bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 3 international trial of adjuvant whole brain radiotherapy (WBRT) or observation (Obs) following local treatment of 1-3 melanoma brain metastases (MBMs).
Authors: Fogarty Gerald , Dolven-Jacobsen Kari , Morton Rachael L. , Hruby George , Nowak Anna K. , Vardy Janette L. , Drummond Katharine J. , Dhillon Haryana M. , Mandel Catherine , Scolyer Richard A. , Shivalingham Brindha , Middleton Mark R. , Burmeister Bryan H. , Lo Serigne , Reisse Claudius H. , Paton Elizabeth J. , Steel Victoria , Williams Narelle C. , Thompson John F. , Hong Angela M.
Published: May 2019

9500

Background: The role of adjuvant WBRT in MBMs is controversial. This trial compares WBRT with Obs after local treatment of 1-3 MBMs. Methods: The primary endpoint is distant intracranial failure (DIF) within 12 months of randomization. The a priori neurocognitive function (NCF) endpoint is Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months. Secondary endpoints include local failure (LF), overall survival (OS) and global quality of life (QoL). Analyses were conducted on intention-to-treat basis with nominal two-sided significance level 5%. Drug therapy was allowed. Effective drugs became available during trial and their impact was analysed. Results: Of 586 eligible patients (pts), 215 consented from 31 sites in 3 countries (Australia, UK and Norway) between 2009 and 2017. Eight (0.04%) who withdrew or had no data collected were excluded. 107 randomized to Obs and 100 to WBRT. Mean age 62 years, 67% males, 61% with single MBM of mean size 2cm, 67% had extracranial disease at randomization. The two arms were well matched. NCF was completed by English speakers; 50 WBRT and 70 Obs at baseline, declining to 26 and 35 respectively at 4 months. Within 12 months, 54 (50.5%) Obs had DIF compared with 42 (42.0%) WBRT pts (OR 0.71; 95%CI 0.41-1.23; p = 0.222). There was no difference in LF (p = 0.100) or OS (log-rank p = 0.861). 53% (Obs) and 59% (WBRT) pts were alive at 12 months. There was no significant between-group difference in mean intervention effect on global QoL (p = 0.083). Pts who received T-cell checkpoint inhibitors and/or mitogen-activated protein kinase (MAPK) pathway inhibitors and WBRT before or within 12 months of randomization had DIF rate 29% compared with Obs and no systemic therapy had 44%, but was not significant (p = 0.228). Obs had greater relative improvement from baseline in HVLT-R at every timepoint. At 4 months, Obs had 20.9% improvement from baseline in HVLT-R-delayed recall compared to 2.7% decline in WBRT; overall adjusted average intervention effect 23.6% (95%CI 9.0, 38.2; p = 0.0018). There was no difference in time to cognitive failure or in proportions with global cognitive impairment. Conclusion: This level one evidence shows WBRT does not improve outcomes in MBMs. This practice-changing trial justifies the recent move away from WBRT that occurred during the course of the trial. Clinical trial information: NCT01503827.
Correlates of overall survival (OS) in metastatic uveal melanoma (mUM) and a randomized trial of cabozantinib (cabo) versus chemotherapy (chemo).
Authors: Olson Daniel , Bao Riyue , Allred Jacob B , Strand Carrie , Zha Yuanyuan , Carll Timothy C. , Labadie Brian , Bastos Bruno R. , Butler Marcus O. , Munster Pamela N. , Schwartz Gary K. , Luke Jason J.
Published: May 2019

