bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.
Authors: Ascierto Paolo Antonio , Melero Ignacio , Bhatia Shailender , Bono Petri , Sanborn Rachel E. , Lipson Evan J. , Callahan Margaret K. , Gajewski Thomas , Gomez-Roca Carlos A. , Hodi F. Stephen , Curigliano Giuseppe , Nyakas Marta , Preusser Matthias , Koguchi Yoshinobu , Maurer Matthew , Clynes Raphael , Mitra Priyam , Suryawanshi Satyendra , Muñoz-Couselo Eva 
Published: September 2018

9520 Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity (NCT01968109; Lipson E, et al. J Immunother Cancer. 2016;4[s1]:173 [P232]). Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] > 12 wk), and duration of response (RECIST v1.1). Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had ≥ 3 prior therapies, and 15 (35%) had BRAFmutations .In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts. Immunopathologic (eg, PD-1/PD-L1 and LAG-3 expression) and clinical characteristics of responders vs nonresponders will be presented. Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109.
Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172).
Authors: Schadendorf Dirk , Ascierto Paolo Antonio , Haanen John B. A. G. , Espinosa Enrique , Demidov Lev V. , Garbe Claus , Lorigan Paul , Gogas Helen , Hoeller Christoph , Guren Tormod Kyrre , Rorive Andree , Rutkowski Piotr , Muñoz-Couselo Eva , Dummer Reinhard , Carneiro Ana , Hospers Geke , Grigoryeva Elena Borisovna , Bhore Rafia , Nathan Paul 
Published: September 2018

9524 Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). We report efficacy and updated safety data from 734 treated pts with ≥1 year of follow-up (database lock: November 2016). Results: Of 734 pts, 50% had LDH>ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received ≥3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1% (Table). The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. Clinical trial information: NCT02156804. [Table: see text]
Association of improved survival (OS) and tumor control (TC) with interleukin-2 (IL2) with development of immune-related events (IREs): Data from the PROCLAIMSM registry.
Authors: Curti Brendan D. , Daniels Gregory A. , McDermott David F. , Clark Joseph , Kaufman Howard , Singh Jatinder , Kaur Meenu , Luna Theresa L. , Gregory Nancy C. , Hua Hong , Morse Michael , Wong Michael K.K. , Dutcher Janice P. 
Published: September 2018

9528 Background: IREs are associated with immunotherapy (IT) for cancer and while reports suggest improvement in TC and OS with induced IREs, the long-term impact is unclear. IL2 has been the major IT for patients (pts) with renal cell carcinoma (RCC) and melanoma (MM) since 1992. We evaluated IREs reports in the PROCLAIMSM data base (2008-2016) of IL2-treated pts. Methods: Reports on 614 (MM) and 843 (RCC) pts were queried for IREs. IREs were categorized as occurring before, during, or after IL-2 and related to any checkpoint inhibitor (CPI). TC (CR+PR+SD) was compared between no IRE and IRE, using Fisher’s exact test. OS curves were estimated by Kaplan-Meier method, and comparison of no IRE/before IL2 with during/after IL2, was analyzed by log-rank test. Results: With a median (med) follow-up of 3.5+ years (range 1-8+ year), 140 IREs were reported in 118 pts (9.6% of all PROCLAIMSM pts): 93 (15%) in MM; 47 (5.6%) in RCC. 25 IREs were prior to IL2; 13 IREs were during IL2; 102 were after IL2. Of the latter 102, 31 were after IL2 and after subsequent CPI; 71 were attributed to IL2 only; and in 13, IREs were due to either IL2 or CPI. TC was 73% for IRE group vs 56% for no IRE group (p = 0.0054). OS was significantly greater for IRE group during/after IL2 compared to no IRE/before IL2 in MM, med 46 months (mo) vs 18 mo (p = 0.0001) and in RCC, med 61 mo vs 43 mo (p = 0.0196), independent of CPI IREs. Med # of IL2 doses was 19 in no IRE group, 39 in IRE during IL2 group, and 25 in IRE after IL2 group. IL2-related IREs were primarily vitiligo and thyroid dysfunction (70% of IL2 IREs), with limited further impact, while CPI-related IREs were often serious, requiring intervention (hypophysitis, colitis, hepatitis, uveitis) (52% of CPI IREs) and possibly chronic management. Conclusions: IREs following IL2 are associated with improved TC and OS. IREs resulting from IL2 and from CPIs are qualitatively different and likely reflect different mechanisms of action of immune activation and response.
Outcomes following progression on BRAF/MEK inhibition in metastatic melanoma.
Authors: Mason Robert , Heng Sharon , Atkinson Victoria 
Published: September 2018

