bluuebunny/crossref_metadata_2025 huggingface dataset:
Malignant mesothelioma in 91 danish women: The environmental asbestos exposure.
Authors: Panou Vasiliki , Vyberg Mogens , Meristoudis Christos , Omland Øyvind , Weinreich Ulla Møller , Hansen Johnni , RÃ¸e Oluf D.
Published: September 2018

8560

Background: Malignant Mesothelioma (MM) is an asbestos-related malignancy that presents mainly in the pleura (MPM) and peritoneum (MAM). In a densely populated area of Aalborg city in North Jutland, Denmark, a large Eternit asbestos factory that was active for 60 years until 1986 and two shipyards were situated. The Region of North Jutland, Denmark has a high mm incidence in women of 1.0/100,000. Methods: From 1974-2015, 101 histological and cytological samples of women diagnosed with mm in Aalborg University Hospital were identified re-evaluated by modern immunohistochemistry. Patient information regarding asbestos exposure was retrieved from medical records and selected Danish registries. Asbestos exposure was classified as primary for asbestos workers; domestic, for women living with an asbestos worker; environmental, when living or working within 10.000 meters from an asbestos emitting location; unknown, where no source of asbestos exposure could be identified. Results: Clinical and histopathological mm diagnosis was certain for 91 women. Potential asbestos exposure is summarized in Table 1. The employment of the women and their relatives include work at the asbestos cement factory, shipyard, construction, laboratory, pipe factory, electrician and insulator. The women with domestic and combined domestic and environmental (secondary) exposure to asbestos were most prone to develop MPM rather than MAM while women primary exposed to asbestos developed MAM rather than MPM (p=0.016). Conclusions: This study showed that the vast majority (64%) of the women diagnosed with mm had documented non-occupational asbestos exposure and almost 1/5 had a sole environmental exposure, by living in proximity to asbestos industry. Environmental asbestos exposure is a serious risk factor for mm in women. Primary asbestos exposure, inferring more intense exposure through occupation, may predispose to peritoneal mesothelioma in women. [Table: see text]
Small cell lung cancer: The immune microenvironment and prognostic impact of checkpoint expression.
Authors: Rivalland Gareth , Walkiewicz Marzena , Wright Gavin Michael , John Thomas
Published: September 2018

8569

Background: To date, immunotherapy has had limited success in small cell lung cancer (SCLC), despite the tumor’s high mutation load. Little is understood of the immune tumor microenvironment in SCLC due to a paucity of resected tumor. We present a SCLC cohort and describe the prognostic impact of checkpoint expression. Methods: SCLC tissue microarrays with triplicate cores from 105 SCLC specimens underwent IHC assessment for PD-L1, PD-L2, LAG3, TIM3, FoxP3, CD4 and CD8 on tumor and/or tumor infiltrating lymphocytes (TILs). Checkpoint positivity was defined > 5% tumor expression or TIL expression in > 5% of the total core area. Associations with clinicopathologic characteristics and survival were assessed. A Cox model was used for univariate and multivariate survival analysis. Results: Tumor expression of PD-L1 was positive (+) in 17/95 (18%), PD-L2+ in 2/96 (2%), and TIM3+ or LAG3+ in no cases. TILs expressed PD-L1+ in 64/95 (67%), PD-L2+ in 22/96 (22%), TIM3+ in 57/96 (59%) and LAG3+ in 43/96 (45%). FoxP3+ lymphocytes were found in all samples (range 0.02 – 2.98% of total core). TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all significantly correlated (p value ≤0.001 for all comparisons), and were associated with high FoxP3+ expression. All four checkpoints were expressed on TILs in 20/105 (19%) patients. PD-L1+ and PD-L2+, but not TIM3 or LAG3, on TILs were significantly higher in limited stage compared with extensive stage SCLC (76% v 52%, p 0.045 and 28% v 7%, p 0.02 respectively). There was no association between stage and tumor expression. TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all associated with improved prognosis. PD-L1+ median OS: 17.2 v 7.9 months (HR 0.36; 95%CI 0.22 – 0.6; p < 0.001). Univariate analysis showed stage and TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were associated with improved survival, but only stage and PD-L1+ TILs remained significant on multivariate analysis (p < 0.01). Conclusions: Immune checkpoint molecules are frequently expressed in SCLC-associated TILs, but not the tumor itself. TIL expression of checkpoint molecules is associated with improved survival. Limited tumor expression of PD-L1 and an exhausted immune cell phenotype may contribute to immunotherapy failure.
Postoperative radiation for tumor control and overall survival in thymic epithelial tumors (TET): A matched-pair analysis.
Authors: Kong Feng Ming , Zang Yong , Wang Weili , Zhang Hong , Smith Jessica , Badve Sunil S. , Kesler Kenneth , Loehrer Patrick J.
Published: September 2018

