bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity of treatment-free survival (TFS), a novel outcome, to subgroup analyses of patients (pts) with advanced melanoma (MEL) treated with immune checkpoint inhibitors (ICI).
Authors: Mantia Charlene , Werner Lillian , Rao Sumati , Ritchings Corey , Tarhini Ahmad A. , Atkins Michael B. , McDermott David F. , Regan Meredith M. 
Published: May 2019

9550 Background: Many pts treated with ICIs can discontinue treatment and experience ongoing disease control and toxicity. We previously proposed a novel outcome, TFS, as the time between ICI therapy cessation and subsequent therapy initiation or death, with integrated graphical analysis to better characterize the unique effects of ICIs (ASCO 2018 #9531). In the CheckMate 067 and 069 trials of ipilimumab (IPI) and nivolumab (NIVO) alone or in combination (NIVO+IPI) in pts with MEL, the 36-month restricted mean TFS was 8.7, 4.6 and 11.1 mo, respectively. We explored the sensitivity of TFS to be informative of overall survival (OS) differences through subgroup analysis. Methods: Data from MEL pts in the CheckMate 067 and 069 trials were pooled and analyzed. TFS was defined as the area between the Kaplan-Meier curves for two endpoints, from randomization: (A) time to ICI therapy cessation; and (B) time to subsequent therapy initiation or death. TFS was estimated by restricted mean survival time until 36 mo since randomization. Differences in restricted mean TFS between subgroups of pts (such as PD-L1 status, lactate dehydrogenase [LDH], performance status [PS], gender) were calculated with bootstrapped 95% CIs. OS from randomization was also estimated. Results: Among 407 pts treated with NIVO+IPI, restricted mean TFS ranged from 8-13 mo across subgroups (Table). Subgroup differences in mean TFS were larger for prognostic factors LDH and PS and smaller in non-prognostic PD-L1 status and gender subgroups. Conclusions: Clinically meaningful TFS was seen across all subgroups. TFS was sensitive to prognostic subgroup differences. These results provide further support for TFS as a relevant clinical endpoint. Additional subgroups and comparisons with single agent NIVO and IPI arms will be presented at the meeting. [Table: see text]
Organ site-specific radiological responses in anti-PD-1 monotherapy treated advanced melanoma patients.
Authors: Bai Xue , Kim Michelle S. , Kasumova Gyulnara , Cohen Justine Vanessa , Lawrence Donald P. , Freedman Christine , Fadden Riley , Rubin Krista M. , Sharova Tatyana , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Boland Genevieve Marie 
Published: May 2019

9552 Background: Melanoma is notorious for its high degree of heterogeneity with the implication that metastases in different sites react differently to immunotherapy. We aimed to explore the site-specific response pattern in anti-PD-1 monotherapy treated advanced melanoma patients. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital (MGH) from Sept 2009 to Dec 2017. Radiological evaluations were carried out by radiologists from the MGH Tumor Imaging Metrics Core using irRECIST 1.1. Statistical analysis was carried out using ANOVA test. Results: Among 61 evaluated patients, 56 (91.8%) had at least one measurable target lesion(s) at baseline, including 35 (57.4%) patients with measurable lymph nodes (LN)/subcutaneous lesion(s), 25 (50.0%) with lung lesion(s), and 21 (34.4%) with liver lesion(s). At week-12 radiological evaluation after anti-PD-1 monotherapy initiation, lesions at different sites responded differently at marginal statistical significance (P = 0.071), namely mean percent changes compared with baseline were 3.75%, 5.12%, and -30.95% for LN/subcutaneous, liver, and lung lesions, respectively. Among patients who had disease under control (CR/PR/SD) (n = 37, 60.7%) by week-12 evaluation, the mean tumor percentage change at week-24 compared with week-12 were -8.94%, -12.18%, and -5.91% for LN/subcutaneous, liver, and lung lesions, respectively (P = 0.479). Conclusions: Although our small sample size limits definitive discrimination in organ site-specific response differences, it appears that lung lesions respond more quickly and to a greater extent compared with LN/subcutaneous and liver lesions in advanced melanoma patients treated with anti-PD-1 monotherapy. We will explore this in a larger, multicenter cohort.
Phase I study of vemurafenib (VEM) and cobimetinib (COB) with heat shock protein 90 (HSP90) inhibitor XL888 in advanced BRAFV600 mutant melanoma.
Authors: Eroglu Zeynep , Chen Ann , Li Jiannong , Markowitz Joseph , Brohl Andrew Scott , Tetteh Leticia , Karpisek Adam , Taylor Hayley , Messina Jane , Sondak Vernon K. , Khushalani Nikhil I. , Smalley Keiran 
Published: May 2019

