizumab, ipi3, and HDI, respectively. Most of the cases were grade III. Further, organs involved included lung, mediastinal lymph nodes, skin and subcutaneous tissue, and eye. Furthermore, a summary of 62 reports in the literature was described. Conclusions: GSLs following anti-CTLA4 and anti-PD1 antibody therapy in patients with melanoma were reported unusually. Reported cases ranged in grade from I to III and appeared manageable. Careful attention to these events and their reporting will be essential to better guide practice and management guidelines.

Supplementary Data from Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Background: First-line treatment with immunotherapy alone or in combination with antiangiogenic agents is a standard of care for advanced RCC. Many patients (pts) develop resistance to first-line treatment and effective second-line and beyond options are needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. The first-in-class HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in previously treated pts with advanced RCC. The cyclin-dependent kinase (CDK) pathway has also been implicated in RCC and is associated with poor clinical outcomes. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. The addition of CDK 4/6 inhibition had synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α-dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: The two-part, open-label, multicenter, phase 1/2 randomized LITESPARK-024 study (NCT05468697) is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib in combination with a modified toxicity probability interval design (Part 1), followed by a direct comparison of belzutifan monotherapy to the combination with respect to safety and efficacy in pts with advanced RCC (Part 2). Pts with histologically confirmed unresectable stage IV RCC with a clear cell component, whose disease progressed on or after having received at least 2 systemic treatments (both an anti-PD-1/PD-L1 monoclonal antibody and a VEGF receptor-targeted tyrosine kinase inhibitor, in sequence or in combination), have measurable disease per RECIST v1.1 by blinded independent central review, and have KPS score of ≥70% will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in Part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, PFS, OS, and safety and tolerability. This abstract was accepted and previously presented at the 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. Citation Format: David F. McDermott, Avivit Peer, Neeraj Agarwal, Michael B. Atkins, Jerry Cornell, Rodolfo F. Perini, Kenneth F. Grossmann, Howard Gurney. The randomized phase 1/2 LITESPARK-024 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT120.

We hypothesize that a significant number of patients do not respond to PD-1/L1 blockade because there are no pre-existing tumor antigen-specific T-cells, and this can be addressed by combination therapy with an oncolytic virus such as T-VEC. S1607 is a single arm Phase 2 study of T-VEC plus pembro in patients with advanced melanoma after PD-1/L1 inhibitor progression. The primary endpoint is ORR by modified RECIST (progression at the first follow-up disease assessment had to be confirmed). Secondary endpoints include durable response rate (response ≥ 6 months), ORR in injected, non-visceral non-injected, and visceral lesions, PFS, OS and toxicity. In Cohort A patients must have at least one measurable visceral lesion; in Cohort B patients must not have any visceral lesions. Each cohort had an independent accrual goal with a 2-stage design. All received intratumoral T-VEC and pembro 200mg IV every 21 days. Tumor biopsy and research blood are taken at baseline and on Day 28 (both injected and non-injected lesions). Tumor assessments are performed every 12 weeks for up to 2 years. 38 evaluable patients were enrolled. As of July 26, 2022, the median follow up was 28 months. Treatment was well tolerated, with 5/38 (13%) grade 3 AE (no grade 4/5) including injection site reactions, lymphocyte count decrease, and hypoxia. Cohort A was closed after stage I (n=11) with no confirmed responses. In Cohort B (n=27), there were 7 confirmed responses (26%; 2 CR, 5 PR; this rejected H0: ORR = 10%, p=0.01). Clinical outcomes are summarized in Table 1. Baseline tumor mutational burden from 17 patients in Cohort B were not different between responder vs non-responders (p=0.96). Translational study is ongoing for pharmacodynamic confirmation. T-VEC plus pembro in melanoma patients who have progressed on prior anti-PD1/L1 therapy has efficacy in the subset of melanoma patients who have non-visceral metastases. Table 1 Cohort A (Visceral) Cohort B(Non-Visceral) N (%; 95% CI) 11 27 Confirmed PR + CR 0 (0%; 0%-28%) 7 (26%; 11%-46%) Confirmed + Unconfirmed 1 (9%; 0%-41%) 9 (33%; 17%-54%) Durable response 0 (0%; 0%-28%) 4 (15%; 4%-34%) Median PFS in months 2.1 (0.7-5.5) 2.3 (1.9-6.2) INJECTED LESIONS 11 27 Confirmed PR + CR 0 (0%; 0%-28%) 6 (22%; 9%-42%) Confirmed + Unconfirmed, PR + CR 1 (9%; 0%-41%) 8 (30%; 14%-50%) NON-INJECTED, NON-VISCERAL LESIONS 8 19 Confirmed PR + CR 0 (0%; 0%-37%) 3 (16%; 3%-40%) Confirmed + Unconfirmed, PR + CR 0 (0%; 0%-37%) 5 (26%; 9%-51%) VISCERAL LESIONS 11 Confirmed PR + CR 0 (0%; 0%-28%) Confirmed + Unconfirmed, PR + CR 1 (9%; 0%-41%) ACQUIRED RESISTANCE 3 2 Confirmed PR + CR 0 (0%; 0%-71%) 2 (100%; 16%-100%) Confirmed + Unconfirmed, PR + CR 0 (0%; 0%-71%) 2 (100%; 16%-100%) Median PFS in months 2.1 (2.0-4.1) NR (8.0-∞) PRIMARY RESISTANCE 8 25 Confirmed PR + CR 0 (0%; 0%-37%) 5 (20%; 7%-41%) Confirmed + Unconfirmed, PR + CR 1 (13%; 0%-53%) 7 (28%; 12%-49%) Median PFS in months 1.8 (0.3-6.2) 2.1 (1.9-3.3) Citation Format: Siwen Hu-Lieskovan, James Moon, John Hyngstrom, Katie M. Campbell, Gino K. In, Theodore F. Logan, Kari L. Kendra, Ding M. Wang, Douglas B. Johnson, Gary C. Doolittle, Alan Tan, Ann W. Silk, Kenneth F. Grossmann, Christopher W. Ryan, Sapna P. Patel, Shay Bellasea, Michael C. Wu, John M. Kirkwood, Helen X. Chen, Antoni Ribas. Combination of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in advanced melanoma patients following progression on a prior PD-1 inhibitor: SWOG S1607 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3275.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59–0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61–1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587

