bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial (BCD-100-2/MIRACULUM) of the novel PD-1 inhibitor (BCD-100) in patients with advanced melanoma.
Authors: Fogt Sergey , Shustova Mariia , Demidov Lev V. , Moiseyenko Vladimir , Tjulandin Sergei , Semiglazova Tatiana , Protsenko Svetlana , Odintsova Svetlana , Zukov Ruslan , Lazarev Sergey , Makarova Yuliya , Nechaeva Marina , Sakaeva Dina , Andreev Aleksey , Tarasova Anna , Fadeeva Natalia , Gavrilova Olesya , Ivanov Roman
Published: May 2019

9549

Background: MIRACULUM (NCT03269565) is a multicenter open-label parallel-arm phase II study investigating the antitumor activity of BCD-100, an IgG1 anti-PD-1 monoclonal antibody with Fc silencing “LALA” mutation, in patients with advanced melanoma. Interim analysis at 6-months is presented. Methods: Patients (pts) with unresectable or metastatic melanoma, without autoimmune disease, and no prior anti-PD-1 or anti-CTLA-4 therapy were eligible. Pts received BCD-100 1 mg/kg Q2W (arm 1) or BCD-100 3 mg/kg Q3W (arm 2) until disease progression or intolerable toxicity. Primary endpoint was ORR assessed per irRECIST by independent central radiology review. A statistical hypothesis that BCD-100 has significant anti-tumor effect (ORR more than 28% in per protocol population) was tested for each study arm with alpha 0.05 and 80% power. Results: 126 pts were treated and 114 were evaluable for the primary endpoint (9 pts dropped out before their first efficacy assessment and 3 pts had major protocol deviations). In arm 1 and arm 2, 17 (27%) and 16 (25%) pts received prior treatment for advanced disease, respectively. The study met its primary endpoint in both study arms. In arm 1, 34% ORR was achieved among 59 response-evaluable patients, including 4 CR and 16 PR, and the disease control rate (DCR) was 68%. In arm 2, 29% ORR was achieved among 55 response-evaluable pts, including 2 CR and 14 PR, and the DCR was 55%. All responses were durable; only one patient in arm 1 presented disease progression, and median PFS and OS were not reached in either study arms at 6 months follow-up. Treatment-related AEs (TRAEs) occurred in 48% of pts in each study arm, including 6% and 5% with grade 3/4 TRAEs in arm 1 and 2, respectively. Immune-related AEs (irAEs) occurred in 29% of pts in arm 1 and 30% of pts in arm 2, including 3% of pts with grade 3/4 irAEs in each arm. Conclusions: Both dosing regimens of BCD-100 (1 mg/kg Q2W and 3 mg/kg Q3W) have durable antitumor activity and a manageable safety profile in patients with advanced melanoma. Clinical trial information: NCT03269565.
Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced/metastatic melanoma resistant to anti-PD-1/PD-L1 therapy.
Authors: Amin Asim , Milhem Mohammed M. , Long Georgina V. , Hoimes Christopher J. , Medina Theresa Michelle , Conry Robert Martin , Lao Christopher D. , Daniels Gregory A. , Reddy Sunil A. , Andtbacka Robert Hans Ingemar , Barve Minal A. , Shaheen Montaser F. , Tueting Thomas , Chisamore Michael Jon , Schmidt Emmett V. , Candia Albert , Obiozor Cynthia Chinedu , Gamelin Erick , Janssen Robert , Ribas Antoni
Published: May 2019

9555

Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH > ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; > 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.
The relationship between obesity and immunotherapy: It's complicated.
Authors: Donnelly Douglas MacArthur , Bajaj Shirin , Zhong Judy , Weber Jeffrey S. , Pavlick Anna C. , Balar Arjun Vasant , Hsu Miles , Osman Iman
Published: May 2019