9506

Background: Survival is poor in mUM and treatment options are limited. MET kinase is over-expressed on UM and the MET inhibitor cabo showed activity in an early trial. Methods: A091201 was a 2:1 randomized phase II study testing progression-free survival (PFS) of cabo (60 mg daily) vs chemo (DTIC/TMZ). We studied baseline metastatic tumor samples (n = 19; 1 lung, 18 liver) by whole exome sequencing (WES) and RNAseq. We correlated data with OS and made comparisons for mUM vs. primary tumors from TCGA (n = 80). Results: 46 patients were accrued with 96% and 63% with liver metastases and elevated LDH, respectively. Toxicities were similar to prior reports of cabo and chemo. The trial stopped at interim analysis due to no difference in PFS (p = 0.964; HR = 0.99) or OS (p = 0.580; HR = 1.21). WES showed tumor mutational burden of 46±4 (mean±SEM) and did not separate OS at 1 year (p = 0.14, two-sided Wilcoxon rank sum test) in A091201. Recurrent known mutations included GNAQ/11, SF3B1, BAP1; novel mutations included GOLGA6L10, PKD1L3, and FAM228B. Gene expression signatures differed significantly between A091201 and TCGA cohorts including MET signaling (p = 7.87e-22), T cell-inflamed (p = 0.004), homologous recombination deficiency (p = 0.004), proliferation (p = 0.009) and hypoxia (p = 5.2e-10) (two-sided Student’s t-test). Tumor immune cell enrichment analysis revealed significant differences with lower M1:M2 macrophage (p = 1.2e-10) and higher Tregs (p = 6.0E-21) in mUM relative to TCGA (two-sided Wilcoxon rank sum test). Epithelial-mesenchymal transition gene expression signature was significantly associated with worse OS in A091201 (p = 0.02) with angiogenesis signature trending toward significance (p = 0.21) (log-rank test). OS separated by differentially expressed genes with OS ≤ 1 year associating with increased expression of the angiogenesis/immune-associated molecule neuropilin 1. Conclusions: These results provide insights between primary and mUM indicating potential novel therapeutic approaches. Support: U10CA180821, U10CA180882, T32GM007019, Exelixis. https://acknowledgments.alliancefound.org ; Clinical trial information: NCT01835145.
Five-year analysis on the long-term effects of dabrafenib plus trametinib (D + T) in patients with BRAF V600–mutant unresectable or metastatic melanoma.
Authors: Nathan Paul D. , Robert Caroline , Grob Jean Jacques , Stroyakovskiy Daniil , Karaszewska Boguslawa , Hauschild Axel , Levchenko Eugeny , Chiarion Sileni Vanna , Schachter Jacob , Garbe Claus , Bondarenko Igor , Davies Michael A. , Ribas Antoni , Flaherty Keith , Burgess Paul , Tan Monique , Gasal Eduard , Schadendorf Dirk , Long Georgina V.
Published: May 2019

9507

Background: First-line treatment with D+T demonstrated prolonged progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600–mutant unresectable or metastatic melanoma. With 5 years of follow-up, we report survival and describe characteristics of patients in the phase 3 COMBI-d and COMBI-v trials with long-term benefit. Methods: Pooled 5-year landmark data for patients treated with D+T in the phase 3 COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials were analyzed. The trials enrolled patients with previously untreated BRAF V600E/K–mutant unresectable or metastatic melanoma. Patients received D 150 mg twice daily plus T 2 mg once daily vs either D + placebo (COMBI-d) or vemurafenib (COMBI-v). The primary endpoints were PFS in COMBI-d and OS in COMBI-v. Results: The pooled population included 563 patients who received D+T (COMBI-d, n = 211; COMBI-v, n = 352). Four- and 5-year PFS and OS rates were similar, suggesting a stabilization (4- and 5-year PFS, 21% [95% CI, 17%-24%] and 19% [95% CI, 15%-22%, respectively]; 4- and 5-year OS, 37% [95% CI, 33%-42%] and 34% [95% CI, 30%-38%], respectively). In patients with normal baseline lactate dehydrogenase (LDH) levels the 5-year PFS rate was 25% vs 8% in patients with elevated baseline LDH levels. Similarly, the 5-year OS rate was considerably higher in patients with normal baseline LDH levels vs those with elevated LDH levels at baseline (43% vs 16%). Among patients with normal baseline LDH levels and < 3 organ sites with metastases, the 5-year PFS and OS rates were 31% and 55%, respectively. In addition, exploratory analyses will be performed to characterize subgroup(s) of patients most likely to experience long-term benefit. Of 299 patients who received subsequent anticancer therapy following treatment with D+T, 151 (51%) received an anti–CTLA-4 therapy and 102 (34%) received an anti–PD-1 therapy. The safety profile of D+T was as previously reported, and no new safety signals were observed. No treatment-related deaths were reported. Conclusions: First-line treatment with D+T leads to durable long-term benefit in many patients with BRAF V600–mutant unresectable or metastatic melanoma. Clinical trial information: NCT01584648; NCT01597908.
FDA analysis of depth of response (DpR) and survival across 10 randomized controlled trials in patients with previously untreated unresectable or metastatic melanoma (UMM) by therapy type.
Authors: Osgood Christy , Mulkey Flora , Mishra-Kalyani Pallavi Shruti , Lemery Steven , Ward Ashley , Keegan Patricia , Sridhara Rajeshwari , Theoret Marc Robert , Pazdur Richard
Published: May 2019