Direct ink writing technique is used to 3D print Ti-metal–organic framework (MOF) NH2-MIL-125 mixed with boehmite dispersal. Pt is also deposited onto 3D-printed monolith using atomic layer deposition (ALD) to offer additional catalytic sites. The Ti-MOF-derived powder sample and the pyrolyzed 3D-printed monolith samples are evaluated for photocatalytic H2 evolution under UV–vis light. As a proof of concept, herein, it is demonstrated that 3D-printed MOF-derived monolith photocatalysts show five times higher H2 evolution performance compared with TiO2/C powder sample due to better interaction between 3D-printed photocatalysts and the incident light. The high surface area, the formation of hierarchical macro- to nanopores, and the optimizable shape/size of the 3D-printed catalyst maximize the exposure of catalytic active sites to incident photons and increase their photocatalytic H2 evolution performance. In addition, the N-functionalized porous carbon from organic linker, and the uniformly distributed Pt/PtOx species deposited by ALD, provide cocatalytic active sites for photocatalytic reaction and further enhance photocatalytic activity 30% of 3D-printed monoliths. This work on the 3D-printed MOF-derived free-standing monoliths for photocatalytic application provides a readily available approach to further fabricate a variety of 3D-printed MOF-based and derived materials for different energy and environment applications.

TPS747 Background: The combination of immunotherapy with antiangiogenic agents is a well-established first-line treatment option for patients (pts) with advanced renal cell carcinoma (RCC), but many pts develop resistance, and effective second- or subsequent-line options are needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α) signaling. HIF-2α is involved in angiogenesis, tumor growth, proliferation, and metastasis, and is a key oncogenic driver in RCC. The HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in pts with heavily pretreated RCC. The cyclin-dependent kinase (CDK) pathway is altered in several cancer types, including RCC, and is associated with poor clinical outcomes. The CDK 4/6 inhibitor palbociclib inhibited cell growth in RCC cell lines, and the antiproliferative effects of CDK 4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL -/- clear cell RCC cell lines. We hypothesized palbociclib could potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 (NCT05468697) is an open-label, multicenter, phase 1/2 randomized study of belzutifan + palbociclib versus belzutifan monotherapy in pts with advanced RCC. Pts must have histologically confirmed unresectable stage IV RCC with a clear cell component, received at least 2 prior systemic regimens (both an anti–PD-1/PD-L1 monoclonal antibody and a VEGF receptor–targeted TKI, in sequence or in combination), have measurable disease per RECIST v1.1 by BICR, have KPS score of ≥70%, and have radiographic disease progression on or after the most recent regimen per investigator. Part 1 will evaluate the safety of belzutifan + palbociclib and determine the recommended phase 2 dose (RP2D) for the combination using a modified toxicity probability interval design. Part 2 will evaluate the safety and efficacy of belzutifan + palbociclib versus belzutifan alone. In part 1, ≤30 pts will be enrolled into 3 dose groups and receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, DOR, PFS, OS, and safety and tolerability. Clinical trial information: NCT05468697 .

Background The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti‐PD‐1 (aPD‐1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front‐line BRAF/MEKi, aPD‐1, or niv/ipi. Methods Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD‐1 in the front‐line setting were identified from a nationwide database comprising de‐identified patient‐level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan‐Meier curves and log‐rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front‐line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival. Results Five hundred and sixty seven patients with advanced disease and treated with front‐line aPD‐1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow‐up of 22.4 months, median overall survival (OS) for patients treated with front‐line niv/ipi was not reached (NR) while median OS for patients treated with aPD‐1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front‐line treatment with PD‐1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses. Conclusions In our real‐world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front‐line niv/ipi or aPD‐1 had longer survival compared to those treated with front‐line BRAF/MEKi., Real‐world overall survival of patients with advanced BRAF mutant melanoma treated with front‐line BRAF/MEK inhibitors, anti‐PD‐1 antibodies, or nivolumab/ipilimumab.