9562

Background: Obesity is a poor prognostic factor in primary melanoma, and preclinical data has linked it to an immunosuppressive phenotype. Paradoxically, recent reports suggest that obesity may confer a survival benefit in patients with metastatic melanoma (MM) who received immune checkpoint inhibition (ICI). Herein we tested the hypothesis that the relationship between body mass index (BMI) and response to ICI depends on type of ICI and tumor type. Methods: We examined 2 cohorts (MM patients [n = 423] and metastatic bladder cancer [MBC] patients [n = 42]). We tested the associations between BMI and PFS, stratified by first vs. second or greater-line of treatment and treatment type (anti-CTLA4, anti-PD1, combination therapy), adjusting for age, gender, stage, LDH level, ECOG status, number of metastatic sites, and BMI classification changes in the MM cohort. Results: We observed a moderate but insignificant association between being overweight (BMI 25.0-29.9 kg/m2) or obese (BMI > 30kg/m2) and better PFS in patients who received first line ICI therapy (aHR 0·77 [95% CI 0·50-1·20]), and an association with worse PFS in patients who received non-first line ICI therapy (aHR 1.31 [0·74-2.33], P interaction = 0.11). Overweight and obese patients receiving combination ICI had a statistically significant survival benefit (aHR 0.27 [0·10-0.70]), p = 0.007), whereas patients receiving the other treatment types showed heterogeneous trends (P interaction = .005). In the MBC cohort, being overweight conferred the greatest PFS benefit, followed by normal BMI, with obesity being associated with the worst PFS (p = 0.035). Conclusions: Stratifying by clinical features including treatment type, treatment line, and tumor type demonstrated vastly different results and reversal of trends, which underpins the complexity of the relationship between BMI and response to ICI. The lack of consistency amongst our data and published reports highlights the need for a thorough investigation, on a significantly larger scale, to truly elucidate obesity's impact on clinical outcomes in cancer. The scientific community must consider this complexity as well as the known detrimental health effects of obesity when counseling patients.
Molecular profiling of melanoma brain metastases (MBM) compared to primary cutaneous melanoma (CM).
Authors: In Gino Kim , Poorman Kelsey Anne , Saul Michelle , O'Day Steven , Farma Jeffrey M. , Daveluy Steven , Olszanski Anthony J. , Gordon Michael S. , Thomas Jacob Stephen , Eisenberg Burton Larry , Flaherty Lawrence E. , Gibney Geoffrey Thomas , Atkins Michael B. , Vanderwalde Ari M.
Published: May 2019

9565

Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.
Quality of life (QoL) and symptom burden in patients (pts) with advanced melanoma during the treatment-free interval (TFI) after discontinuation of nivolumab (NIVO) or NIVO plus ipilimumab (IPI).
Authors: Taylor Fiona , Regan Meredith M. , Schadendorf Dirk , Atkins Michael B. , Lawrance Rachael , Moreno-Koehler Alejandro , Moshyk Andriy , Rao Sumati , Ritchings Corey , KOTAPATI SRIVIDYA , Lord-Bessen Jennifer , Rizzo Jasmine I. , McDermott David F. , Middleton Mark R.
Published: May 2019

9568

Background: The TFI after discontinuation of study therapy has been reported to be longer with NIVO+IPI compared to NIVO or IPI alone, but QoL during the TFI has not been reported in advanced melanoma (MEL) studies. 1-y data from CheckMate (CM) 067 showed maintenance of QoL after treatment (tx) discontinuation with NIVO or NIVO+IPI. Here, we present long-term QoL results from CM 067 during the TFI (period off study tx and free of subsequent therapy), based on an updated 4-y dataset. Methods: In CM 067, 945 pts were randomized 1:1:1 to receive NIVO 3 mg/kg + placebo; NIVO 1 mg/kg + IPI 3 mg/kg × 4, then NIVO 3 mg/kg; or IPI 3 mg/kg × 4 + placebo. Patient-reported outcomes (PRO) were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, visual analog scale) at baseline, on-tx visits, and follow-up (FU) visits 1 (FU1; 30 d after last dose) and 2 (FU2; 84 d after FU1). EQ-5D-3L was also collected at survival FU visits every 3 mo after FU2 in the first year and every 6 mo thereafter. Within the PRO analysis population, 480 of 764 pts who discontinued protocol tx (for any reason, including drug toxicity; n = 155) had PRO scores, collected prior to initiation of subsequent anticancer therapy, evaluated. Mean changes in PRO scores from last on-tx visit were reported for each FU visit. Results: Across tx arms, PRO scores were maintained from last on-tx visit to FU1 or FU2 for pts who discontinued for any reason. EORTC QLQ-C30 functional and symptom scales remained stable during the TFI. Among pts who discontinued tx due to toxicity, clinically meaningful deterioration in QoL was observed in a few subscales at FU1, but QoL was restored to the same level as the last on-tx visit in all except one subscale by FU2. PRO scores remained stable beyond FU2 for the EQ-5D-3L, regardless of reason for discontinuation. Data interpretation at later FU visits was limited due to smaller sample sizes. Sensitivity analyses for mean change in PRO scores from randomization to FU visits will be presented. Conclusions: QoL was maintained during the TFI, compared to last on-tx visit, in pts with MEL treated with NIVO or NIVO+IPI.
Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Hemadri Amit , Lin Huang , Lin Yan , Rose Amy , Sander Cindy , Najjar Yana , Zarour Hassane M. , Kirkwood John M. , Davar Diwakar
Published: May 2019

9571

Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR≥2 to NLR≥5) with NLR≥5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR≥1 (ORR 64%), NLR≥2 (ORR 61%), NLR≥3 (ORR 52%), NLR≥4 (ORR 43%), NLR≥5 (ORR 43%). Elevated NLR ( < 5 vs. ≥5) was associated with poorer PFS (median 21.5 mths vs. 5.2 mos; p = 0.00041) and OS (median 35.4 os vs. 10.6 mos; p < 0.0001). In a multivariate model, elevated NLR ( < 5 vs. ≥5) was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR≥3 to NLR≥5), although NLR≥5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.
Association of medication (Med) and antibiotic (Abx) use with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Hemadri Amit , Lin Huang , Lin Yan , Rose Amy , Sander Cindy , Najjar Yana , Zarour Hassane M. , Kirkwood John M. , Davar Diwakar
Published: May 2019