8572

Background: Due to lack of randomized trials, the role of postoperative radiation therapy (PORT) in thymic epithelial tumors (TET) remains controversial. This study aimed to evaluate whether PORT improves tumor control and overall survival (OS) in patients with resected TET in a large single institution database. Methods: This is a retrospective study of all TETs seen at Indiana University between 1975 and 2016. Patients with resected thymoma (T) or thymic carcinoma (TC) were eligible disregarding their margin status or stage. Study endpoints were progression free survival (PFS) and OS. Age, gender, race, tumor size, stage, pathology, grade, completeness of resection and adjuvant treatment modality were analyzed for significance on PFS and OS. Multivariate Cox model was used to identify significant factors for propensity score matching. Differences between the PORT and surgery alone group were estimated using stratified log-rank test. Results: A total of 478 patients with previous surgical resection were eligible. Masaoka Stage was: I-86 (22%); II-87 (23%); III-107 (28%); and IV-106 (27%), respectively. Multivariate analysis demonstrated that gender (HR = 1.4, p = 0.03), stage (HR = 1.3, p = 3×10-3), TC (HR = 1.6, p = 0.03) and PORT (HR = 1.6, p = 0.002) were significantly associated with PFS. Age (HR = 1.1, p = 4×10-7), TC (HR = 3.2, p = 3×10-5), stage (HR = 1.4, p = 0.003) were associated with OS. PORT was given to 126 (26%) patients. Propensity score matching based on independent prognostic factors identified 99 patients for PORT, matched to 285 patients without. The 5-/10-year intra-thoracic progression free rates were 77%/69% and 85%/68%, for patients with and without PORT (p = 0.009), respectively. The 5-/10-year PFS rates were 39%/18% and 61%/32%, for patients with and without PORT (p = 0.002), respectively. The median survival, 5-/10-year OS rates for patients treated with PORT were 150 (95%CI 111~277) months, 87%/57% and respectively, compared to 192 months (95%CI 167~279), 88%/69% for patients receiving surgery alone ( p = 0.13). Conclusions: This matched-paired analysis from a single institution suggests that PORT does not impact the PFS or OS in a selected population of resected TET.
Pembrolizumab in patients with recurrent thymic carcinoma: Results of a phase II study.
Authors: Giaccone Giuseppe , Thompson Jillian , McGuire Colleen , Manning Maria , Kallakury Bhaskar , Chahine Joeffrey J , Subramaniam Deepa Suresh , Liu Stephen V. , Gibney Geoffrey Thomas , Kim Chul , McCutcheon Justine N
Published: September 2018

8573

Background: There are few treatment options for thymic carcinoma after chemotherapy. We completed a single institution phase II study of pembrolizumab (P) in patients with recurrent thymic carcinomas. Methods: Main eligibility criteria included: progression after ≥ 1 chemotherapy line, ECOG PS 0-2, no history of autoimmune disease, and adequate organ function. P was given at 200mg IV every 3 weeks. The primary objective of the study was response rate (RR) by RECIST v1.1 criteria; secondary objectives were PFS and OS, and safety. Results: From 3/2015 to 12/2016 we accrued 41 patients. Of 40 eligible patients, 29 were male, 19 Caucasians, median age was 57 years (range 25-80), 14 had squamous carcinoma histology, and 19 ECOG PS 0. Median number of cycles delivered was 6 (range 1-31). The most common side effects were mild fatigue (10), diarrhea (4) and rhinorrhea (4). Six patients developed multiple grade 3-4 immune-relates AEs (irAEs): myocarditis/myositis (1), myositis/myocarditis/hepatitis/myasthenia gravis (1), myositis/hepatitis (1), bullous pemphigoid (1), hepatitis (1), hepatitis/pancreatitis/diabetes mellitus type 1 (1). There were no treatment related deaths. The 2 patients who developed myocarditis required a pacemaker. Three patients interrupted treatment because of irAEs (all responders) and 3 because of progression around the time of the irAE. irAEs were more frequent in females (4/6; p = .026). Five patients developed hypothyroidism and 1 hyperthyroidism. RR assessed in all 40 eligible patients was 22.5%: 1 complete response, 8 partial responses (plus 1 unconfirmed), 20 stable disease and with 11 progressions. Two partial responses show minimal residual disease with no PET uptake. Two responders have progressed and 5 responses are beyond 12 months duration. Of 29 cases tested for PD-L1 staining (Dako 22C3), high PD-L1 (≥50% tumor cells positive) was seen in 8 (28%); 6/9 responders had high PD-L1 expression. Targeted NGS in 15 cases did not show correlation between mutational burden and response. Conclusions: P has activity in patients with thymic carcinoma. irAEs are more frequent than in other tumors. Further analysis of NGS, Nanostring and PD-L1 expression and updated survival will be presented. Clinical trial information: NCT02364076.
Paraneoplastic syndrome and survival in thymic epithelial tumors (TET): The Indiana University experience.
Authors: Wang Weili , Zhang Hong , Lu Ray , Smith Jessica , Conces Louise , Badve Sunil S. , Kesler Kenneth , Nelson Robert P , Kong Feng-Ming (Spring) , Loehrer Patrick J.
Published: September 2018

