bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.
Authors: Atkins Michael B. , Kirkwood John M. , Wolchok Jedd D. , Callahan Margaret K. , Kluger Harriet M. , Postow Michael A. , Segal Neil Howard , Lesokhin Alexander M. , Balogh Agnes , Re Sandra , Sznol Mario 
Published: May 2019

9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.
Efficacy of hypofractionated radiotherapy (Rx) in melanoma patients who failed anti-PD-1 monotherapy: Assessing the abscopal effect.
Authors: Saiag Philippe , Baghad Bouchra , Fort Magali , Aouidadd Iman , Roger Anissa , Mazeron Jean-Jacques , Otmezguine Yves , Blom Astrid , Longvert Christine , Boru Blandine , Funck-Brentano Elisa 
Published: May 2019

9537 Background: Radiotherapy (Rx) and anti-PD-1 mAb are potentially synergistic. No study has tested this combination only in pts who failed on anti-PD-1 mAb, which allows to assess the abscopal effect. We evaluated this combination in a cohort of advanced melanoma pts after failure of anti-PD-1 monotherapy. Methods: Analysis of a prospective database in a referral center searching for advanced melanoma pts with confirmed (2 CT-scans) progressive (PD) or stable (SD) disease on anti-PD-1 monotherapy, who later received concurrent Rx without modification of anti-PD-1 mAb regimen. Radiologists performed independent tumor evaluations (RECIST 1.1) every 3 m, both on radiated and non-radiated lesions, with abscopal effect defined as a partial (PR) or complete (CR) response outside radiated fields. Results: 26 pts (21 achieving PD, 5 SD, 10 pt ≥3 involved organs), mean age 70 Y, were included. Anti-PD-1 mAb was first line in 50% of pts. Rx, consisting of hypofractionnated Rx (3-5 sessions, 26 Gy), standard palliative Rx, or gamma-knife in respectively 23, 2, and 1 pts, was begun on a single site in 73% of pts or on 2 sites after a median of 5 m after beginning anti-PD-1 mAb. Median follow-up after onset of anti-PD-1 mAb was 17 (7-35) m, with 65% of pts alive at last follow-up. Best response was 7 CR (27%, including CR in 4 pts with prior PD) 1 PR, 3 SD (12%), 15 PD (58%). Abscopal effect was seen in 10 pts (38%). No correlation between the occurrence of CR and BRAF/NRAS mutation status, number of metastatic sites, presence or absence of brain metastases, and LDH level was seen. Anti-PD-1 mAb could be discontinued in 6 pts with CR, without relapse to date. No unusual adverse event was recorded. Conclusions: In pts who have previously failed on anti-PD-1 mAb, obtaining with concurrent Rx and without modifying anti-PD-1 mAb, CR or PR in 30% of pts, median OS not achieved, and abscopal effect in > 1/3 of pts is probably not due only to late efficacy of anti-PD-1 mAb but suggests a synergy with RT. Release after radiation of tumor neoantigens may stimulate immune response. Hypo-fractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in melanoma pts who failed on anti-PD-1 mAb. Controlled studies are needed.
ctDNA as a noninvasive monitoring tool in metastatic melanoma.
Authors: Varaljai Renata , Wistuba-Hamprecht Kilian , Seremet Teofila , Santiago Diaz Joey Mark , Nsengimana Jeremie , Sucker Antje , Griewank Klaus , Horn Peter , von Neuhoff Nils , Shannan Batool , Chauvistré Heike , Vogel Felix Christian Eduard , Horn Susanne , Becker Jürgen C. , Newton-Bishop Julia , Stang Andreas , Neyns Bart , Weide Benjamin , Schadendorf Dirk , Roesch Alexander 
Published: May 2019