9572

Background: Retrospective studies suggest that various med could dichotomous effects in regards to immunotherapy. These include adverse (antibiotics) and positive (aspirin, beta-blockers) influences. To evaluate potential additive or detrimental effects of various med in patients (pts) receiving PD-1 immunotherapy, we performed a retrospective evaluation of med intake in 172 pts with stage IV cutaneous MEL focusing on aspirin (asp), antacid (ant), antibiotic (abx), bisphosphonate (bisp), metformin (met) and statin (stat) intake. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Med intake was documented based on chart review in all pts. Intake was confirmed by analyzing at least one other note from a non-oncological provider. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how categorical variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mths). Results: 172 pts with advanced MEL were evaluated. Asp, ant, abx, bisp, met and stat use was documented in 62, 82, 29, 4, 15 and 57 pts respectively. ORR was not significantly related to intake of asp, ant, bisp, met and stat use; although ORR was lower in pts who received abx (p=0.0328). There was no significant difference in PFS and OS in pts who received asp, ant, bisp, met and stat. In patients who received abx compared to those who did not, median PFS (16.6 mths vs. 19.8 mths) and median OS (23.8 mths vs. 35.4) were both lower. Abx use did not interact with other meds. Conclusions: In this retrospective series of advanced MEL pts treated with PD-1 blockade, abx use was adversely associated with response to PD-1 blockade. Abx use was also associated with poorer PFS and OS. Conversely, neither a positive nor negative association with ORR, PFS and/or OS was seen with asp, ant, bisp, met and stat use. These results validate prior studies suggesting that abx use is associated with worse outcomes in pts receiving PD-1 blockade possibly by mediating intestinal dysbiosis.
Disparities in the occurrence of late effects following treatment among adolescent and young adult melanoma survivors.
Authors: Gingrich Alicia , Goldfarb Melanie , Sauder Candice , Li Qian , Wun Theodore , Keegan Theresa
Published: May 2019

9580

Background: Melanoma is the third most common cancer in the adolescent and young adult (AYA) population and the incidence worldwide is increasing. However, no studies have addressed the occurrence of late effect medical conditions following melanoma treatment in these young survivors. Methods: All patients ages 15-39 diagnosed with cutaneous melanoma from the 1996-2012 and surviving ≥ 2 years were obtained from the California Cancer Registry and linked to statewide hospitalization data. The influence of age at diagnosis, sex, race/ethnicity, neighborhood socioeconomic status (SES), and health insurance on the development of late effects by system was evaluated using multivariable Cox proportional hazards regression models. Results: Of 8,524 patients, 35.6% were male, 83.1% non-Hispanic white, 82.1% had private health insurance, 60.3% were considered high SES, and 70.7% had no documented co-morbidities at diagnosis. After controlling for competing factors, males had an increased risk of developing late effects across all systems, including cardiac [HR:2.13, 95%CI 1.87-2.42], neurologic (HR:2.24, CI 1.92-2.63), lymphedema (HR:2.22, CI 1.89-2.62), bleeding events (HR:2.35, CI 2.00-2.77), major infection/sepsis (HR:2.23, CI 1.95-2.56), and second cancers [HR:1.66, CI 1.47-1.89]. In addition, patients with public or no insurance (vs. private) had a greater risk of developing all studied late effects, including lymphedema (HR:2.48, CI 2.04-3.01), respiratory illness (HR:2.21, CI 1.85-2.64) renal dysfunction (HR:2.31, CI 1.90-2.81), and subsequent cancers (HR:1.82, CI 1.54-2.16). AYA patients residing in low SES neighborhoods had a similar increased risk of developing late effects. However, neither age nor race/ethnicity had an impact on the occurrence of late effects. Conclusions: Of AYA melanoma survivors, males, those with public or no health insurance, and those living in low SES neighborhoods had a much greater likelihood of developing of late effects. Strategies to improve surveillance and secondary prevention of these late effects is needed among AYA melanoma survivors, particularly for this demographic.
Circulating tumor DNA (ctDNA) in metastatic melanoma (MM) patients (pts) with brain metastases (mets).
Authors: Lee Jenny HJ , Menzies Alexander M. , Carlino Matteo S. , Kefford Richard , Scolyer Richard A. , Long Georgina V. , Rizos Helen
Published: May 2019