9508

Background: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 may not capture the full spectrum of benefit that patients with melanoma derive from targeted kinase inhibitors (TKI) or immunotherapies. We explored the relationship between DpR and overall survival (OS) in patients treated with TKI (BRAF, MEK inhibitors), immunotherapy (antibodies targeting PD-1 or CTLA-4), or chemotherapy (dacarbazine or paclitaxel). Methods: Ten randomized controlled trials of patients with previously untreated UMM were pooled and evaluated by type of therapy. DpR was grouped by maximal tumor shrinkage (G0 = no shrinkage or increase, G1 = ≤25%, G2 = 26-50%, G3 = 51-75%, G4 = 76- < 100%, and G5 = 100%). We performed an exploratory analysis evaluating the association between DpR and OS using hazard ratios (HR) generated from a Cox proportional hazards model where maximal tumor shrinkage category was included as a time varying covariate. Results: There were 3778 patients evaluable for tumor response. The table displays the HR for OS by DpR group and therapy type. Estimated OS at 24m in patients with deep response ( > 75%; G4+G5) treated with TKI and immunotherapy was 69% and 92%, respectively, although many patients were censored. Conclusions: For patients with previously untreated UMM a larger DpR correlates with a longer OS, regardless of therapy type. Deep response ( > 75%) is associated with a high rate of estimated OS at 24 months in patients treated with immunotherapy. Analysis of DpR provides additional granularity of response data and may provide a more nuanced prediction of clinical outcome. [Table: see text]
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.
Retrospective analysis of patients with sentinel lymph node (SLN) positive melanoma (MEL) who received adjuvant nivolumab (NIVO) without completion lymph node dissection (CLND).
Authors: Eroglu Zeynep , Babacan Nalan , Grossmann Kenneth F. , Markowitz Joseph , Brohl Andrew Scott , Cisneros Jennifer , Cruse Wayne , Harrington Michael , Gonzalez Ricardo Jorge , Sarnaik Amod , Zager Jonathan S. , Sondak Vernon K. , Khushalani Nikhil I.
Published: May 2019