8574

Background: Paraneoplastic syndromes (PNS) are commonly associated with thymic epithelial tumors (TET), especially thymoma. The purpose of this analysis is to examine the clinical impact of PNS in TET. Methods: Patients with pathologically diagnosed TET at a single institution were reviewed retrospectively. The primary and second endpoints for this study were overall survival (OS) and recurrence rates. Clinical factors included age, gender, race, performance score, histology, WHO classification, Masaoka stage, post-operative status, tumor size and number of positive lymph nodes. Cox proportional hazards model was used to identify significant prognostic factors for OS between different PNS groups. Results: From 1975 to 2016, 733 patients with TET (thymoma (T) -71%, thymic carcinoma (TC) -26% and neuroendocrine tumor (NET)-3%) were seen at Indiana University. Of these, 203 (28%) had PNS including myasthenia gravis (n = 130), red cell aplasia (n = 20), hypogammaglobulinemia (n = 14), systemic lupus erythematosus (n = 12) or other PNS (n = 64). Among these, 37 (18%) had two or more types of PNS. PNS were seen in 35% (183/523) of T, 9% (16/187) of TC and 15% (3/20) of NET ( p < 0.001), respectively. Recurrence rates and mortality at 5 year were 8% and 10% in PNS (+) group compared to 13% and 16% in PNS (-) group ( p < 0.05). Intrathoracic recurrences were more common in PNS (+) patients (89% vs 77%; p = 0.016). In both groups, adverse factors for survival included: older age, advanced stage, number of positive lymph nodes and TC histology (all p-values < 0.05). However, post-operative R1/2 status was adverse prognostic factor only in the PNS (-) group ( p = 0.001). Conclusions: PNS is common in TETs. Patients with PNS have lower risk of recurrence and mortality compared to patients without PNS, but may have a higher risk of intrathoracic recurrence.
Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial.
Authors: Thress Kenneth Stephen , Markovets Aleksandra , Barrett J Carl , Chmielecki Juliann , Goldberg Sarah B. , Shepherd Frances A. , Vowler Sarah , Oxnard Geoffrey R.
Published: September 2018