9581

Background: Brain mets are common in pts with MM, occurring in up 50% of pts. Serial ctDNA levels at baseline and early on therapy predict objective response (OR) and overall survival (OS) in MM pts without brain mets receiving immune checkpoint inhibitors (ICI). The predictive utility in pts with brain mets is unknown. Methods: BRAF/NRAS ctDNA at baseline and early on ICI therapy (week 3-8) was analysed using mutation specific digital droplet PCR (detection threshold 2.5 copies/ml plasma) in MM pts with brain mets. Intracranial (IC) and extracranial (EC) disease volume (sum of product of diameters of ALL mets [SPD]) and OR, progression-free survival (PFS) and OS were analyzed. Results: 48 pts with brain mets were studied, 40 with concurrent EC disease (SPD EC med 892mm2 [25-22417mm2], IC med 200mm2 [9-1487mm2]) and 8 with isolated IC mets (SPD med 150mm2 [66-1035mm2]). At baseline, ctDNA was detectable in 28 (58%) pts, 28/40 (70%) with IC + EC mets and 0/8 with isolated IC mets. Baseline ctDNA reflected EC disease volume (Pearson’s r = 0.4, p = 0.01) but not IC volume (r = 0.1, p = 0.5). Baseline ctDNA did not associate with IC or EC OR or PFS, however, undetectable ctDNA was associated with superior OS (HR 0.4, p = 0.01). Early on therapy, ctDNA predicted EC response but not IC response; EC OR was 65% if ctDNA undetectable and 6% if detectable (p < 0.01), IC OR was 35% if undetectable and 12% if detectable (p = 0.1). Nevertheless, undetectable ctDNA early on therapy was associated with a superior PFS (HR 0.3, p < 0.01) and OS (HR 0.2, p < 0.01), indicating survival is largely determined by extracranial disease activity. In the 8 pts with IC disease only, 7/8 had disease progressive disease as best response. 1/8 subsequently developed detectable ctDNA at week 12, with multiple new EC mets seen at first restaging scan at this time. Conclusions: ctDNA does not appear to be a useful biomarker for detecting brain mets nor monitoring brain response in melanoma pts receiving ICI. This has important implications when using ctDNA in the setting of surveillance in the metastatic and adjuvant setting.
An analysis of nivolumab-mediated adverse events and association with clinical efficacy in resected stage III or IV melanoma (CheckMate 238).
Authors: Mandalà Mario , Larkin James M.G. , Ascierto Paolo Antonio , Del Vecchio Michele , Gogas Helen , Cowey C. Lance , Arance Fernandez ANA Maria , Dalle Stéphane , Schenker Michael , Grob Jean Jacques , Chiarion-Sileni Vanna , Marquez-Rodas Ivan , Butler Marcus , Di Giacomo Anna Maria , Middleton Mark R. , Lutzky Jose , Millward Michael , de Pril Veerle , Lobo Maurice , Weber Jeffrey S.
Published: May 2019

9584

Background: In both previous 18- and 24-month follow-up reports from CheckMate 238, NIVO demonstrated significantly longer recurrence-free survival (RFS) than ipilimumab (IPI) in patients (pts) with resected stage IIIB/C or stage IV melanoma. Here we provide a more comprehensive analysis of treatment-related adverse events (TRAEs) for NIVO over discrete follow-up intervals and an investigation of the association of these AEs with efficacy (RFS). Methods: Eligible pts were aged ≥15 years and underwent complete resection of stage IIIB/C or IV melanoma. A total of 453 pts were treated with NIVO 3 mg/kg Q2W for up to 1 year. The primary endpoint was RFS. Pts were followed for safety for up to 100 days following their last dose; as of the previous 18-month database lock, all pts had been off study drug for > 100 days. Here safety data were analyzed within discrete time intervals: months 0–3 of treatment (0–3), months 3–12 of treatment (3–12), and from last dose to 100 days after last dose (+100). In addition, the association of TRAEs with RFS was investigated using the 24-month efficacy dataset, accounting for time-delay bias within the first 12 weeks after randomization. Results: The incidence of the first onset of TRAEs reported in ≥5% of pts was highest in the 0–3 time frame; the most common TRAEs with NIVO were fatigue (28% for 0–3 vs 6% for 3–12 vs 2% for +100), pruritus (16% vs 7% vs 1%), and diarrhea (15% vs 7% vs 2%). Most TRAEs with NIVO resolved within 3 months of occurrence, except for endocrine AEs, which could have required hormone supplementation, and skin AEs (median overall resolution time of 48 and 22 weeks, respectively). Similar results were observed in an analysis taking into account repeat occurrences of TRAEs over time. Analyses investigating the association of TRAEs with RFS are ongoing and will be presented. Conclusions: These results in pts with resected stage IIIB/C or IV melanoma are consistent with the established safety profile of NIVO. Based on the time periods analyzed, the majority of TRAEs with adjuvant NIVO occurred early during treatment, and patients had a reduced frequency of TRAEs after the treatment course. The majority of select TRAEs resolved within 3 months. Clinical trial information: NCT02388906.
A sequential dual cohort phase II clinical trial on adjuvant low-dose nivolumab with or without low-dose ipilimumab as adjuvant therapy following the resection of melanoma macrometastases (MM).
Authors: Schwarze Julia Katharina , Vandersleyen Valerie , Awada Gil , Jansen Yanina , Seremet Teofila , Neyns Bart
Published: May 2019