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

BackgroundRandomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.MethodsData of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (>6 months and ResultsOf 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3–49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7–30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.ConclusionIn this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.

Background: Patients with advanced melanoma primarily refractory to single agent PD-1 blockade therapy have an option of receiving the CTLA-4 blocking antibody ipilimumab, but if ipilimumab should be given as a single agent or in combination with the anti-PD-1 nivolumab has not been established prospectively. Methods: Patients aged >18 with metastatic or unresectable melanoma without objective response to anti-PD-1 therapy given without CTLA-4 therapy were randomized 3:1 to receive either ipilimumab 3mg/kg + nivolumab 1mg/kg q3 wks x4 cycles followed by nivolumab 480mg q4wks (ipi/nivo) up to 2 years, or ipilimumab 3mg/kg q3weeks x4 cycles (ipi). Additional key eligibility criteria included ECOG Performance Statue (PS) 0-2, no active central nervous system metastases, autoimmune disease, or need for steroids at doses of >10 mg of prednisone or the equivalent. The primary endpoint was progression free survival (PFS). Disease assessments were performed every 12 weeks until progression. Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. All patients were to submit a fresh tumor biopsy and whole blood for correlative endpoints prior to cycle 1 and again at week 5. Results: 92 eligible patients were enrolled, 69 to ipi/nivo, 23 to ipi. Median age was 64 and 69 in the ipi/nivo and ipi arm respectively. 67% and 65% were male. 65% of patients in both arms had ECOG PS of 0. With a median follow up of 25.3 months, the hazard ratio (HR) for PFS was 0.63 (90% CI 0.41, 0.97) with a statistically significant 1-sided p-value of 0.04 favoring ipi/nivo. The 6-month PFS estimates were 34% (90% CI: 25%-44%) and 13% (4%-27%) for ipi/nivo and ipi respectively. ORR was 28% for ipi/nivo (95% CI 17%-40%) and 9% for ipi (95% CI: 3%-34%). With a median follow up of 24.4 months, 39/69 patients in the ipi/nivo arm and 12/23 patients in the ipi arm had died. 12-month OS was 63% (90% CI 52%-72%) in the ipi/nivo arm and 57% (38%-71%) months in the ipi arm. HR for OS was 0.94 (90% CI 0.54, 1.62) in favor of ipi/nivo with a p-value of 0.42. Adverse event rates were similar in both arms. One treatment related death was reported in the ipi/nivo arm due to disseminated intravascular coagulation and one treatment related death was reported in the ipi arm due to colonic perforation. Conclusions: This is the first prospective randomized study comparing ipi/nivo to ipi alone in patients with melanoma without response to anti-PD1 therapy. Ipi/nivo was associated with improved progression free survival as compared to ipi alone. The response rate of 28% to ipi/nivo as compared to 9% to ipi alone implies that patients who do not respond to PD-1 alone can be rescued with ipi/nivo. The toxicity of combination therapy was manageable. Ipi/nivo is an appropriate standard in patients with metastatic melanoma who do not respond to single-agent PD-1 therapy. ClinicalTrials.gov Identifier: NCT03033576 Funding: NIH/NCI grants: U10CA180888, U10CA180819, U10CA180821, U10CA180868; Other grants: SU2C-AACR-CT06-17 Citation Format: Ari M. Vanderwalde, James Moon, Kari Kendra, Nikhil I. Khushalani, Frances Collichio, Jeffrey A. Sosman, Alexandra Ikeguchi, Adrienne I. Victor, Thach-Giao Truong, Bartosz Chmielowski, David C. Portnoy, Michael C. Wu, Kenneth F. Grossmann, Antoni Ribas. S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT013.