9018

Background: Osimertinib, an EGFR T790M-selective tyrosine kinase inhibitor (TKI), provides high and durable response rates in patients (pts) with T790M positive advanced NSCLC whose disease has progressed following EGFR-TKI therapy. We investigated whether changes in the levels of plasma EGFRmutations post-osimertinib treatment are associated with clinical outcome. Methods: We studied pts from the AURA Phase I study (NCT01802632) with acquired resistance to EGFR-TKIs, T790M positive baseline genotyping (in tumor or plasma), and plasma samples collected at baseline and 6 weeks (wks) post- osimertinib (20–240 mg daily) treatment. Plasma samples were analyzed for the presence of detectable EGFR mutations (Ex19del, L858R and T790M) using BEAMing digital PCR (Sysmex/Inostics). In pts with detectable plasma EGFR mutations at baseline, clinical outcomes (by investigator, per RECIST 1.1) were compared for pts with or without detectable plasma EGFRmutations at 6 wks. Results: Evaluable baseline and 6 wk plasma samples were collected from 160 pts with T790M positive genotyping, of whom 143 had detectable EGFR mutations at baseline (median allelic fraction for Ex19del: 7.09%; L858R: 3.81%; T790M: 2.12%). In this cohort, the overall median progression-free survival (mPFS) was 9.3 months (m; 95% CI 8.2, 9.7). Clearance of plasma EGFRmutations at 6 wks was seen in 92/143 (64%) pts. mPFS was longer in pts with plasma clearance (10.9 m; 95% CI 9.5, 15.2) compared with pts without (5.5 m; 95% CI 3.9, 6.7), as was objective response rate (ORR; 70%; 95% CI 59%, 79% vs. 35%; 95% CI 22%, 50%). Conclusions: Clearance of plasma EGFR mutations after 6 wks of osimertinib therapy appears to be associated with improved ORR and mPFS in pts with T790M positive NSCLC. Evidence or lack of such a “plasma response” measured at 6 wks could, potentially, be used to predict subsequent outcomes on therapy. Further research is needed to better understand whether continued detection of plasma EGFR mutations at 6 wks may indicate the presence of heterogeneous resistance mechanisms, which could, potentially, be targeted by combination therapies. Validation of these results in an independent cohort of pts is ongoing. Clinical trial information: NCT02228369.
Pulse-continuous dose erlotinib as initial targeted therapy for patients with EGFR-mutant lung cancers with untreated brain metastases.
Authors: Kris Mark G. , Arbour Kathryn Cecilia , Riely Gregory J. , Ni Ai , Beal Kathryn , Daras Mariza , Hayes Sara A. , Young Robert J. , Rodriguez Christopher R , Pao William , Yu Helena Alexandra
Published: September 2018

9039

Background: Clarke (Neurooncol 2010) reported responses with intermittent high pulse doses of erlotinib (leading to higher concentrations in CSF) given to patients with EGFR-mutant central nervous system metastases developing on standard erlotinib doses. In a phase 1 study of pulse-continuous dose erlotinib, no patient developed progression in existing or new brain or leptomeningeal metastases (Yu Ann Oncol 2016). This phase 2 trial tested pulse-continuous dose erlotinib in patients with lung cancers with EGFRmutations with brain metastases. Methods: Patients had no prior EGFR TKI or radiation to the brain and at least 1 target brain metastasis. All received initial daily "pulse" doses of erlotinib 1200 mg days 1&2 and "continuous" 50 mg doses days 3-7 (doses and schedule from the Yu Phase 1 study), weekly until progression. The co-primary endpoints were overall and brain metastasis response by RECIST 1.1. Results: We enrolled 19 patients with EGFR-mutant lung cancers: median age 61yrs (range 45-80), 74% women, 95% Karnofsky PS ≥80%, 1 leptomeningeal disease, 33% prior pemetrexed-based chemotherapy. The median size of target brain metastases was 13 mm (range 10-19 mm). 32% were on dexamethasone for cerebral edema. The partial response rate overall was 74% (95% CI 51-89%) and also 74% in brain metastases. Of 10 patients with progression, 9/10 occurred in non-brain sites (4 EGFRT790M, 1 with progression in brain as well), 1 with leptomeningeal. The median progression free survival was 10 mo (range 7-NR mo). Pulse doses were reduced in 68% (median delivered pulse dose 1050 mg days 1&2, range 600-1200 mg). Incidences of any gradeof rash and diarrhea were 84% and 63% respectively. There were no grade 4 or 5 toxicities. Conclusions: Pulse-continuous dose erlotinib alone controlled brain and leptomeningeal metastases in 89% (95% CI 67-98%) of patients with EGFR-mutant lung cancers with central nervous system spread pretreatment, with an overall response rate of 74% and progression free survival and rates of rash and diarrhea comparable to series with erlotinib 150 mg daily. Supported by Astellas, CA 129243, CA 008748. NCT01967095 Clinical trial information: NCT01967095.
Genetic subtypes of large cell neuroendocrine carcinoma (LCNEC) to predict response to chemotherapy.
Authors: Derks Jules , Leblay Noémie , van Suylen Robert Jan , Thunnissen Erik , den Bakker Michael , Groen Harry J.M. , Smit Egbert F. , Damhuis Ronald , van de Broek Esther , Chabrier Amélie , Foll Matthieu , McKay James , Fernandez-Cuesta Lynnette , Speel Ernst-Jan M. , Dingemans Anne-Marie C. ,   PALGA Group Coauthors
Published: September 2018