9585

Background: Optimal dosing and duration of adjuvant treatment with anti-PD-1 checkpoint inhibitors, e.g. nivolumab (NIVO), following complete resection of melanoma (MEL) lymph node metastases has not been established. We investigated a regimen of low-dose NIVO with/without low-dose ipilimumab (IPI) as adjuvant therapy in MEL pts. Methods: After complete resection of MM, pts were treated with IPI 50mg (fixed dose, 1x) plus NIVO 10mg (fixed dose, Q2w x4) (Cohort-A), or NIVO 10mg (Q2w x9, Q8w x4) (Cohort-B). One-year relapse-free survival (RFS) rate served as primary endpoint. Sample size (34 pts) was calculated according to a Fleming one-stage clinical trial design. Recruitment to Cohort-B was closed prematurely following registration of NIVO in the adjuvant setting by EMA. Secondary endpoints were safety, distant metastasis-free survival (DMFS) and overall survival (OS). Quantitative measurement of BRAF/ NRAS mutant circulating tumor DNA (ctDNA), as well as tumor gene expression profiling were performed. Results: 34 pts (15M/19F, 31 stage III/3 stage IV) and 22 pts (12M/10F, 21 stage III/1 stage IV) were enrolled in Cohort-A/-B, respectively. After a median follow-up of 86w for Cohort-A and 36w for Cohort-B, estimated 12 months (m) RFS-rate was respectively 55% (95% CI, 39–72) and 78% (95% CI, 73-82), 12m OS-rate was 97% (95% CI, 94-100) and 100%, and 12m DMFS-rate was 79% (95% CI, 92-65), no distant metastases occurred in Cohort-B. Median RFS for Cohort-A was 84w (95%, CI 28-139), not-reached in -B. Median DMFS and OS had not been reached at time of analysis in either cohort. All grade treatment-related adverse events were observed in 21 (61%)/17 (77%) with 3 (8%)/1 (4%) grade 3 irAE in Cohort-A/-B, respectively. One patient in Cohort-A had a detectable level of ctDNA at baseline and relapsed 33w after initiating treatment. Tumor profiling is ongoing at time of submission. Conclusions: The investigated adjuvant low-dose regimens have an acceptable safety profile. Survival rates resemble those of standard regimens. These regimens could be economically advantageous alternatives for pts without access to standard regimens. Clinical trial information: NCT02941744.
Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection: REDUCTOR trial.
Authors: Blankenstein Stephanie A. , Rohaan Maartje W. , Klop W. Martin. C. , Van Der Hiel Bernies , Van De Wiel Bart A. , Peeper Daniel S. , Haanen John B. A. G. , Van Akkooi Alexander Christopher Jonathan
Published: May 2019

9587

Background: The aim of this study is to evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib and trametinib (BRAF and MEK inhibitor respectively) to allow radical surgical resection in patients with unresectable BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Methods: A total of 25 patients with BRAF-mutated, unresectable locally advanced stage III or oligometastatic stage IV (≤3 metastases) melanoma will be treated with dabrafenib and trametinib for 8 weeks. Response evaluation by positron emission tomography/computed tomography (PET/CT) will occur at 2 and 8 weeks. If sufficient downsizing occurs, surgical resection will be performed. Biopsies for translational research will be taken at baseline and 2 weeks. The dissection specimen will be stored at 8 weeks. Results: Currently 20 patients have been included. Of these, 2 patients showed PD upon treatment and did not proceed to surgery. In 17/18 (94%) patients resection was possible after neoadjuvant treatment, of which 16 (94%) were R0 resections. Median follow-up time is 28 months with a median recurrence free survival of 9 months in patients undergoing surgery. The 1-year overall survival (OS) was 94% and 2-year OS 82%. Median OS was not reached. Metabolic response rates (RR) on PET/CT at 8 weeks were: 4 (20%) CR, 14 (70%) PR, 0 (0%) SD, 2 (10%) PD. Pathologic RR differed: 7 (35%) CR, 7 (35%) PR, 3 (15%) SD, 0 (0%) PD and in 3 patients (15%) no pathologic response was measured, since no resection was performed. Most patients (85%) experienced any toxicity, of which 50% was grade 1, 20% grade 2 and 3 patients (15%) experienced grade 3 toxicity. The most common reported toxicity was fever. Conclusions: Neoadjuvant dabrafenib and trametinib shows to be a potent cytoreductive treatment, allowing radical resection of metastases in 16/20 (80%) patients with prior unresectable locally advanced melanoma. Patients with no recurrence remained disease-free for a prolonged period of time. If there was recurrent disease, this usually occurred within months after surgery and this may present an opportunity for further tailored adjuvant therapy. Clinical trial information: NTR4654.
Extra-mammary Paget’s disease (EMPD) of the skin: A comprehensive genomic profiling (CGP) study.
Authors: Tse Julie , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Pavlick Dean , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Miller Vincent A. , Necchi Andrea , Bratslavsky Gennady , Ross Jeffrey S.
Published: May 2019