9502 Background: Desmoplastic melanoma (DM) is a rare cancer defined by a dense fibrous collagen matrix. It is associated with high UV exposure leading to a high mutational load. When locally advanced, the standard of care is wide excision and radiation therapy due to its propensity for local relapses. Metastatic DM has a high response rate (RR) to PD-1 blockade therapy (Eroglu et al. Nature 2018). We hypothesized that neoadjuvant treatment with anti-PD-1 monotherapy may induce pathologically confirmed regressions in a high percentage of cases, potentially allowing for less extensive local treatment. Methods: Patients > 18 years old with histologically confirmed resectable (primary, recurrent, or regional lymph node metastasis) DM with clinical evidence of residual disease received pembrolizumab 200 mg q3 weeks (wk) 3 followed by excision. No adjuvant therapy was administered. Primary endpoint: pathological complete response (pCR), with the assumption that pCR of 25% would be considered a positive result worthy of future study. To test this hypothesis, a single arm trial with 25 eligible patients would have a 3.4% probability of a positive result with a true pCR of 5%, and a power of 90% of a positive result if the true pCR is 25%. Secondary endpoints: clinical RR by imaging and clinical exam, median overall survival (OS), and evaluation of safety/tolerability of neoadjuvant pembrolizumab. Adverse events were assessed q3 wk. Disease assessments occurred at baseline and q9 wk. NCT02775851. Results: We enrolled-29 eligible patients with resectable DM. One patient refused treatment and was omitted from further analysis. Median age was 75, 79% were male, primary sites of disease were 72% H&N, 10% torso, 14% extremities, 3% unknown. No patients received prior systemic therapy. Mean time from C1D1 treatment to surgery was 84.2 (range: 52-135) days, mean number of cycles received 3.3 (range: 2-4). 26/27 (93%) of patients underwent wide excision of the resectable disease, of which 14 (54%) underwent sentinel lymph node biopsy. One patient underwent resection of a nodal recurrence thus did not require wide excision. pCR was noted in 15/27 (56%) of patients (95% CI: 35%-75%). One patient without a pCR had a major pathologic response with 0.2 mm residual melanoma. In addition, one patient with a clinical CR did not undergo resection by choice. None became inoperable. Clinical RR was 52% (95% CI: 32%-71%). Median OS has not been reached, with two nontreatment related deaths (acute hypoxic respiratory failure; unknown). No > grade 2 related adverse events were observed. Conclusions: Neoadjuvant pembrolizumab in resectable DM results in a high pCR rate with excellent tolerance, which supports consideration of PD-1 blockade therapy prior to surgery. Funding: U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial information: NCT02775851.

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.

Background: COVID-19 has led to a change in care for patients with chronic conditions, involving a transfer of drug administration from an outpatient to a community setting. Aim: To investigate patient preferences for treatment settings in the light of the current pandemic. Methods: Patients, who prior to the pandemic had attended two different outpatient clinics in a university hospital for their infusions or injections, were interviewed by telephone. The semi-structured interviews were analyzed using qualitative and quantitative methods. Results: Out of 49 patients with either anti-inflammatory or immunoglobulin treatments (response rate: 83 %), 24 (49.0 %) switched from subcutaneous (sc) injections in the hospital to the community setting, 18 (36.7 %) from intravenous infusions (iv) in the hospital to sc administration at home and 7 (14.3 %) moved to iv at home. During the pandemic 38 (80.9 %) wanted to continue their treatment at home, but after the pandemic 22 (46.8 %) would opt to go back to the hospital. Satisfaction was high with both settings, slightly favoring drug administration in hospital. Qualitative data shows that patients while emphasizing the importance of the relationship with the healthcare team, had increased concerns about safety as a result of COVID-19. Conclusions: The experience during the COVID-19 pandemic has increased self-management-skills in some patients, but long-term follow-up is needed. It has repercussions for future shared decision making for patients and their healthcare teams.

IMPORTANCE: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care. OBJECTIVE: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. EVIDENCE REVIEW: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed. FINDINGS: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility. CONCLUSIONS AND RELEVANCE: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

Immunotherapy has broadened the therapeutic scope and response for many cancer patients with drugs that are generally of higher efficacy and less toxicity than prior therapies. Multiple classes of immunotherapies such as targeted antibodies and immune checkpoint inhibitors (ICI), cell-based immunotherapies, immunomodulators, vaccines, and oncolytic viruses have been developed to help the immune system target and destroy malignant tumors. ICI targeting programmed cell death protein-1 (PD-1) or its ligand (PD-L1) are among the most effective immunotherapy agents and are a major focus of current investigations. They have received approval for at least 16 different tumor types as well as for unresectable or metastatic tumors with microsatellite instability-high (MSI-H) or mismatch repair deficiency or with high tumor mutational burden (defined as ≥10 mutations/megabase). However, it is important to recognize that immunotherapy may be associated with significant adverse events. To summarize these events, we conducted a PubMed and Google Scholar database search through April 2020 for manuscripts evaluating treatment-related adverse events and knowledge gaps associated with the use of immunotherapy. Reviewed topics include immune-related adverse events (irAEs), toxicities on combining immunotherapy with other agents, disease reactivation such as tuberculosis (TB) and sarcoid-like granulomatosis, tumor hyperprogression (HPD), financial toxicity, challenges in special patient populations such as solid organ transplant recipients and those with auto-immune diseases. We also reviewed reports of worse or even lethal outcomes compared to other oncologic therapies in certain scenarios and summarized biomarkers predicting adverse events.