9548 Background: The field of liquid biopsy provides a promising alternative to standard tissue biopsies. Previous work has shown that plasma circulating cell-free DNA (ctDNA) can reflect the heterogeneous spectrum of mutations in cancer including metastatic melanoma. Our project aimed to establish and statistically validate plasma-based assays for tumour load and therapy monitoring in melanoma. Methods: On a large cohort of stage III and stage IV melanoma patients (N = 96) who received signalling targeted or immune checkpoint inhibitors we showed that the most common oncogenic drivers of this disease such as the BRAFV600E, NRASQ61 and the TERTC250T and TERTC228T promoter mutations (termed TERTprom) can be analysed in ctDNA with highly sensitive droplet digital PCR technology (detection of mutant ctDNA down to 0.01% analytical sensitivity). Results: Our research has demonstrated that ctDNA (irrespective of the genotype) significantly correlates with tumour stage (P < 0.05). Using receiver operating characteristics (ROC) analyses thresholds were established for risk stratification and response prediction. Elevated ctDNA at baseline was a significant predictor of disease progression compared to elevated LDH or S100 in multivariable cox proportional hazards model (Hazard ratio [HR] 7.43, P = 0.05). During therapy, patients with low ctDNA load (below the ROC threshold) had significantly better radiological outcomes and prolonged progression free survival (PFS) compared to patients with high ctDNA load (P < 0.0001). Our findings were confirmed on an independent cohort of metastatic melanoma patients (N = 35) treated with immune checkpoint inhibitors, where also during therapy low ctDNA load correlated with prolonged PFS (P = 0.003). An added benefit of ctDNA was demonstrated in about 80% of the patients, where ctDNA analyses preceded the radiological diagnosis of response or relapse. Progression was detected in plasma ctDNA in average 3.5 months earlier as compared to routine imaging techniques. Finally, we demonstrated that the occurrence of NRASQ61 mutation in BRAFV600-inhibitor treated patients at therapy baseline was associated with treatment failure. The sub-clonal NRASQ61 mutation at therapy baseline was an independent predictor of shorter PFS (HR 2.69, P = 0.02) as compared to BRAFV600E patients without the NRASQ61 mutation at therapy baseline. Conclusions: In sum, our results support the value of ctDNA as a sensitive biomarker for real-time therapy monitoring and early detection of disease progression.
Patient-reported quality of life (QoL) of advanced melanoma patients in a Phase 3 study of nivolumab (NIVO) with or without ipilimumab (IPI) versus IPI: CheckMate 067 4-year data.
Authors: Schadendorf Dirk , Larkin James M.G. , Wolchok Jedd D. , Chiarion-Sileni Vanna , Taylor Fiona , Lawrance Rachael , Moreno-Koehler Alejandro , Lord-Bessen Jennifer , Rizzo Jasmine I. , Moshyk Andriy , KOTAPATI SRIVIDYA , Hodi F. Stephen 
Published: May 2019

9551 Background: Early CheckMate 067 data showed maintenance of QoL in patients with advanced melanoma treated with NIVO with or without IPI based on 1-year data; however, the long-term QoL of these patients has not been evaluated previously. The patient-reported outcomes (PRO) analyses presented here for CheckMate 067 is the first time QoL results have been evaluated in this melanoma population over a 4-year period. Methods: In CheckMate 067, 945 patients were randomized 1:1:1 to receive NIVO (3mg/kg Q2W) + placebo (PBO), NIVO+IPI (1mg/kg+3mg/kg Q3W X 4) followed by NIVO (3mg/kg Q2W), or IPI (3mg/kg Q3W X 4) + PBO. PRO data were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, VAS) at baseline, weeks 1 and 5 of each 6-week tx cycle, and off-tx follow-up (FU) visits. Mean changes in PRO scores from baseline (randomization) were evaluated descriptively for the PRO analysis population, with conclusions drawn from time points with ≥30 patients completing assessments per tx arm. Least square mean changes from baseline were assessed using a longitudinal mixed model analysis adjusting for repeated measures, including all on-tx data for patients. Results: Completion rates at baseline ranged from 89-92% across tx arms. Of 813 patients included in the PRO analysis population (278 NIVO, 274 NIVO+IPI, 261 IPI), > 200 receiving tx remained for the first year, > 100 receiving tx remained after 2 years, and > 50 receiving tx remained after 3 years. QoL, including assessment of functioning and symptom burden, was maintained for the duration of tx and in FU, with no sustained clinically meaningful deterioration in any tx arm. Global health status (EORTC QLQ-C30) and general QoL (EQ-5D-3L VAS) were also maintained during prolonged tx. Overall, results from the mixed model analysis support the long-term maintenance of QoL over the course of tx. Conclusions: Patient-reported QoL and symptoms in patients with advanced melanoma were maintained from baseline during extended tx with NIVO with or without IPI. Clinical trial information: NCT01844505.
Phase 1b study of PV-10 and anti-PD-1 in advanced cutaneous melanoma.
Authors: Agarwala Sanjiv S. , Ross Merrick I. , Zager Jonathan S. , Shirai Keisuke , Essner Richard , Smithers Bernard Mark , Atkinson Victoria , Wachter Eric Andrew 
Published: May 2019