9537 Background: Restrictions in Australia dictate the prescription of BRAF/MEK inhibitors prior to immunotherapy in BRAF mutant metastatic melanoma (BRMM). We analysed patients (pts) with advanced BRMM after treatment with a BRAF/MEK inhibitor and use of second line immunotherapy (PD-1 inhibitor or CTLA4 inhibitor). Methods: Patients (pts) with BRMM from Princess Alexandra Hospital treated between June 2013 to June 2016 were identified retrospectively. Demographics, treatment pattern and survival were analysed. Results: 92 pts were identified. 50% had an elevated LDH at diagnosis. 30 pts had brain metastasis at diagnosis, of these pts 11 had cerebral progression on BRAF/MEK. 41 pts had radiotherapy, 50% had stereotactic/gamma knife and 50% WBRT. 68 pts progressed giving a median progression free survival (PFS) of 9 months (95% CI 6.4 – 11.6 m). The median PFS for pts with normal LDH was 14 months, opposed to 9 months if elevated. On progression 31 pts (36.5%) were not offered second line immunotherapy due to rapid deterioration or declining performance status. 26 (30.6%) were treated with PD-1 inhibitor; 7 (8.2%) had Ipilimumab, of these, 4 then had PD-1; 1 had combination therapy; 23.5% of pts continued on BRAF/MEK at analysis. Of the patients exposed to immunotherapy, 27 pts experienced disease progression, giving a median PFS survival of 2.5 months (95% CI 1.2 –3.6m). Conclusions: After BRAF/MEK inhibition, due to rapid disease progression and poor performance status a significant proportion of patients do not receive immunotherapy and received best supportive care. Disease control with single agent PD-1 is short after BRAF/MEK inhibitors. These patients may have benefited from first line immunotherapy. This cohort, while small, suggests further data is needed about optimal sequencing of targeted and immunotherapy.
Analysis of circulating tumor DNA (ctDNA) in pseudoprogression in anti-PD1 treated metastatic melanoma (MM).
Authors: Lee Jenny HJ , Long Georgina V. , Menzies Alexander M. , Guminski Alexander David , Kefford Richard , Rizos Helen , Carlino Matteo S. 
Published: September 2018