Introduction Anti-PD-1 antibodies are commonly used as frontline therapy for patients with metastatic melanoma. Although these medications can cause long term responses, a significant number of patients will not respond or will lose response. Optimal second-line therapy after losing response to anti-PD-1 antibodies is not well established. Therefore, we retrospectively compared the overall survival of patients who lost response to anti-PD1 antibodies between patients treated with single agent ipilimumab or ipilimumab and nivolumab. Methods A de-identified U.S. nationwide electronic health record-derived database was reviewed for patients with advanced melanoma treated with single agent anti-PD1 antibodies in the frontline setting and who subsequently received second-line ipilimumab or combination ipilimumab and nivolumab. Overall survival from initiation of second-line therapy was compared using Kaplan Meier curves and log-rank analysis. Other known prognostic markers for melanoma were analyzed for correlation with survival in a similar fashion. Disease characteristics between the two groups were compared using chi-square analysis. Results A total of 842 patients with advanced melanoma who received frontline anti-PD-1 antibodies were included for analysis. Of these, 57 received either ipilimumab ( n = 22) or ipilimumab in combination with nivolumab ( n = 35) in the second-line setting. Median survival from second-line therapy initiation for those treated with ipilimumab alone was 6 months and was 5.6 months for those treated with combination ipilimumab and anti-PD-1 antibodies, p = 0.81. Conclusions In this small, retrospective analysis, for patients who lost response to frontline anti-PD-1 therapy, patients treated with ipilimumab had similar survival to those who received ipilimumab in combination with anti-PD-1 antibodies.

Background Anti-PD-1 antibodies have changed the treatment landscape for patients with metastatic melanoma. Two of these antibodies, pembrolizumab (P) and nivolumab (N), are currently FDA approved in the frontline setting for these patients. The efficacy of these drugs has not been directly compared; thus we aimed to compare the overall survival for patients with metastatic melanoma treated with either front line P or N in routine clinical practice. Methods This study included patients with advanced melanoma treated with frontline P or N using the U.S. nationwide Flatiron Health electronic health record (EHR)-derived database. Overall survival (OS) from the start of frontline therapy was estimated for each treatment group using Kaplan-Meier curves with a log-rank test. OS comparative-effectiveness was estimated using a propensity score-matched Cox regression model to reduce bias for pairs of P (n = 371) and N treated subjects (n = 371). Propensity scores were generated using age, gender, ECOG, LDH (elevated or not), BRAF (mutated or not), KIT (mutated or not), NRAS (mutated or not), PD-L1 expression (0% or greater), BMI and primary site. Results From a total of 7650 melanoma patients, 888 had advanced disease treated with frontline P (n = 486) or N (n = 402). 58% of N treated patients received flat 240 mg q2 week dosing and 38% of P treated patients received flat 200 mg q3 week dosing. Median OS for patients treated with P was 22.6 months(m) and was 23.9 m for those treated with N (p = 0.91). In the propensity score matched analysis (n = 742), there was no difference in survival between patients treated with P or N (HR 1.10; 95% CI 0.87-1.39). Conclusions In our retrospective real world analysis of patients with advanced melanoma, no statistical difference in OS was noted between patients treated with frontline P compared to N. This supports the current practice of choosing either P or N based on patient and provider preference. Legal entity responsible for the study Huntsman Cancer Institute. Funding Has not received any funding. Disclosure K.F. Grossmann: Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Castle Biosciences. S. Patel: Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.

BACKGROUND: Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). OBJECTIVES: We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. METHODS: Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. RESULTS: Survival curves (n = 887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi-squared 39.29, P < .001). However, a multivariate Coxproportional hazards model showed no significant survival difference (hazard ratio 1.07, P = .55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P = .96). LIMITATIONS: Breslow depth, ulceration status, and specific cause of death were not available for all patients. CONCLUSIONS: Patients with MPM had similar survival times as patients with SPM. (J Am Acad Dermatol 2018;79:238–44.)

Zusammenfassung. Der Begriff personenzentrierte Gesundheitsversorgung ist in aller Munde. Man könnte vermuten, dass es sich dabei um ein modisches Schlagwort handelt. Tatsächlich bezeichnet der Begriff ein theoretisch fundiertes Wertesystem, das weltweit zunehmend Beachtung findet.

AIMS The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

Background National guidelines support both surgical and radiotherapy (RT) as initial treatment options for early-stage oral cavity squamous cell carcinoma (SCC). There remains limited data evaluating the survival outcomes of RT and the current practice patterns for these lesions. Methods We conducted a retrospective review of 8274 patients in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2008 with T1 to T2N0M0 oral cavity SCC. Primary outcomes were 5-year overall survival (OS) and disease-specific survival (DSS). Results Surgical therapy had significantly improved OS (140 months; p < .001) and DSS (217 months; p < .001) compared to surgery with adjuvant RT (104 and 163 months, respectively) and definitive RT (68 and 136 months, respectively). The use of radiation alone was associated with an increased T classification, hard palate, retromolar trigone primary site lesions, and advanced patient age. Conclusion Primary radiation without surgery continues to be used in a subset of early-stage oral cavity SCCs, in which it is associated with decreased OS and DSS. © 2017 Wiley Periodicals, Inc. Head Neck 39: 876–880, 2017