9553 Background: Resistance to BRAF+MEK inhibitors(i) in BRAF-mutant melanoma is common. Multiple resistance mechanisms involve HSP90 clients, and a phase 1 study of VEM with XL888 showed PFS rates similar to the combination of BRAF+MEKi (Eroglu, CCR, 2018). Methods: Combination of VEM (960 mg PO BID) and COB (60 mg QD for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60 or 90 mg PO twice weekly) was investigated in a phase 1 study of advanced melanoma, with a modified Ji dose escalation design. Dose-limiting toxicity (DLT) was defined as related grade ≥3 adverse event or inability to deliver 75% of XL888 in first 4 weeks. Results: 25 pts (9 female, median age 62, 15 with M1C disease, 6 with prior anti-PD-1 therapy) were enrolled. After 2 DLTs (rash and acute kidney injury) in first cohort, a lower dose of VEM 720 mg BID and COB 40 mg, with the same XL888 cohorts was investigated. 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose. Most common grade 3 toxicities included diarrhea (8), hypertension (6), rash (5), alkaline phosphate/GGT elevation (4). 11 patients required dose reductions of VEM and/or COB. Objective responses (PR/CR) were observed in 18 of 25 pts (72%; 95% CI: 51-88%). Median PFS was 8.1 months (4.7 – NA); median overall survival was not reached, with 1-year OS of 71% (45-86%). Single cell RNA-Seq (10X genomics) was performed on baseline and on-treatment tumor biopsies; 8 days of treatment was associated with an increase in immune cell influx (CD4+ and CD8+) and a decrease in number of melanoma cells. At day 8, one patient (now without progression for nearly 2 years) had no tumor cells remaining with only immune cells and stromal fibroblasts left. Further analyses will be presented. Serial plasma BRAF circulating tumor (ct)DNA levels were obtained, with decrease in ctDNA levels corresponding with response and 83% of patients with disease progression showing an elevation in ctDNA from baseline. Conclusions: VEM/COB plus XL888 had significant toxicity, requiring dose-reductions that may have contributed to the low PFS rate despite high response rate. Caution must be used in combination of BRAF+MEKi with other agents. Clinical trial information: NCT02721459.
Phase II trial of nab-paclitaxel (ABI) and ipilimumab (ipi) in patients with treatment naïve metastatic melanoma.
Authors: Ludford Kaysia , Johnson Daniel H. , Hennegan Tarin , Gruschkus Stephen K. , Haymaker Cara L. , Bernatchez Chantale , Jackson Natalie , Hwu Patrick , Diab Adi 
Published: May 2019