9591

Background: EMPD is an intraepidermal adenocarcinoma which frequently progresses into invasive/metastatic disease. Methods: 29 EMPD underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: All patients had locally recurrent and/or metastatic disease. The 20 (69%) male and 9 (31%) female patients had a median age of 70 years (range 45 to 101 years). The primary EMPD site, known in 90% of cases and involved the scrotum (6 cases), groin (6 cases), vulva (5 cases), anus (3 cases), perineum (2 cases), abdomen (2 cases), penis (1 case) and buttock (1 case). was used for sequencing in 15 (52%) cases and a metastatic site 14 (48%) cases. The GA/tumor frequency was 5.0. The most frequent currently untargetable GA involved TP53 (48%), CDKN2A (38%), CDKN2B (31%), KMT2C (28%), and MYC (14%). The most frequent potentially targetable GA were identified in ERBB2 (35%), ERBB3 (17%) and PTEN (14%) and rarely in PDGFRA, CDK4/6, NF1/2, and ROS1 (fusion) all at 3%. The ERBB2 GA included short variant (SV) activating mutations (21%), amplifications (10%) and multiple ERBB2 GA in 3%. This finding is in contrast with mammary Paget’s disease which classically features > 90% of cases with ERBB2 amplification. No EMPD cases were either MSI-High or stained positively for PD-L1 expression. The median and mean TMB were 5.2 mut/Mb and 6.3 mut/Mb, respectively; 4 (14%) had TMB ≥ 10 mut/Mb and 1 (3%) had TMB ≥ 20 mut/Mb. Conclusions: EMPD is a rare source of relapsed/metastatic adenocarcinoma which features GA that are distinct from the more common disease originating on the nipple of the breast including a lower ERBB2 GA frequency and lower relative frequency of ERBB2 amplification versus SV mutations. A variety of MTOR pathway, cell cycle and kinase targets are also identified when EMPD undergoes CGP. However, the low TMB and absence of both MSI-High status and PD-L1 expression in EMPD cohort indicates a likely lack of benefit for immunotherapies for patients suffering from this rare form of malignancy.
Resensitization of uveal melanoma (UM) to immune checkpoint inhibition (ICI) by IMCgp100 (IMC).
Authors: Yang Jessica , Orloff Marlana M. , Sacco Joseph J. , Hernandez-Aya Leonel Fernando , Lee Karla , Merrick Sophie , Nathan Paul D. , Pan Samuel , Lutzky Jose , Middleton Mark R. , Nesson Alexandra , Singh-Kandah Shahnaz V. , Hernandez Susana , Sato Takami , Carvajal Richard D.
Published: May 2019

9592

Background: ICI responses in UM are rare (~5% with anti-CTLA4/PD1 monotherapy; 10-12% with combination ICI). IMC is a bispecific agent composed of a high affinity T cell receptor targeting the gp100 melanoma antigen fused to an anti-CD3 scFv that increases intratumoral CD8+ T cell infiltration and PD1/PDL1 expression, and may enhance response to post-IMCgp100 ICI. Methods: We previously reported on 19 UM pts treated in the phase I dose escalation cohort of IMC (IMCgp100-102). We performed a retrospective analysis of clinical features and response to pre- and post-IMC ICI for the 12 pts in this cohort as well as 17 other pts (n = 29) treated with post-IMC ICI at 7 centers from 8/2016 to 1/2019. 21/29 pts (including 10/12 pts from IMCgp100-102) are evaluable for response and/or survival and are included in the analysis. Results: Baseline characteristics (n = 21): median age 56 (range 45-69); 57% female; median number of prior therapies 2 (range 1-4). Pre- and post-IMC ICI included: IPI+NIVO (3 pre; 8 post), anti-PD1 monotherapy (7 pre; 8 post), and anti-CTLA4 monotherapy (4 pre; 5 post). 20 pts were evaluable for post-IMC ICI response (1 died before restaging): 3/20 (15%) had partial responses (53-78% regression); 5/20 (25%) had stable disease (SD) > 16 weeks; 1/20 had SD of unknown duration. Median PFS and OS from the initiation of post-IMC ICI were 4.9 (95% CI 2.7-10.7) and 10.1 (95% CI 5.7-NR) months, respectively. 13 pts received pre-IMC ICI, all with eventual disease progression. 3 pts had treatment duration or SD lasting > 6 months. Of these 3 pts, 2 had clinical benefit (defined as objective response or SD > 16 weeks) with post-IMC ICI. There was no clear association between rates of Gr ≥ 2 irAE with pre- or post-IMC ICI and response. For the 10 evaluable pts treated on IMCgp100-102, no marked difference in prior response to IMC (3 SD among 5 ICI responders vs 2 SD among 4 ICI non-responders) or mean tumor shrinkage with IMC (-14.0% vs -18.0%) was observed, but rates of Gr ≥ 2 fever, rash, and/or hypotension with IMC were higher among ICI responders (80% vs 50%). Conclusions: Survival outcomes with post-IMC ICI compare favorably to historical figures in pretreated UM pts. IMC may re-sensitize pts who had prior clinical benefit with ICI to subsequent ICI.
Validation of a panel of risk factors for predicting breast cancer reappearance.
Authors: Corso Giovanni , Veronesi Paolo , Maisonneuve Patrick , Goldhirsch Aron , Sacchini Virgilio , Caldarella Pietro , De Scalzi Alessandra Margherita , Galimberti Viviana
Published: May 2019