Surgical management of external ear melanoma presents unique technical challenges based on the unique anatomy and reconstruction concerns. Surgical technique, including preservation of cartilage, is variable and impact on recurrence is unclear. Our goal was to investigate surgical approach, including extent of surgical resection and sentinel lymph node biopsy (SLNB), and the impact on recurrence. In this retrospective review of primary clinical stage 1/2 external ear melanoma, demographics, tumor characteristics, surgical resection technique (including cartilage-sparing vs. cartilage removal), and SLNB results were evaluated for recurrence risk. One hundred and fifty-six patients total had an average follow-up of 5.6 years. Twenty-nine (18.6%) patients underwent cartilage-sparing surgery and 99 (63.5%) patients underwent SLNB, 14.1% of whom had micrometastatic disease. Ten (6.4%) patients recurred loco-regionally. Recurrence was associated with Breslow depth, initial stage at diagnosis, and SLNB status. Cartilage-sparing surgery was not associated with increased recurrence. Sentinel lymph node identification rate was 100% based on clinical detection with use of lymphoscintigraphy. In addition to confirming established risk factors for melanoma recurrence, we confirm the feasibility of SLNB in stratifying recurrence risk. Although we did not see an increased recurrence risk with surgical technique and cartilage-sparing approaches, these findings are limited by small sample size.

Non-communicative adult ICU patients are vulnerable to inadequate pain management with potentially severe consequences. In German-speaking countries, there is limited availability of a validated pain assessment tool for this population. Aim The aim of this observational study was to test the German version of the Critical-Care Pain Observation Tool (CPOT) in a heterogeneous adult ICU population. Methods The CPOT's feasibility for clinical use was evaluated via a questionnaire. For validity and reliability testing, the CPOT was compared with the Behavioural Pain Scale (BPS) and patient's self-report in 60 patients during 480 observations simultaneously performed by two raters. Results The feasibility evaluation demonstrated high satisfaction with clinical usability (85% of responses 4 or 5 on a 5-point Likert scale). The CPOT revealed excellent criterion validity [agreement between CPOT and BPS 94.0%, correlation of CPOT and BPS sum scores r = 0.91 (P < .05), agreement of CPOT with patient self-report 81.4%], good discriminant validity [mean difference of CPOT scores between at rest and non-painful stimulus 0.33 (P < .029), mean difference of CPOT scores between at rest, and painful stimulus 2.19 (P < .001)], for a CPOT cut-off score of >2 a high sensitivity and specificity (93% and 84%), high positive predictive value (85%), and a high negative predictive value (93%). The CPOT showed acceptable internal consistency (Cronbach's alpha 0.79) and high inter-rater reliability [90% agreement, no differences in CPOT sum scores in 64.2% of observations, and correlation for CPOT sum scores r = 0.72 (P < .05)]. Self-report obtained in patients with delirium did not correlate with the CPOT rating in 62% of patients. Conclusion This is the first validation study of the CPOT evaluating all of the described validity dimensions, including feasibility, at once. The results are congruent with previous validations of the CPOT with homogeneous samples and show that it is possible to validate a tool with a heterogeneous sample. Further research should be done to improve pain assessment and treatment in ICU patients with delirium.

9582 Background: Granulomatous and sarcoid-like lesions (GSL) affecting the skin, lungs, thoracic lymph nodes, eyes and other organs following treatment with immune checkpoint inhibitors (ICIs) have been described in sporadic reports in the literature but the true incidence is unknown. Methods: We sought to estimate the incidence of GSL in the context of prospectively conducted ECOG-ACRIN E1609 phase III adjuvant trial in high-risk resected melanoma (N=1670 patients) testing ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). Descriptive statistics were used to calculate the incidence. Results: Among 1670 total patients treated with ICIs or with HDI in E1609, 1034 were treated with ipilimumab and 636 with HDI. Six GSL cases were reported among 1670 total patients treated with ipilimumab or with HDI as summarized in the table along with the corresponding CTCAE grades. More cases were observed with ipi10, followed by ipi3 and HDI, respectively. Organs involved included skin and subcutaneous tissue (granuloma annulare, granulomatous dermatitis), eye (ocular sarcoidosis), lymph nodes (noncaseating granulomatous lymphadenitis), lung and mediastinal lymph nodes (sarcoidosis, granulomatous inflammation). Conclusions: The incidence of granulomatous and sarcoid-like lesions (GSL) with adjuvant ipilimumab therapy in high-risk melanoma is rare. Reported cases ranged in grade from 1-3 and appeared manageable. Since most cases are asymptomatic, it is possible that GSLs are under-recognized and therefore, under-reported. A larger analysis including patients treated with anti-PD1 antibodies is currently underway. Clinical trial information: NCT01274338. [Table: see text]

TPS9585 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time, we are not able to predict which patients will derive benefit from AT and experience cure. While curative intent is the goal of treatment for primary melanoma, patients with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with response and survival. Treating with anti-PD1 while tumor remains visible in the body may generate a stronger immune response against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies of NAT with anti-PD-1 therapy have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with pembrolizumab (PEM, NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients with Stage IIIB to oligometastatic, resectable Stage IV are randomized 1:1 to AT or NAT. Patients getting AT undergo surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin adjuvant therapy within 84 days of surgery, relapse after surgery, or death due to any cause. Secondary endpoints include RECIST and iRECIST response rates, as well as a number of surgical outcomes. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT after 3 doses of PEM. Surgical pathology grossing instructions to ensure readout for pathologic response are provided in the form of training slides. Enrollment is at 40% of a planned 500 patients. Clinical trial information: NCT03698019.