9590

Background: Until recently, most patients (pts) with SLN+ MEL underwent CLND, a procedure mandated in published trials of adjuvant anti-PD-1 therapy to date. Following MSLT-II, this practice has dramatically changed with most pts now undergoing surveillance or adjuvant therapy without CLND. In addition, pts with in-transit/satellite MEL were excluded or not reported in these prior adjuvant studies. Our aim was to explore real-world outcomes of adjuvant NIVO in these pts. Methods: We carried out a single center retrospective analysis of stage 3 MEL pts who received adjuvant NIVO. Results: 32 pts with SLN+ MEL who did not undergo a CLND and started adjuvant NIVO within 3 months of surgery were included. Median age was 60 (26-77); per AJCC v7, 12 pts had Stage 3A, 11 stage 3B, and 9 pts had Stage 3C MEL. One was acral MEL; 18 had an ulcerated primary. 6 pts had BRAF-mutant MEL, 20 had BRAF-WT, and 6 unknown. NIVO treatment was 240 mg Q2wks or 480 mg Q4wks, up to one year. 21 pts developed grade 1/2 immune-related adverse events (irAEs), and 1 pt stopped NIVO due to toxicity (fatigue). With median follow-up of 7 months, only 1 pt had a recurrence, which was in the in SLN+ nodal basin; pt was rendered disease-free with surgery. The relapse-free rate (RFS) rate at 1 year was 95% (95% CI, 71-100). Of 21 pts with in-transit/satellite recurrent MEL (median age 68 [29-84]) who started adjuvant NIVO (no prior drug treatment), 5 had BRAF-mutant MEL, 14 BRAF-WT, 2 unknown; two were acral-lentiginous. 3 pts had recurrences: 2 regional and 1 distant mets, treated with surgery, TVEC, or BRAF-targeted therapy. Median follow-up was 8 months from NIVO start; 1-year RFS was 72% (95% CI 32-91). 15 pts developed irAEs; in 12, these were grade 1-2 and in 3, were grade 3 that led to discontinuation. Conclusions: While preliminary, these findings suggest that adjuvant anti-PD-1 therapy may be effective in SLN+ pts who forego CLND prior to adjuvant treatment, as 1-year RFS rate appears similar to rates in the published adjuvant anti-PD-1 trials that mandated CLND. This therapy may be similarly effective in pts with resected in-transit/satellite stage 3 melanoma. Further follow-up will be presented.
The CYP2C19 rs4917623 single nucleotide polymorphism to predict tamoxifen efficacy in estrogen receptor-positive breast cancer patients.
Authors: Yoshimoto Nobuyasu , Naito Akihiro , Kawaguchi Nobuko , Kato Miwa , Kondo Naoto , Wanifuchi-Endo Yumi , Toyama Tatsuya
Published: May 2019

e12001

Background: Tamoxifen is a selective estrogen receptor modulator that is widely used to treat estrogen receptor (ER)-positive breast cancer. However, not all patients benefit from the incorporation of tamoxifen into an adjuvant therapy. This is also the case when tamoxifen is used in chemoprevention, since only half of participants benefit from the drug. In order to improve treatment response, we attempted to identify single nucleotide polymorphisms (SNPs) that correlated with tamoxifen efficacy. Methods: ER-positive breast cancer patients at our hospital were enrolled on this study between January 2007 and September 2010. The primary endpoint was ER-positive breast cancer-free survival. We examined 17 SNPs in these patients. The survival benefit associated with each genotype was determined with a log-rank test, and the hazard ratio was analyzed using a Cox proportional-hazards model. Results: The median follow-up time of the 320 patients enrolled on the study was 3298 days. Of 240 patients who received any endocrine therapy, ER-positive breast cancer-free survival in patients with the 2q35 rs13387042 AA genotype was significantly shorter than in those who had the AG or GG genotype (p < 0.0001), and the hazard ratio was significantly higher (HR 8.83; 95% CI 2.09–25.53, p = 0.0064). Of the 145 patients who received tamoxifen therapy, there was a trend among ER-positive breast cancer patients with the CYP2C19 rs4917623 TT genotype to have a shorter disease-free period (p = 0.0635) when compared to patients with TC or CC genotypes. Similarly, there was a trend for the TT genotype patients to exhibit a higher hazard ratio (HR 2.62; 95% CI 0.86–7.55, p = 0.0861). Conclusions: The rs4917623 SNP in the CYP2C19 gene, which encodes a metabolic enzyme, predicts tamoxifen efficacy. This finding will facilitate selection of ER-positive breast cancer patients for tamoxifen treatment; it may also be useful for selection of patients most likely to benefit from tamoxifen-dependent chemoprevention.
Clinical practice patterns on the use of adjuvant bisphosphonate for early breast cancer: A Canadian perspective.
Authors: Zibdawi Lara , Simos Demetrios , Kassam Shaqil , Rana Amira , Kassam Farrah , Rahim Yasmin
Published: May 2019