9559 Background: PV-10 (rose bengal disodium) is a small molecule oncolytic immunotherapy in development for solid tumors, where intralesional injection can yield immunogenic cell death and tumor-specific reactivity in circulating T cells. It has been administered as a single agent to over 300 cutaneous melanoma patients (pts) in Phase 1-3 testing and under expanded access. Methods: Study PV-10-MM-1201 (NCT02557321) is a Phase 1b/2 study of PV-10 in combination with anti-PD-1 (pembrolizumab) for patients with advanced cutaneous melanoma (Stage IIIB-IV M1c). Patients must have at least 1 injectable lesion and be candidates for pembrolizumab. In Phase 1b pts receive combination treatment q3w for 5 cycles then pembrolizumab alone for up to 24 months; the primary endpoint is safety and tolerability with objective response rate (ORR) and progression free survival (PFS) key secondary endpoints (by RECIST 1.1 after 5 cycles then q12w). Results: Full accrual of the Main Cohort of Phase 1b was reached in April 2018, with an intent-to-treat population of 23 pts (3 IIIC/IIID, 8 M1a, 7 M1b, 5 M1c; median age 70 years, range 28-90). Treatment-Emergent Adverse Events (TEAEs) were consistent with established patterns for each drug, principally Grade 1-2 injection site reactions attributed to PV-10 and Grade 1-3 immune-mediated reactions attributed to pembrolizumab, with no significant overlap or unexpected toxicities: 6 Grade 1-2 TEAEs were attributed to the combination in 6 pts. Response of injected lesions was 77% CR (3% PR) achieved after a median of 3 injections / lesion administered over a median of 4 treatment cycles of PV-10 (range 1-5). Most pts had extensive uninjected tumor burden, and a best overall response of CR was achieved in 9% of pts (1 each M1a and M1b), with 57% of pts achieving PR (including 4 of 5 M1c pts). Response assessment is ongoing; final ORR and PFS data for the Main Cohort will be presented along with correlative T cell data. Conclusions: The primary endpoint for Phase 1b was met, with acceptable safety and tolerability of the combination and no unexpected safety issues identified. Two Phase 1b Expansion Cohorts (24 pts each) have been opened to pts refractory to prior checkpoint inhibition and pts with in-transit or satellite disease. Clinical trial information: NCT02557321.
Correlation of immune-related adverse events with peripheral baseline immune markers and overall survival in patients with metastatic melanoma on ipilimumab and chemotherapy.
Authors: Esfahani Khashayar , Thebault Pamela , Lapointe Rejean , Jamal Rahima , Miller Wilson H. 
Published: May 2019