e12004

Background: The aim of this clinical study was to assess a panel of risk factors for ipsilateral breast tumor recurrence (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (1994-2006). Clinicopathological features, follow-up and survival at 15 years were considered for statistical analysis. Results: Significant increased risk for IBTR were verified with younger age ( < 50 years) [HR = 1.31 (1.15-1.49), p < 0.0001], lobular subtype [HR 1.40 (1.15-1.70), p = 0.0007)], pT3 [HR 1.90 (1.42-2.54), p < 0.0001] or pT4 [HR 2.70 (1.47-4.97), p = 0.001], metastatic axillary lymph nodes [HR 1.50 (1.29-1.73), p < 0.0001], peritumoral vascular invasion (PVI) [HR = 1.27 (1.10-1.46), p = 0.001], luminal B [HR 1.57 (1.33-1.87), p < 0.0001], HER2-positivity [HR 1.85 (1.32-2.59), p = 0.0004] and triple-negative subtype [HR 1.76 (1.28-2.43), p = 0.0005]. Older age ( > 70 years) [HR 1.50 (1.05-2.15), p = 0.03] and positive family history [HR 1.86 (1.48-2.34), p < 0.0001] were risk factors for contralateral BC. Significant protective factors for IBTR were mucinous subtype [HR 0.45 (0.27-0.77), p = 0.003], total mastectomy [HR = 0.37 (0.30-0.46), p < 0.0001], hormonotherapy [HR 0.56 (0.45-0.69), p < 0.0001], chemotherapy [HR 0.77 (0.66-0.90), p = 0.001] and external radiotherapy [HR 0.39 (0.31-0.50), p < 0.0001]. Hormonotherapy was also confirmed as a protective factor for contralateral second BC [HR 0.51 (0.38-0.69), p < 0.0001]. Cumulative incidence for IBTR at 5, 10, and 15 years was higher than for than for contralateral BC. Conversely, overall survival for IBTR was lower than for contralateral BC. Conclusions: We classified factors influencing IBTR and contralateral BC into high- and low-risk groups. The high-risk group for IBTR included: age < 50 years, positive axillary nodes, PVI positivity, luminal B, HER2-positive, lobular and triple-negative subtypes. The low-risk group included: adjuvant treatments (hormone-chemotherapy, external radiotherapy) and mucinous histotype. We hypothesize that in the low-risk group, adjuvant treatments exert a strong impact in the prevention of IBTR risk (HER2-positive and triple negative BC should be considered also for neo-adjuvant therapies); this was not confirmed in the high-risk group, in which a more aggressive surgery is still theoretically justified. The proposed panel represents the basis for a nomogram to predict BC reappearance.
Decisions on adjuvant chemotherapy for patients with breast cancer based on clinical and evolving Oncotype DX criteria.
Authors: Zekri Jamal , Al-Foheidi Meteb Owaish , Alata Maaz Kamal , Rasmy Ayman Ahamd , Rasool Haleem J. , Abdelrahman Hossam A. , Hussain Adnan , Sorour Yasser , Mashhour Miral
Published: May 2019

e12009

Background: Oncotype-DX assay recurrence score (ODX-RS) cut-off values have recently changed in response to the results of the TAILOR-X trial. We aim to explore decisions for ACT based on physicians’ clinical assessment and on evolving ODX-RS. Methods: Patients who underwent ODX testing after curative surgical resection of estrogen receptor positive (ER+), Her2 non-over-expressed (Her2-) and lymph node negative (LN-) BC were included. Patients with micro-metastases to LNs were excluded. Data was collected retrospectively from the electronic records. Management of these patients was guided by the results of the old ODX-RS-1 (<18, 18-30 & ≥31) risk grouping. For the purpose of this study, treatment decisions were also assumed according to TAILOR-X results (ODX-RS-2). Decisions of 3 medical oncologists on ACT were solicited by blinding them to the RS values to investigate inter-physicians discrepancy and concordance with ODXA RS-1&2. Results: Sixty six consecutive patients fulfilled the inclusion criteria. Median age was 50.5 (range: 21-73) years. There was one male patient and 37 out of 65 females (56.9%) were pre-menopausal. Median tumor size was 21.5 (range: 10-55) mm and the grade were I, II and III in 6 (9.1%), 46 (69.7%) and 41 (21.2%) patients respectively. The 3 oncologists’ had discrepancies about ACT recommendations in 29 (44%) patients. Based on majority opinion (≥2 oncologists), ACT would have been recommended to 22/41 (53.7%) and 24/46 (52.2%) patients with low risk tumors according to ODXA RS-1 and ODXA RS-2 respectively. Similar number of patients (n=12) would have received ACT regardless of ODXA RS cut-off value (table). Conclusions: Decisions on ACT for patients with ER+/Her2-/LN- early BC should be guided by ODX-RS to prevent overtreatment and discrepancies in management. Broadly, ODXA RS-1 and ODXA RS-2 seem to guide ACT decisions in similar proportions of patients. Nevertheless minor differences exist and need to be studied in larger cohorts. [Table: see text]
Oncotype recurrence score (RS) and discordance in patients with secondary invasive breast events (SIBE).
Authors: Zimmerman Brittney Shulman , Cascetta Krystal Pauline , Blanter Julia , Eggert Lauren , Molot Madeline , Ru Meng , Nayak Anupma , Bleiweiss Ira , Jaffer Shabnam , Tiersten Amy
Published: May 2019