9554 Background: Conventional chemotherapies possess intrinsic immune-regulatory properties. Some taxanes for instance, stimulate antigen presentation and impair regulatory T-cells while leaving effector T cells intact. Combining chemotherapies with immune checkpoint inhibitor at carefully designed dosing regimens may increase tumor cell susceptibility to immune-mediated death and thus enhance therapeutic efficacy. We describe the safety and updated efficacy of ABI and ipi in patients with metastatic melanoma. Methods: In this open-label, single center, phase II trial, ABI was administered to treatment naïve metastatic patients at 150mg/m2 on days 1,8 and 15 every 4 weeks and ipi at 3mg/kg on day 1 every 3 weeks limited to 4 cycles until disease progression or unacceptable toxicity. Endpoints included ORR, OS and safety. Results: 18 of 21 enrollees between 6/2013 and 6/2015 with Stage IV melanoma (M1c: 56%, M1b: 33%, M1a: 11%) were included in the analysis. The median age was 57 years old (33-69) and 67% were men. 44% harbored BRAF mutations. Median duration of treatment was 9 weeks (5 to 17). Median follow-up time for OS analysis was 22.5 months (2 to 52 months). 12 and 24 month OS were 77.8% and 60.6% respectively with median not yet reached. The ORR by by irRECIST was 27.8%. Grade 3 adverse events were reported in 50% of patients, the most common being neutropenia. 17% of patients had grade 3 immune-related adverse events, the most common being hypophysitis and colitis. Immune analysis showed absolute lymphocyte count was significantly elevated post treatment compared with pre-treatment (p = 0.024). In addition, deep immune analysis of peripheral blood samples and tumor tissue including nanostring, gene expression and TCR sequencing will be assessed and reported. Conclusions: The combination of ipi and ABI in this small study demonstrates acceptable safety, tolerability and clinical activity. ABI may contribute to tumor cytoreduction and enhance antitumor clinical response of ipi without impactful immunosuppression. This data together with further immune analysis may provide rationale to design prospective chemo-immunotherapy regimens and treatments for metastatic melanoma and other solid tumors. Clinical trial information: NCT01827111.
Characterization of the genetics of mucosal melanoma in patients treated with immunotherapy.
Authors: Buchbinder Elizabeth Iannotti , Weirather Jason L. , Manos Michael P. , Brennick Ryan C. , Ott Patrick Alexander , Haq Rizwan , Izar Benjamin , Hodi F. Stephen 
Published: May 2019

9556 Background: Mucosal melanomas can be effectively treated with checkpoint inhibitors, although the response rates are lower than those observed for melanomas arising in cutaneous sites. The mechanistic basis for the lower efficacy of immunotherapies in mucosal melanoma has been suggested to be related to their lower mutational burden. However, there has been limited characterization of the genetics in this melanoma subtype. Methods: Tumor genotyping was performed on all mucosal melanoma patients seen within the Dana Farber Cancer Institute from 2011 until the present by Oncopanel analysis. Results: We identified a total of 57 mucosal melanoma patients whose tumors had been genotyped. Of these 42 received immunotherapy and had response data available. Within the cohort of mucosal melanoma patients, 37.3% had durable clinical benefit (DCB) to their first line of IO therapy. These patients had an average mutational burden/megabase of 6.41 (95% CI 3.53-11.01) but tumor mutational burden did not correlate with response in this cohort. The pattern of mutations in mucosal melanomas was distinct from cutaneous melanomas, as the most frequent mutations were in SF3B1, ATRX, KIT and NF1 genes. Patients with KIT aberrations had a higher DCB rate compared patients with wildtype KIT (73 vs. 33%). In addition, there were several genetic differences observed based upon the site of origin of the mucosal melanoma. A higher rate of SF3B1 mutations was observed in patients with melanoma of anal/rectal origin while patients with vulvar/vaginal melanoma had higher rates of ATRX mutations, which frequently correlated with p53 ( TP53) mutations. Conclusions: This analysis is one of the first to look at genetic patterns in a large cohort of a relatively rare type of melanoma and correlate with response. Our findings confirm the low mutational burden observed in mucosal melanoma despite the high response rate observed in these patients. In addition, this study uncovered a higher rate of response to immunotherapy in mucosal melanoma patients with a KIT mutation.
Stereotactic radiotherapy combined with immunotherapy is safe and effective: Results from a phase I clinical trial.
Authors: Ratnayake Gishan , Reinwald Simone , Shackleton Mark J. , Moore Maggie A. , Voskoboynik Mark , Ruben Jeremy , Van Zelm Menno , Yu Di , Ward Rachel , Smith Robin , Haydon Andrew Mark , Senthi Sashendra 
Published: May 2019