9561 Background: Very few predictive markers have been validated for immune-related adverse events (irAE), which are the number one reason for cessation of treatment and treatment-related deaths on checkpoint inhibitors. In a phase II trial of combined ipilimumab (ipi) with carboplatin/paclitaxel (C/P) (NCT01676649), we sought to determine baseline peripheral blood markers predictive of irAEs and to correlate these adverse with subsequent survival. Methods: Thirty patients with untreated unresectable/metastatic melanoma were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and Ipi (3mg/kg) every 3 weeks x 4. irAEs were graded according to the CTCAE v5.0. Median follow-up was 60 months. Baseline blood markers was assessed by a 37 multiplex cytokine-chemokine platform (Meso Scale Discovery) and multiparameter flow cytometry. Results: Grade 2 or higher irAE occurred in 11/30 of patients (4 colitis, 2 hepatitis, 2 hypophysitis, 3 rash). Median survival was 43.8 months in patients with irAE and 14.5 months for those without irAE (p = 0.001). Pts with irAE had lower baseline circulating levels of IL-6 (3.6 vs. 19.8 pg/mL, p = 0.049), TNF alpha (7.6 vs. 11.6 pg/mL, p = 0.003), CXCL9 (83.4 vs. 116.8 pg/mL, p = 0.042) and CCL3 (52.3 vs. 76.4 pg/mL, p = 0.012), but higher baseline circulating dendritic cells (DC) (4.9 vs. 2.9 % of total PBMC, p = 0.002) and a lower level of myeloid-derived suppressor cells (MDSC) (0.8 vs. 1.7 %, p = 0.049). There was no correlation between baseline B cell circulating numbers or differentiation and irAEs. Conclusions: Although results from previous studies of ipi monotherapy vary, our small study shows a highly significant correlation between irAEs and improved long term outcome for patients treated with ipi/C/P. Our exploratory analysis also identifies putative predictive immune and cytokine-chemokine markers of irAEs, which are associated with: 1) Antigen presentation dysregulation (high DC cells) and lack of adequate auto-immune suppression (low MDSC), as also seen in classic autoimmune diseases; and 2) A low inflammatory baseline signature (low TNF, IL-6, CCL3, CXCL9) consistent with possible immune exhaustion and reduced lymphocytic homeostatic fitness. Our combined markers depict a dysregulated immune landscape favorable to the expansion of self-reactive immune cells under CTLA-4 blockade. Our results are hypothesis generating and require further evaluation in a larger group of patients, including PD-1 treated cohorts. Clinical trial information: NCT01676649.
Pretreatment steroid use and completion of immunotherapy: A population-based study.
Authors: Lu-Yao Grace L. , Nikita Nikita , Johnson Jennifer Maria , Keith Scott W. , Wen Kuang-Yi , Zinner Ralph , Ghosh Natasha , Banks Joshua , Hegarty Sarah , Wilson Melissa 
Published: May 2019

9567 Background: The relationship between immunosuppressants and immunotherapy (IO) is an active area of research. Here we study the impact of pre-treatment steroid use on the completion of ipilimumab (ipi) therapy. Methods: This population-based study identified patients diagnosed with melanoma and treated with ipi (brand name Yervoy) in 2010-2014 from the linked Surveillance, Epidemiology and End Result-Medicare files. “Completion of IO on time” was defined as receiving 4 cycles of IO within 90 days. Otherwise, the patients were considered to have delayed or incomplete IO. The frequencies of patients completing each dose, up to 4 doses were tabulated. Exact Clopper-Pearson 95% confidence intervals (CI) were computed for prevalence estimates. A crude relative risk (RR) for completing IO was calculated. Results: We identified 1,205 melanoma patients treated with ipi with a median age of 71 years. Among 709 patients with no pre-treatment steroids, 35.7% had completed 4th dose of IO, compared to 20.3% of patients who received pre-treatment steroids within 1 month of IO (Table). In these patients, having no exposure to steroids in the year prior to initiating IO was associated with a 28% increased probability of completing the IO regimen (RR=1.28, 95% CI: 1.07-1.53). Conclusions: This large scale real-world study demonstrated both the overall completion rate of ipi in melanoma patients as well as the negative impact of pre-treatment steroids on rate of treatment completion. Further studies on treatment outcomes associated with pre-IO steroids use are warranted. [Table: see text]
The clinical utility of neuron-specific enolase serum levels as a biomarker for Merkel cell carcinoma.
Authors: van Veenendaal Linde M. , Bertolli Eduardo , Korse Catharina M. , Klop W. Martin. C. , Tesselaar Margot Et , Van Akkooi Alexander Christopher Jonathan 
Published: May 2019