9061

Background: To treat LCNEC with non-small cell lung carcinoma type chemotherapy (NSCLC-ct, i.e. gemcitabine/taxanes or pemetrexed) or small cell lung carcinoma type (SCLC-ct, i.e. platinum-etoposide) is subject of debate. Molecular studies have identified two mutually exclusive subtypes in LCNEC, the co-mutated TP53 and RB1and the STK11/ KEAP1 (predominantly RB1 wildtype(wt)) group. We investigated if overall survival (OS) and progression free survival (PFS) correlates with targeted next-generation sequencing (TNGS) results in LCNEC treated with NSCLC-ct or SCLC-ct. Methods: For this population based retrospective cohort study all diagnoses of stage IV ct treated high grade neuroendocrine carcinomas (NEC, not being SCLC) were retrieved from the Netherlands Cancer Registry and Pathology Registry (PALGA) (2003-2012). Panel-consensus pathology revision of original tumor slides was performed on (N = 230) and TNGS for genes TP53, RB1, STK11 and KEAP1 analyzed with a multi-sample variant caller (Needlestack). Results: LCNEC was consensus diagnosed in 146/230 and 77 passed quality control for TNGS. Mean coverage was 2832x, a mutation(mt) in TP53 was present in 87%, RB1mt in 46%, STK11mt in 13% and KEAP1mt in 18% of sequenced LCNEC. RB1 was co-altered with TP53 in 94% of LCNEC; mutually exclusive to STK11mt (100%) but not KEAP1mt (57%). NSCLC-ct or SCLC-ct was specified in 92% of patients and RB1wt LCNEC treated with NSCLC-ct (n = 22) showed a trend to better OS compared to SCLC-ct (n = 13) (8.5 months (95% confidence interval (CI): [6.3-10.6]) vs. 5.8 [5.5-6.1] months, p = 0.055). Due to reported resistance in NECs we analyzed NSCLC-ct without pemetrexed-ct; OS was significantly longer for NSCLC-ct (n = 15) compared to SCLC-ct (9.6 [7.7-11.6] vs. 5.8 [5.5-6.1] months, p = 0.026). PFS of RB1wt NSCLC-ct treated patients was significantly longer than SCLC-ct (p = 0.044), without pemetrexed (p = 0.018). In patients with RB1mt LCNEC OS/PFS was not significantly different for NSCLC-ct vs. SCLC-ct. Conclusions: In LCNEC with RB1wt, NSCLC-ct correlates with a more favorable outcome compared to SCLC-ct. However, RB1mt LCNEC treated with NSCLC-ct do similarly worse as SCLC-ct. Prospective studies should be initiated.
Nivolumab-induced interstitial lung disease (ILD) in Japanese patients with non-small cell lung cancer: A study on risk factors for fatal outcome.
Authors: Kato Terufumi , Sakai Fumikazu , Baba Tomohisa , Kusumoto Masahiko , Kenmotsu Hirotsugu , Sugiura Hiroaki , Tominaga Junya , Oikado Katsunori , Sata Masafumi , Endo Masahiro , Yanagawa Noriyo , Sasaki Shinichi , Iwasawa Tae , Saito Yoshinobu , Fujiwara Yutaka , Ohe Yuichiro , Ito Yoshihiko , Tahara Yasuhiro , Kuwano Kazuyoshi
Published: September 2018