9557 Background: There is growing evidence to suggest synergism between stereotactic ablative radiotherapy (SABR) and immunotherapy (IO) against metastatic melanoma. The optimal timing and dosing of SABR for this purpose has not been established. Here, we report results from a Phase I trial, finding the best outcomes with low dose SABR delivered late. Methods: Metastatic melanoma pts with at least two metastases received SABR to a single metastatic site. All pts had standard dose IO with anti-PD1 and/or anti-CTLA4. Following a standard 3+3 design, pts were escalated through three SABR doses (10Gy, 15Gy and 20Gy) delivered at three different time points (Cycle 1, 2, or 3 of IO). Dose limiting toxicity (DLT) were defined as Grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or cox regressions were used to assess the impact of SABR dose, timing and use of combination IO on toxicity, progression-free (PFS) and overall survival (OS) while controlling age, gender and baseline performance status. Results: Between April 2016 and August 2018, 24 pts were enrolled. The median age was 66 years and most were ECOG 0-1 (92%). The median follow-up was 10 months. Three pts (12.5%) developed DLTs (enterocolitis, hepatitis and liver function derangement). None occurred at SABR treated sites and all were in pts receiving 15Gy. DLTs were not associated with SABR timing (p = 0.44) or use of combination IO (p = 0.72). On this basis the IDSMC recommended stopping the trial and maximum tolerated SABR dose was defined at 10 Gy. The median PFS and OS were respectively 5.4m (95% CI 2.1m-NR) and 16.9m (95% CI 7.1m-NR). The median PFS for those receiving 10Gy was numerically higher than those receiving 15Gy (11.8m vs 2.6 m, p = 0.42). The only treatment related factor associated with improved PFS (HR = 0.14, p = 0.02) and OS (HR = 0.09, p = 0.04) was receiving SABR with Cycle 3. SABR dose (PFS p = 0.75, OS p = 0.67) and IO type (PFS p = 0.13, OS p = 0.06) were not significant. Conclusions: SABR combined with IO is generally safe overall. We found the optimal therapeutic index may be achieved with 10Gy delivered with the third cycle of IO; a strategy that warrants further testing. Clinical trial information: ACTRN12616001064493.
Mutation landscape of Chinese melanoma patients.
Authors: Huang Fuxue , Li Dandan , Wen Xizhi , Wang Fang , Zhang Xiaoshi , Lin Xuan , Chen Shuyin , Liu Hao , Han-Zhang Han , Liu Jing 
Published: May 2019

9563 Background: Treatment options for melanoma, which has the highest mutation burden among common cancers, has proliferated in the past decade. Genomic profiling has becoming essential to clinical decision making. However, limited studies have interrogated the genomic landscape of Chinese melanoma patients. We also investigated the correlation between tumor mutation burden (TMB) and clinical outcomes of immunotherapy (IO). Methods: In this study, we retrospectively surveyed the genomic profiling of primary tumors of 81 (40 males, 41 females) metastatic Chinese melanoma patients with a median age of 52, using a panel consisting of 295 cancer-related genes, spanning 2.02MB of human genome. Patients used IO as first line treatment (n = 25) were enrolled for survival analyses. Results: In this cohort, 15, 24 and 42 were acral, mucosal and cutaneous melanoma, respectively. Collectively, we identified 1,114 mutations, spanning 248 genes, with BRAF, MYC and NBN being the most frequently mutated genes, occurring in 40%, 27% and 21% of patients, respectively. Mutation spectrum varied significantly by subtypes. BRAF (57%) and LRP1B (26%) were the most frequently mutated genes in cutaneous melanoma (CM). KIT and NRAS, reported to be frequently mutated in CM, each occurred in only 12% patients in this cohort. MYC amplification was the most commonly seen mutation in acral and mucosal melanoma (MM). Other frequent mutations in MM included: NBN (38%) RUNX1T1(29%) and TP53 (29%). In acral melanoma (AM), CCND1, FGF3/19, NF1and NBN were frequently mutated. It is interesting to note that no TP53 mutation was observed in AM. AM and MM had significantly more CNVs than CM. Of the 25 patients underwent IO, our data revealed a positive correlation between TMB and PFS (p = 0.007). Such correlation also exited in each subtype. Furthermore, we derived a cutoff of 15, which can effectively distinguish clinical response. Patients with TMB > 15 mut/Mb had a significantly longer PFS than patients harboring TMB < 15 mut/Mb (P = 0.02). Patients with CM had a longer PFS than patients with AM or MM (p = 0.018). No correlation between PDL1 expression and PFS was observed. Conclusions: Our study revealed a distinctive mutation landscape for each subtype. Furthermore, we also revealed a positive correlation between TMB and PFS as well as a lack of correlation between PDL1 expression and PFS.
Anal melanoma: A comparative comprehensive genomic profiling study.
Authors: Ross Jeffrey S. , Madison Russell , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Edgerly Claire I. , Duncan Daniel , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Jurdi Adham Adel , Miller Vincent A. 
Published: May 2019