e12002

Background: Adjuvant bisphosphonates (ABPs) in menopausal women with early breast cancer (EBC) decrease the risk of BC relapse and modestly improve overall survival (OS). In the era of personalized medicine, a one size fits all approach is not ideal–it is important to identify the subgroup of patients who may not derive a clinically meaningful benefit to avoid over treatment, unnecessary toxicity, and optimize resource utilization. Objectives: To better characterize how Canadian medical oncologists (MOs) use ABPs and whether practice patterns are concordant with the CCO/ASCO guideline. Methods: A brief survey was circulated by e-mail to 618 Canadian MOs between Nov 2017 - May 2018. Questions were designed to gather data on demographics, patient selection, choice of bisphosphonate, schedule/duration of treatment and barriers to use. No incentive was provided. Results: Sixty-eight MOs from 8 Canadian provinces completed the survey (response rate 11.0%). Most practiced in Ontario (65.7%) and just over half (51.5%) were community oncologists. MOs offered ABPs to 52.2% of menopausal women with EBC. Use was higher in the community compared to the academic setting (p=0.049). Most used zoledronic acid (85.3%) every 6 months (95.6%) for 3 years (69.1%) and started treatment within 3 months of completing adjuvant chemotherapy/radiation (67.7%). Factors associated with use of ABPs were: high Oncotype Dx score (89.1%), high tumor grade (72.1%), triple negative disease (63.6%), osteoporosis (87.7%)/osteopenia (83.9%) and use of aromatase Inhibitor (75.0%). The most common factor precluding use of ABPs was presence of comorbidities (89.7%). About 1/3rd indicated they would offer ABPs to women with stage I HR positive/Her2 negative EBC. Conclusions: Canadian MOs have added intravenous ABPs to their armamentarium of therapies in keeping with the spirit of the recent guideline. High-risk disease features and low bone density appear to be influencing the decision-making process. Further work aimed at identifying those patients who are unlikely to benefit from treatment is needed.
Use of treatment pathways reduce cost and decrease ED utilization and unplanned hospital admissions in patients (pts) with stage II breast cancer.
Authors: Weese James L. , Shamah Corey J. , Sanchez Federico Augusto , Perez Moreno Ana Cristina , Mitchell Dorry , Sessa Thomas , Gutantes Jean , Huibregtse Carol , Clement Kevin , Barry-Weers Anne Marie , Amy Bock , Bjegovich-Weidman Marija
Published: May 2019

e12012

Background: VIA Oncology evidence-based pathways have been integrated into our medical oncology workflows since November 2014. Within 3 months, compliance was high for our 42 medical oncologists at 19 sites working with a common EHR with over 85% of pts treated on pathway. The aim of this study was to determine if there was a significant difference in the overall cost of treatment between pts treated on pathway versus off pathway, and whether on pathway pts had a lower rate of ED use and unplanned admissions within 30 days of chemotherapy as required in the new CMS directives. Methods: Newly diagnosed stage 2 breast cancer pts diagnosed between January 1, 2016 to December 31, 2017 were identified from the tumor registry for the system. The VIA database was queried to separate these pts into two groups–those pts who were treated on pathway, and those who were off pathway. The data warehouse was utilized to determine the total charges of adjuvant medical oncology treatment for these pts. In addition, data was extracted for the same groups to determine those pts who sought ED evaluation and or hospital admission within 30 days of chemotherapy treatment. Statistical analysis was performed utilizing Fisher’s exact test to compare proportions and t-test to compare treatment costs and ED/hospitalizations between the on and off pathway groups. Results: During the 2 years, 412 (93%) Stage 2 breast cancer pts were treated on pathway (including clinical trials); 32 (7%) were off pathway. 81% of the on-pathway group were + for ER and/or PR and 17% were HER-2 +; 78% of the off-pathway group were + for ER and/or PR and 38% were HER-2 +. Mean cost for treating the on-pathway group was $111,067 compared to $200,717 for the off-pathway pts (p=0.01). 18.8% of the off-pathway pts were seen in the ED / unplanned admissions and had more multiple visits compared to 12.1% of on-pathway pts within 30 days of chemotherapy (p=0.026). Conclusions: Standardized usage of evidence based pathways can be used successfully across a large number of providers over wide geography. Adherence to pathways results in significant cost savings for each patient, and significant reduction in ED/hospital utilization for on pathway patients.
Weight change after (neo)adjuvant chemotherapy in a cohort of breast cancer survivors: Trends by race, hormone positivity, and chemotherapy regimen.
Authors: Colton Bradley S , Kareff Samuel , Li Shaw , Alintah Princess , Dash Chiranjeev , Dilawari Asma Ali
Published: May 2019