9501 Background: We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design. Methods: Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)]. The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically signifcant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%. Conclusions: Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial Acknowledgement: With special thanks to Elad Sharon, MD, MPH, and Larissa Korde, MD, MPH. National Cancer Institute, Investigational Drug Branch, for their contributions to this trial, as well as Nageatte Ibrahim, MD, and Sama Ahsan, MD Merck. Clinical trial information: NCT02506153.

BACKGROUND Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was sought to evaluate the activity of dalantercept in RM-SCCHN. METHODS Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016. © 2016 American Cancer Society.

BRAF kinase gene V600 point mutations drive approximately 40% to 50% of all melanomas, and BRAF inhibitors (BRAFi) have been found to significantly improve survival outcomes. Although radiation therapy (RT) provides effective symptom palliation, there is a lack of toxicity and efficacy data when RT is combined with BRAFi, including vemurafenib and dabrafenib. This literature review provides a detailed analysis of potential increased dermatologic, pulmonary, neurologic, hepatic, esophageal, and bowel toxicity from the combination of BRAFi and RT for melanoma patients described in 27 publications. Despite 7 publications noting potential intracranial neurotoxicity, the rates of radionecrosis and hemorrhage from whole brain RT (WBRT), stereotactic radiosurgery (SRS), or both do not appear increased with concurrent or sequential administration of BRAFis. Almost all grade 3 dermatitis reactions occurred when RT and BRAFi were administered concurrently. Painful, disfiguring nondermatitis cutaneous reactions have been described from concurrent or sequential RT and BRAFi administration, which improved with topical steroids and time. Visceral toxicity has been reported with RT and BRAFi, with deaths possibly related to bowel perforation and liver hemorrhage. Increased severity of radiation pneumonitis with BRAFi is rare, but more concerning was a potentially related fatal pulmonary hemorrhage. Conversely, encouraging reports have described patients with leptomeningeal spread and unresectable lymphadenopathy rendered disease free from combined RT and BRAFi. Based on our review, the authors recommend holding BRAFi and/or MEK inhibitors ≥3 days before and after fractionated RT and ≥1 day before and after SRS. No fatal reactions have been described with a dose4 Gy per fraction, and time off systemic treatment should be minimized. Future prospective data will serve to refine these recommendations.

Purpose To address the gap in evidence-based information required to support the development of advanced practice nursing (APN) roles in Switzerland, stakeholders identified the need for guidance to generate strategic evaluation data. This article describes an evaluation framework developed to inform decisions about the effective utilization of APN roles across the country. Approach A participatory approach was used by an international group of stakeholders. Published literature and an evidenced-based framework for introducing APN roles were analyzed and applied to define the purpose, target audiences, and essential elements of the evaluation framework. Through subsequent meetings and review by an expert panel, the framework was developed and refined. Findings A framework to evaluate different types of APN roles as they evolve to meet dynamic population health, practice setting, and health system needs was created. It includes a matrix of key concepts to guide evaluations across three stages of APN role development: introduction, implementation, and long-term sustainability. For each stage, evaluation objectives and questions examining APN role structures, processes, and outcomes from different perspectives (e.g., patients, providers, managers, policy-makers) were identified. Conclusions A practical, robust framework based on well-established evaluation concepts and current understanding of APN roles can be used to conduct systematic evaluations. Clinical Relevance The evaluation framework is sufficiently generic to allow application in developed countries globally, both for evaluation as well as research purposes.

Background Delirium in older emergency department (ED) patients is associated with severe negative patient outcomes and its detection is challenging for ED clinicians. ED clinicians need easy tools for delirium detection. We aimed to test the performance criteria of the modified Richmond Agitation Sedation Scale (mRASS) in identifying delirium in older ED patients. Methods The mRASS was applied to a sample of consecutive ED patients aged 65 or older by specially trained nurses during an 11-day period in November 2015. Reference standard delirium diagnosis was based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria, and was established by geriatricians. Performance criteria were computed. Analyses were repeated in the subsamples of patients with and without dementia. Results Of 285 patients, 20 (7.0%) had delirium and 41 (14.4%) had dementia. The sensitivity of an mRASS other than 0 to detect delirium was 0.70 (95% confidence interval, CI, 0.48; 0.85), specificity 0.93 (95% CI 0.90; 0.96), positive likelihood ratio 10.31 (95% CI 6.06; 17.51), negative likelihood ratio 0.32 (95% CI 0.16; 0.63). In the sub-sample of patients with dementia, sensitivity was 0.55 (95% CI 0.28; 0.79), specificity 0.83 (95% CI 0.66; 0.93), positive likelihood ratio 3.27 (95% CI 1.25; 8.59), negative likelihood ratio 0.55 (95% CI 0.28; 1.06). Conclusion The sensitivity of the mRASS to detect delirium in older ED patients was low, especially in patients with dementia. Therefore its usefulness as a stand-alone screening tool is limited.