9566 Background: We performed a comprehensive genomic profiling (CGP) study of AM and CM to learn of potential genomic alterations (GA) linked to targeted and immune checkpoint inhibitor (ICPI) therapies. Methods: 90 AM and 1804 CM FFPE tissues from late stage underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001). GA/tumor was significantly higher in CM (UV light exposure) as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). PD-L1 expression was higher in AM than CM (P = 0.0023). AM and CM were all MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). Of potentially targetable GA, AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway GA were common in both tumor types. Additional potentially targetable alterations in PDGFRA and ERBB2 kinases were seen in AM but not in CM. Conclusions: CM is distinct from AM featuring higher GA/tumor, higher TMB and frequent BRAF V600E GA that predict benefit from ICPI and anti-BRAF therapies. Although both AM and CM feature MTOR pathway targets, AM does have higher PD-L1 expression than CM and is characterized by an array of potentially targetable kinase genes including KIT, PDGFRA, ERBB2 and to a lesser extent than CM, BRAF.[Table: see text]
Efficacy of immune checkpoint inhibitors (ICIs) for in-transit melanoma.
Authors: Nan Tie Emilia , Lai-Kwon Julia Elizabeth , Na Lumine , Rtshiladze Michael Alexander , Bozzi James , Read Tavis , Atkinson Victoria , Au-Yeung George , Long Georgina V. , McArthur Grant A. , Sandhu Shahneen Kaur , Saw Robyn , Walpole Euan Thomas , Menzies Alexander M. , Smithers B. Mark , Gyorki David E. 
Published: May 2019

9583 Background: The efficacy of ICIs in metastatic melanoma is well-established. However, there is limited data regarding their efficacy in in-transit melanoma metastases (ITM). This study assessed the efficacy of ICI in patients with ITM. Methods: A multisite, retrospective review of patients with ITM treated with ICI from 2004-2018. Demographic and clinicopathological factors (age, sex, primary site, AJCC version 8 stage, BRAF status, prior locoregional therapies) were collected. Objective response rate (ORR) based on a clinician-assessed best overall response, progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Results: Fifty-four patients were included: 27 (50%) female; median age 69 (range 19-89); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10(19%) BRAF mutant. Forty (74%) received single agent PD-1 inhibitor (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PDL-1/MEK inhibitor (atezolizumab and cobimetinib). ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single agent anti PD-1, 38% for single agent anti-CTLA4, and 40% for anti-PD-1/anti-CTLA-4 (Table). The median follow-up was 15 months (2-46). The median PFS was 11.7 months (6.6-N/A). PFS at 1 and 2 years were 48% and 39%. Fourteen (56%) progressed locoregionally and 11 (44%) progressed distantly. OS at 1 and 2 years were 85% and 63%; the median OS was not reached. No clinicopathological features were associated with ORR. Conclusions: ICI produces objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence despite locoregional therapies. [Table: see text]
A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma.
Authors: Najjar Yana , McCurry Dustin , Lin Huang , Lin Yan , Davar Diwakar , Drabick Joseph J. , Neves Rogerio Izar , Ernstoff Marc S. , Puzanov Igor , Skitzki Joseph J. , Pingpank James F. , Holtzman Matthew Peter , Sander Cindy , Rose Amy , Kirkwood John M. , Tarhini Ahmad A. 
Published: May 2019

9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.