9546 Background: We have previously shown that undetectable ctDNA either at baseline or during therapy predicted response in mm patients (pts) treated with anti-PD1 antibodies (aPD1). Pseudoprogression, defined as radiological progression prior to response, occurs in 8% of pts treated with aPD1. We sought to determine if ctDNA could differentiate pseudoprogression from true progression, defined as continued clinical or radiological disease progression. Methods: Between July 2014 and May 2016, pts receiving aPD1 had serial bloods for ctDNA. Included pts either had RECIST PD at first restaging or early clinical progression. Those with untreated brain metastases were excluded from the analysis. ctDNA was quantified using digital droplet PCR for mutations (BRAF/NRAS) at baseline and during the first 12 wks of treatment. Based on our prior studies, ctDNA results were grouped in to ‘favorable’ and ‘unfavorable’ ctDNA profiles (see Table), and these were compared in pts with true and pseudoprogression. Results: 29 pts were included, 28 with RECIST PD at first restaging and one with early clinical progression. 9 (31%) pts had a subsequent RECIST PR or SD and were considered pseudoprogression and 20 (69%) had true progression. Of the pseudoprogressors, 7/9 pts remained in response with a median follow-up of 20 months (mths). 2/9 pts had disease progression at 7 and 18 mths, with ctDNA that remained detectable with a > 10-fold decrease during treatment in both patients. Of those with true progression and a favourable profile, 1 had a > 10-fold decrease in ctDNA by wk 12 and was switched to MAPK therapy prior to further imaging, and the other had an undetectable ctDNA at wk 6 which increased again at wk 12. The latter pt had a new lesion on first restaging CT scan despite PR in all existing lesions with true PD on second restaging at wk 24. Conclusions: ctDNA in patients with mm at baseline and early on aPD1 treatment differentiates pseudo from true progression. [Table: see text]
Patterns of histologic response to neoadjuvant targeted therapy in patients with BRAF mutant melanoma.
Authors: Eroglu Zeynep , Khushalani Nikhil I. , Rich Jeani , Sarnaik Amod , Zager Jonathan S. , Markowitz Joseph , Brohl Andrew Scott , Sondak Vernon K. , Messina Jane 
Published: September 2018

9584 Background: While BRAF and MEK inhibitors are approved for patients with BRAF V600 + unresectable/metastatic melanoma, their role in the neoadjuvant setting is less well defined. Results from small trials have noted robust response rates, but less is known about histological patterns of response in resected tumor specimens and relation to outcome in these patients (pts). Methods: In a retrospective study, we analyzed the clinical and pathologic patterns of response to neoadjuvant BRAF ± MEK inhibitor therapy in pts with locally advanced melanoma subsequently rendered disease free with surgery. Results: Twenty pts were identified, nine with stage IIIC and 11 with stage IV melanoma. Seven patients received neoadjuvant vemurafenib (VEM), 12 received dabrafenib + trametinib (D+T), and one encorafenib + binimetinib. The median duration of treatment was 7.8 months. Seven patients (35%) had a pathologic complete response (pCR); six of them had received combination therapy, 5 with D+T, 1 VEM with an HSP90 inhibitor. Four distinct histologic patterns were observed in the resected tumor specimens: necrotic, fibrotic/melanotic (tumoral melanosis), hyalinized, or mixed. With median follow-up of 25 months (range 1-60), six pts (30%) had experienced recurrence; three developed CNS metastases. Four of the six patients had received neoadjuvant D+T; three were restarted on their prior targeted therapy at recurrence and all responded. All 6 pts with recurrence had residual disease in the surgical specimen; three had no necrosis identified. In contrast to the 13 pts with persistent tumor, none of the 7 pCR pts has relapsed (p = 0.05). There was a trend towards improved relapse-free-survival (RFS) with a pCR, with a 1 yr of RFS-rate of 50.4% vs 100% in pCR.(p = 0.08) Of the 14 patients without subsequent recurrence, 9 had either a pure necrotic histology, or a mixed histological pattern that included necrosis. Conclusions: In locally advanced or M1a BRAF mutant melanoma, attaining a pCR to neoadjuvant targeted therapy may correlate with improved patient outcomes and be more likely achieved with combination therapy. Presence of necrosis in the surgical specimen appears be a favorable prognostic factor.
Long term follow up (LTFU) of adjuvant zoledronic acid (ZOL) in high risk early stage breast cancer (ESBC) defined by bone marrow (BM) disseminated tumor cells (DTC).
Authors: Vidula Neelima , Hwang Jimmy , Greenberg Sally , Melisko Michelle E. , Goga Andrei , Moasser Mark , Cudos Ariadna Gasol , Angelidakis Austin Nicholas , DeLuca Amy , Petrillo Laura A , Magbanua Mark Jesus Mendoza , Park John , Rugo Hope S. 
Published: September 2018