e12018

Background: It is estimated that over 50% of breast cancer survivors gain weight during treatment; patients receiving chemotherapy are at higher risk for weight gain. Previous studies have reported limited information about weight gain with current chemotherapy regimens. Methods: Individual data were collected from a cohort of 98 breast cancer patients treated with neoadjuvant or adjuvant chemotherapy between 2015 and 2017 at Lombardi Comprehensive Cancer Center. Weight was recorded from baseline visits and ≥ 1 visit following completion of chemotherapy. Regimens were grouped into anthracycline- (AC) and non-anthracycline-based (NAC) chemotherapy. Results: Overall, 49% ( n = 48) of patients gained weight after chemotherapy, though African-American patients demonstrated higher baseline BMI. Patients with ER-positive cancers displayed greater weight gain than hormone-negative counterparts ( p = 0.04); PR- or HER2-status was not associated statistically significant changes in weight ( p = 0.12 and 0.82, respectively). Among patients who did gain weight, NAC was associated with greater weight gain (4.47kg) than AC-based regimens (2.54kg) ( p = 0.03). Conclusions: ER positivity and NAC may serve as independent predictors of weight gain during chemotherapy. Further studies might consider further analyzing these trends to demonstrate additional long-term patterns. Baseline and After Chemotherapy BMI (kg/m2) and Weight Change (kilograms and percentage change) (P* derived from ANOVA). [Table: see text]
Impact of treatment on patient-reported pain and fatigue in early breast cancer patients receiving adjuvant radiotherapy.
Authors: Wan Bo Angela , Pidduck William , Zhang Liying , Yee Caitlin , Wang Katie , Chow Selina , Chan Stephanie , Drost Leah , Soliman Hany , Leung Eric , Sousa Philomena , Lewis Donna , DeAngelis Carlo , Taylor Prince , Chow Edward
Published: May 2019

e12019

Background: Patients who receive radiotherapy (RT) for breast cancer often report pain and fatigue which contribute negatively to quality of life (QoL). We aim to identify demographic, treatment, and disease characteristics associated with pain and fatigue using the Edmonton Symptom Assessment Scale (ESAS). Methods: We identified all patients diagnosed with non-metastatic breast cancer from 2011 Jan-2017 Jun at the Odette Cancer Centre with at least one ESAS completed pre- and post-RT. Data on systemic treatment, RT, demographics, and disease stage were extracted. To identify factors associated with pain and fatigue pre- and post-RT and their changes, univariate and multivariable linear regression analysis was conducted. p < 0.05 was considered statistically significant. Results: This study included 1222 female patients (mean age 59 years old) who completed ESAS on average 28- and 142-days pre-RT (baseline) and post-RT respectively. In multivariable analysis, higher baseline pain scores associated with adjuvant chemotherapy (p < 0.001) and eventual receipt of locoregional (p = 0.026) or chest wall RT (p = 0.003), whereas higher baseline fatigue scores associated with higher disease stages (p = 0.001) and locoregional RT (p < 0.001). Post-RT symptom severity correlated only with locoregional RT (higher pain scores, p < 0.001). Reductions in pain was associated with adjuvant chemotherapy (p = 0.002) and chest wall RT (p = 0.031). Reduction in fatigue was associated with adjuvant chemotherapy (p = 0.011) and locoregional RT (p = 0.007) although both had higher pre-RT scores in univariate analysis. Conclusions: Patients at higher disease stages or who received chemotherapy or chest wall RT tended to experience more severe short-term morbidity. However, patients who received locoregional RT tended to have greater pain that persisted after RT completion compared to those who did not.