9570 Background: To date no adequate biomarker for Merkel Cell carcinoma (MCC) has been identified. The introduction of immunotherapy (IT) for metastatic MCC increases the need for a biomarker. Serum Neuron-specific enolase (NSE) has already been tested and is commonly used as a biomarker for several small cell malignancies. However, the role of NSE in MCC is still unclear. Aim: To investigate the role of NSE as a biomarker in MCC. Methods: A prospective cohort of MCC patients treated from 2016 to July 2018 was analyzed. Kaplan Meier curves with log rank test, Cox regression and mixed models were used to analyze NSE. A separate evaluation was performed for patients treated with IT. Results: A total of 78 patients (42 males, median age 71 years, stage I&II, III and IV MCC in 37(47%), 39(50%) and 2(3%) patients at time of diagnosis with 474 NSE levels (median 15 ; IQR 12,6-22 ng/ml were included. Baseline NSE (n=36) had no influence on survival or progression. During follow-up (FU) NSE levels correlated with tumorload (p=0,01) with increase of 15 ng/ml per class (no tumorload, localized MCC, nodal and distant metastases, respectively). NSE level during FU was able to detect progression (AUC 0,89). Several cut off values were evaluated. A NSE of 18,2 ng/ml was considered the most optimal level for clinical use (sensitivity 91%, specificity 78%, PPV 48%, NPV 98% to detect progression). During IT (n=16; 195 NSE values) all complete responders (n=7) had a normalized NSE (<18,2 ng/ml), all partial responders (n=3) had a decreasing NSE. In non-responders (n=6) all NSE levels remained elevated, one patient responded after switching to different IT with normalizing NSE values. Conclusions: NSE seems to be a valuable biomarker in MCC. NSE correlates with tumorload; is able to rule out progression and distinguishes responders from non-responders during IT.
Association between baseline disease characteristics and relapse-free survival (RFS) in patients (pts) with BRAF V600-mutant resected stage III melanoma treated with adjuvant dabrafenib (D) + trametinib (T) or placebo (PBO).
Authors: Schadendorf Dirk , Dummer Reinhard , Hauschild Axel , Santinami Mario , Atkinson Victoria , Mandalà Mario , Chiarion-Sileni Vanna , Larkin James M.G. , Nyakas Marta , Dutriaux Caroline , Haydon Andrew Mark , Mortier Laurent , Robert Caroline , Schachter Jacob , Ortmann Christine-Elke , De Jong Egbert , Gasal Eduard , Kefford Richard , Kirkwood John M. , Long Georgina V. 
Published: May 2019

9582 Background: In the COMBI-AD trial (NCT01682083), 12 mo of adjuvant D+T led to significant improvement of RFS vs PBO (hazard ratio [HR], 0.47; P < .001) in pts with resected BRAF V600–mutant stage III melanoma; 3- and 4-year RFS rates were 59% and 54%, respectively. Previous results demonstrated consistent treatment benefit across baseline disease stage according to AJCC edition 7 or 8. Here, we further explored the association between baseline disease characteristics and RFS to identify pt subgroups likely to benefit from adjuvant treatment. Methods: Randomized pts with completely resected BRAF V600E/K–mutant stage III melanoma received 12 mo of adjuvant D (150 mg BID) + T (2 mg QD) or PBO. Within each subgroup, predictive value was explored using Kaplan-Meier analysis, and HRs were calculated using a Pike estimator. Results: Minimum follow-up was 40 mo for 870 enrolled pts (D+T, 438; PBO, 432). Kaplan-Meier analysis demonstrated treatment benefit across all subgroups analyzed. Assessment of RFS by extent of primary tumor (T stage) showed consistent benefit favoring D+T vs PBO (HR [95% CI]; T1, 0.42 [0.25-0.70]; T2, 0.51 [0.34-0.76]; T3, 0.55 [0.39-0.77]; T4, 0.42 [0.29-0.60]). HRs by nodal burden (N stage) also showed consistent treatment benefit (N1, 0.52 [95% CI, 0.37-0.72]; N2, 0.38 [95% CI, 0.28-0.53]; N3, 0.58 [95% CI, 0.41-0.83]). Substantial treatment benefit was observed in pts with baseline in-transit metastases (HR, 0.45 [95% CI, 0.24-0.82]) and those with no in-transit metastases detected at baseline (HR, 0.49 [95% CI, 0.40-0.60]). When RFS was assessed according to melanoma presentation, treatment benefit favoring D+T vs PBO was observed in pts with superficial spreading melanoma (HR, 0.48 [95% CI, 0.35-0.66]) and those with nodular melanoma (HR, 0.53 [95% CI, 0.37-0.75]). Conclusions: These results confirm earlier findings showing that treatment benefit with adjuvant D+T vs PBO is independent of baseline factors. Clinical trial information: NCT01682083.