e12001 Background: BM DTC & peripheral blood CTC indicate metastatic potential. Adjuvant bisphosphonates in postmenopausal patients (pts) result in less bone metastases and better survival. We studied ZOL’s impact on DTC, CTC, and outcomes in ESBC (ASCO, 2010) and now report updated LTFU. Methods: Forty-five pts with ESBC and DTC > 4/mL BM were given ZOL every 4 weeks for 24 months (mo). DTC were quantified at baseline (BL), 12 and 24 mo of ZOL with immunomagnetic enrichment and flow cytometry (Clin Cancer Res, 2015). Serial CTC, survival, recurrence and toxicity were studied. Results: Forty-five pts received ZOL (56% HR+, 18% HER2+, 40% TN, 96% prior chemo). BL median DTC was 13.3/mL (range 4-333). Median DTC decreased from BL to 12 mo (median reduction 6.5/mL, range -57.2 to 23.6) and from BL to 24 mo (median reduction 4.6/mL, range -43.1 to 160.1). For 33 pts with BM at all 3 times, DTC decreased: BL median 11.5/mL (range 4-59.3), 12 mo median 6.8/mL (range 0-28.5), 24 mo median 6.5/mL (range 0.3-168.6). At 12 & 24 mo, 32% & 26% had undetectable DTC respectively. Median CTC was 0.2/mL at BL (n = 45), 0.25/mL at 6 mo (n = 30), 0/mL at 12 mo (n = 22) & 0.2/mL at 24 mo (n = 23). At 123 mo median FU (range 5-154), 9 (20%) pts recurred. Median time to recurrence was 21 mo (range 6-105); 67 % (6/9) TN, 22% (2/9) ER+/HER2+. The first sites of recurrence were CNS in 33% (3), bone & viscera in 22% (2), viscera in 22% (2) and local in 22% (2). BL DTC > 30/mL was associated with higher recurrence (50% > 30 vs. 14% < 30, p = 0.039). All 3 pts with CNS disease had BL DTC > 30/mL. Of the pts who recurred, 4 had ≥ 1 serial BMA; 2/4 had increasing DTC before recurrence. Of 32 disease free pts with BMA at all 3 times, 72% (23) had decreased DTC from BL to 24 mo. Of the 13.3% (6) pts who died, 67% (4) had BL DTC > 30/mL, which was associated with a greater risk of death (50% > 30 vs. 5% < 30, p = 0.006). BL CTC > 0.8/mL was associated with higher recurrence (60% > 0.8 vs. 15% < 0.8, p = 0.047) & death (60% > 0.8 vs. 8% < 0.8, p = 0.013). ZOL was well tolerated. Conclusions: At 123 mo FU, BL DTC > 30/mL and CTC > 0.8/mL correlated with recurrence & death. In this single arm phase II study, adjuvant ZOL decreased DTC over time, supporting the anti-tumor effect of bisphosphonates. Clinical trial information: NCT00295867.
Chemotherapy induced-hair loss: A digni-life with DigniCap— Our experience and patient’s satisfaction.
Authors: Loparco Dario , Lutrino Stefania Eufemia , Orlando Laura , Schiavone Paola , Caliolo Chiara , Quaranta Annamaria , Fedele Palma , Marino Antonella , Calvani Nicola , D'amico Maria , Chetrì Maria Concetta , Caloro Manuela , Rizzo Pietro , Nacci Angelo , Sponziello Francesco , Mazzoni Enrica , Cinefra Margherita , Ferrara Pasqualinda , Cinieri Saverio 
Published: September 2018