10059 Background: Circulating tumor DNA (ctDNA) analysis has been promoted as a less-invasive surrogate assay for tumor-tissue based tumor oncogene analysis. Here, we associate detection of BRAF mutant ctDNA with PFS and OS in patients with tissue-confirmed BRAFV600 mutant melanoma enrolled in S1320, a randomized phase 2 clinical trial of continuous versus intermittent dosing of dabrafenib and trametinib. Methods: Patients with BRAFV600 melanoma received continuous therapy with dabrafenib and trametinib for 8 weeks after which patients were randomized 1:1 to proceed with intermittent treatment on a 3-week-off, 5-week-on schedule or to continue with continuous therapy. Pre-treatment blood samples were interrogated using the Guardant 360 ctDNA assay for all exons of 30 known oncogenes including BRAF and for all exons with known oncogenic mutations in the COSMIC database in 40 additional oncogenes. Clinical responses were assessed at 8-week intervals by RECIST v1.1 and PFS and OS estimates were compared using log-rank test in patients with detectable versus undetectable BRAFV600 mutant ctDNA,. Results: Somatic BRAFV600E or BRAFV600K ctDNA was detected in 34 of 50 patients with baseline (before lead-in cycle 1) blood samples available for analysis including 16 of 23 (70%) patients randomized to continuous dosing, 15 of 21 (71%) randomized to intermittent dosing, and 3 of 6 (50%) who were not randomized due to disease progression at 8 weeks or other factors. Four additional patients had other detectable somatic mutations but no detectable BRAFV600 ctDNA at baseline, and 12 patients had no detectable somatic ctDNA mutations at baseline. Detection of BRAFV600 ctDNA was associated with baseline disease stage (p = 0.008). There was no difference in the overall response rate based on baseline ctDNA detection. Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021). Conclusions: The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib. Clinical trial information: NCT02196181.

TPS10090 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time we are not able to predict which patients will derive benefit from AT and experience cure. While curative surgery is the goal of early treatment of primary melanoma, some cases with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with survival. Treating with anti-PD1 while tumor transiently remains in the body may generate a stronger immune response from tumor-infiltrating lymphocytes against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies using NAT with have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with PEM (NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients are randomized 1:1 to the AT or the NAT. Patients getting AT receive surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin AT within 84 days of surgery, relapse after surgery, or death due to any cause. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT with 3 doses of PEM. Enrollment is at 94 of a planned 500 patients. Clinical trial information: NCT03698019.

10039 Background: S1320 is a phase 2 randomized clinical trial presented at the 2020 AACR Annual Meeting in April demonstrating that continuous dosing of dabrafenib and trametinib yields longer PFS than intermittent dosing of these agents in patients with BRAFV600E/K melanoma. Here we look at the association between prior exposure to ICB and PFS in patients randomized to either intermittent or continuous dosing on S1320. Methods: Patients without disease progression after 8 weeks of dabrafenib and trametinib were randomized 1:1 to proceed with intermittent therapy (3-week-off, 5-week-on) or to stay on the continuous daily dosing schedule. The design called for 206 randomized patients with the primary outcome of PFS. Response assessments were made using RECIST v1.1 at 8-week intervals. A post-hoc analysis assessed differences in PFS in the pool of all randomized patients based on prior exposure to anti-PD1 antibodies, a randomization stratification factor. Kaplan-Meier estimates and multivariable Cox regression models (controlling for pre-randomization age, Zubrod performance status, LDH, unknown primary, M-Stage) were used to evaluate the association between this stratification factor and PFS. Results: Of 242 patients treated on study, 105 were randomized to continuous dosing, 101 to intermittent dosing, and 36 were not randomized due to disease progression at 8 weeks or other factors. 37% of the 242 enrolled and 37% of the 206 randomized patients had previously been treated with ICB. Among all randomized patients, there were no differences in baseline characteristics comparing patients with and without prior immune checkpoint inhibitor exposure: age median 62 vs 59, LDH elevation 37% vs 39%,, stage IVB/C 73% vs 64%, Zubrod performance status 0, 57% vs 58%. PFS was longer in patients with prior ICB exposure (hazard ratio = 0.60, 95% confidence interval 0.41,-0.98, median = 6 vs 9 months from randomization, 8 vs 11 months from starting treatment). There was no difference in the association between prior ICB exposure and PFS between arms (interaction p-value = 0.62). Conclusions: In patients without early progression on dabrafenib and trametinib, PFS was longer with prior to exposure to ICB . Although the groups had similar baseline characteristics and rates of randomization, these results could still be influenced by non-controlled factors influencing clinicians’ decisions to start a patient on immune versus targeted therapy. Clinical trial information: NCT02196181.