e12016

Background: Oncotype RS is a 21-gene assay used to predict the likelihood of distant recurrence and benefit of chemotherapy in patients with node-negative, tamoxifen treated breast cancer (BC). We developed a database to determine rates of SIBE and identify cases of discordance between Oncotype RS and tumor grade (TG). Our goal was to recognize patients with discordant tumors who had SIBE, with implications for patient management. Methods: We identified 618 patients (645 samples) with early-stage, hormone positive BC treated between 2006-2018, with tumor characteristics available for analysis. Among these patients, there were 24 SIBE (n = 24) from 23 patients (3.7%). When stratified by RS using traditional cutoffs (Paik, 2004), rates of SIBE were 2.8%, 5.0% and 4.5% in low, intermediate and high-risk groups respectively. Discordance was defined as 1 or 2-step difference between RS (low, intermediate, high risk) and TG (well (WD), moderately (MD) and poorly (PD) differentiated). Prior studies demonstrated 7-19% “2-step discordance” between TG and RS (i.e. PD tumors with low-risk RS or WD tumors with high-risk RS). N(%) or median were used to describe patients’ characteristics between groups and compared by Mann-Whitney U test at the confidence level of 5%. Results: Of the 24 SIBE, 42% had low RS ( < 18), 46% had intermediate RS (18-30) 12% had high RS ( > 31). Median RS was 22 and median age at secondary event was 61 (67% post-menopausal). At time of SIBE, 54% were metastatic, 25% locally recurrent and 21% contralateral. Within this dataset, 63% were 1-step and 4% were 2-step discordant. Significantly fewer patients were treated with systemic chemotherapy in the discordant group (p < 0.01), though 94% displayed MD or PD TG. Discordant tumors tended to have lower RS (median 14 vs. 24) and be larger. There were no significant differences in menopausal status or Oncotype ER/PR score. Conclusions: Although the sample size of patients with SIBE is small, our data suggests that patients with discordant tumors of low-risk RS but higher TG may be receiving inadequate treatment (i.e. no chemotherapy). In addition to RS, other factors such as discordance, TG and size should perhaps be considered when determining treatment plans.
Role of adjuvant chemotherapy in small (≤5 mm) node-negative and hormone receptor-negative breast cancer.
Authors: Master Samip R. , Dadi Neelakanta , Shah Chintan , Burton Gary Von , Shi Runhua
Published: May 2019

e12021

Background: There is currently lack of adequate data to support for or against the role of adjuvant chemotherapy for small( < = 5mm) hormone negative and node negative breast cancer. We did a retrospective analysis from National Cancer Database (NCDB) to assess the effect of adjuvant chemotherapy in HER2 positive/ Hormone receptor negative (HER+HR-) and triple negative breast cancer. Methods: Data was analyzed from approximately nine thousand women registered in the (NCDB) who were diagnosed with triple negative and HER+ HR-small ( < = 5mm) and node negative breast cancer between 2010 and 2014 and had follow-up to the end of 2015. The primary predictor variable was the receipt of chemotherapy, and outcome variable was overall survival. Additional variables addressed and adjusted included age, race, Charlson Comorbidity Index and grade of cancer. Results: Approximately 59% patients received adjuvant chemotherapy. The five year overall survival in women with triple negative for breast cancer who received chemotherapy was 79% , compared to 87% , for those who did not receive chemotherapy(p < 0.00001). The five year overall survival in women with Her2+HR- for breast cancer who received chemotherapy was 68% , compared to 84% , for those who did not receive chemotherapy(p < 0.00001).In multivariate analysis, after adjusting for secondary predictor variables, avoidance of adjuvant chemotherapy was associated with 59.5% reduction in risk of death. Conclusions: Our analysis suggests that there are no role for adjuvant chemo in small breast cancers that are Her+ HR- and triple negative. The receipt of adjuvant chemotherapy lead to decrease in overall survival.