e12016 Background: Alopecia (A) is one of the most emotionally distressing side effects of chemotherapy (CT). CT-induced A may lead to a negative body image, contributing to worsen the quality of life (QoL). The cancer treatments, especially in breast cancer (BC) patients (pts), often bring with it body image challenges, causing low self-esteem and having a detrimental effect on intimate relationships. DigniCap System (DCS), using the scalp cooling system, has been shown to reduce CT-induced A. The aim of this observational prospective study was to describe our experience. Methods: From February to December 2016, 31 consecutive pts with early stage BC who received anthracycline and/or taxane-based neoadjuvant or adjuvant treatment were enrolled. A nurse and a psychologist were dedicated. All pts received a psychological evaluation (EORTC QLQ-BR23; EORTC QLQ-C30; TAM; VAS). A has been graduated according to the Dean’s scale: G0 = no A; G1 < 25% A; G2 = 25–50% A; G3 = 50–75% A; G4 > 75% A. Results: A total of 31 pts were enrolled; 2 pts were not included because too early. Median age was 48 years (range 33-66). The majority of pts (96.5%) received adjuvant CT; only one patients received preoperative CT. Fifteen pts (51.7%) received 4 courses of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 iv on day 1, every 21 days) followed by 12 courses of paclitaxel (P) (80 mg/m2 iv weekly); the remaining pts received 4 courses of EC (n = 13; 44.8%) or P and concurrent trastuzumab (2 mg/Kg iv; loading dose 4 mg/kg) for 12 consecutive doses (n = 1; 3.4%). All grade of A was observed in 96.5% (n = 28): G1 in 15 pts (51.7%), G2 in 5 pts (17%), G3 in 7 pts (24.1%) and G4 in 1 pt (3.4%). Among G1/2 DCS-related side effects, sore scalp and coldness were the main toxicity (52%). The other adverse events (AEs) were: headache G1/2 (44.8%); neck pain (34.5%) and heavy head (41.4%). No serious AEs were reported. Overall, 7% (n = 2) of pts discontinued DCS because of unsatisfactory hair preservation (n = 1) and headache (n = 1). Conclusions: Our results confirm previous evidences, showing that DCS is a good chance to keep hair during CT. In particular, it is interesting that 26 pts (89.6%) did not use wig or head cover.
Adjuvant treatment decision in patients with node-negative, ER+/Her2-, early stage breast cancer with Oncotype DX (ODX) recurrence score (RS) of 11-30: Impact of clinicopathologic features.
Authors: Garcia Gwenalyn , Kedia Shiksha , Thumallapally Nishitha , Moussaly Elias , Abbasi Saqib , Murukutla Srujitha , Dai Qun 
Published: September 2018

e12022 Background: The ODX RS predicts the risk of distant recurrence and the benefit of adjuvant chemotherapy (CT) in patients with ER+/Her2- breast cancer. High RS predicts a large benefit whereas low RS predicts minimal benefit from CT. A prospective trial showed that patients with low RS of 0-10 may be safely spared adjuvant CT. Recommendations in patients with intermediate RS are less clear. We performed a retrospective study of adjuvant therapy decision in patients with RS 11-30. Methods: We identified patients with ER+/Her2-, node-negative breast cancer with ODX RS 11-30 treated at our center from 2010-2016. Data on patient age, type of surgery, tumor size, grade, lymphovascular invasion (LVI), RS and treatment were collected. Statistical associations were tested using Chi square/Fisher's exact test and t test. Logistic regression analysis was used to determine odds ratios (OR). Results: 76 patients were identified. 86% (65/76) of them received adjuvant endocrine therapy alone and 14% (11/76) received adjuvant CT plus endocrine therapy. Patient characteristics are shown in the table. Using univariate analysis, significant predictors of receiving CT included RS, LVI, and ER positivity. In the patients who received CT, RSs were all ≥ 18 whereas in the group who did not receive CT, 42% (27/65) patients had RS 11-17. Increase in RS was associated with increase in the likelihood of receiving CT (OR 1.40, 95% CI 1.14-1.74, p=0.00017). Decrease in ER positivity was correlated with increased likelihood of receiving CT (OR 0.922, 95% CI 0.856-0.992, p=0.03). The presence of LVI increased the likelihood of receiving CT (OR 26.24, 95% CI 4.16-165.43, p=0.0005). Conclusions: In patients with ER+/Her2-, node-negative breast cancer with RS 11-30, the majority received endocrine therapy alone. RS and some clinicopathologic features (LVI, ER) impacted the decision to receive CT. [Table: see text]