9077

Background: We investigated case reports of nivolumab-induced ILD in patients with non-small cell lung cancer to identify risk factors for poor prognosis of ILD. Methods: Among data obtained during post-marketing surveillance of nivolumab, case reports of ILD with detailed clinical course and chest imaging (CT) findings were assessed by the ILD Expert Review Committee, which consists of respiratory medicine specialists and expert chest radiologists. The imaging findings were examined and classified into those with typical or atypical patterns. Atypical patterns included shadows limited to surrounding tumors designated as “peritumoral infiltration”, relapse of radiation pneumonitis, worsening of underlying infection, and predominant shadow in diseased side. CT pattern was classified as DAD (diffuse alveolar damage) or non-DAD. Data were analyzed using a multivariate stepwise logistic regression analysis. Results: Among 160 reported cases of ILD, 140 cases were considered to be induced by nivolumab. Imaging findings showed typical patterns in 92 patients, and 23 (25.0%) died of ILD. Atypical patterns were noted in 48 patients, and 5 (10.4%) died of ILD. The following table summarizes the results of univariate and multivariate analyses of risk factors for poor prognosis of ILD. See table. DAD pattern was observed in 20, 14 (70%) among them showed fatal outcome, whereas non-DAD pattern showed it in 14/120 (11.7%). Male and pretreatment CRP level were significant risk factors for fatal outcome. Conclusions: Nivolumab-induced ILD may show some atypical pattern that was not seen in conventional chemotherapy or EGFR-TKI. Outcome of patients with atypical patterns was better than those with typical patterns. DAD pattern at CT, male, and pretreatment level of CRP were identified as risk factors of fatal outcome. [Table: see text]
Updated safety and clinical activity of durvalumab monotherapy in previously treated patients with stage IIIB/IV NSCLC.
Authors: Balmanoukian Ani Sarkis , Antonia Scott Joseph , Hwu Wen-Jen , Hamid Omid , Gutierrez Martin , Jamal Rahima , Jerusalem Guy Heinrich Maria , Ahn Myung-Ju , Kim Dong-Wan , Cunningham David , Kim Sang-We , Brahmer Julie R. , Lutzky Jose , Weiss Jared , Jin Xiaoping , Antal Joyce , Gupta Ashok Kumar , Segal Neil Howard
Published: September 2018

9085

Background: Preliminary analyses of an ongoing Phase 1/2 study of single-agent durvalumab showed antitumor activity and a tolerable safety profile in advanced NSCLC, with higher ORR and longer OS in pts with high vs. low/negative PD-L1 tumor expression. Here we present updated safety analyses (primary endpoint) for all NSCLC pts and clinical activity based on investigator-assessed RECIST v1.1 in pts who had received prior treatment for advanced NSCLC. Methods: Durvalumab (10 mg/kg q2w) was given until unacceptable toxicity or disease progression, or for up to 12 mos; retreatment was permitted upon disease progression after completion of 12 mos of treatment. PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high = ≥25% and PD-L1 low/negative = <25% of tumor cells with membrane staining). Results: As of 24 Oct 2016, 245 pts with previously treated NSCLC (53% squamous) received durvalumab and were followed for a median of 29.2 (range 0.3–40.5) mos; 142 pts (58%) had treatment-related adverse events (AEs), most frequent: fatigue (18%), decreased appetite (9%), and nausea, rash, and diarrhea (each 8%). 25 pts (10%) had treatment-related Grade 3/4 AEs, most frequent: fatigue and hyponatremia (each 2%); there were no treatment-related deaths. 4% had treatment-related serious AEs including colitis and pneumonitis (each 2%). In the overall population, 12 mo OS rate was 47% (95% CI 40–53) and 18 mo OS rate was 38% (95% CI 31–45). Antitumor activity and survival by PD-L1 status are shown in the table. Conclusions: Consistent with earlier reports, durvalumab had a manageable safety profile in Stage IIIB/IV NSCLC, with encouraging clinical activity as 2L+ therapy. Higher tumor PD-L1 expression enriched clinical benefit of response rate and survival endpoints. Clinical trial information: NCT01693562. [Table: see text]
Baseline-derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) to predict the benefit of immune checkpoint inhibitors (ICI) in advanced non-small cell lung cancer (NSCLC) patients.
Authors: Mezquita Laura , Auclin Edouard , Ferrara Roberto , Audigier-Valette Clarisse , Tessonnier Laurent , Charrier Melinda , Boucher Marie Eve , Lahmar Jihene , Caramella Caroline , Remon Jordi , Planchard David , Adam Julien , Gazzah Anas , Chaput Nathalie , Soria Jean-Charles , Besse Benjamin
Published: September 2018

9089

Background: dNRL (Neutrophils/Leucocytes-Neutrophils) and LDH were recently correlated to ICI benefit in melanoma. We tested if dNLR and LDH could have the same role in NSCLC patients. Methods: Baseline dNLR and LDH were collected in 234 patients treated with PD1/PDL1 inhibitors from Nov. 2013 to Dec. 2016, in a discovery (D) cohort (N = 161) from Gustave Roussy and an independent validation (V) cohort (N = 73) from 2 centers. ICI benefit was analyzed according to overall survival (OS), progression free survival (PFS) and response rate (RR) by RECIST 1.1. Kaplan-Meier and Cox regression were performed. Results: In the D cohort, 100 patients (62%) were males, 136 (85%) smokers and PS ≤1, with median age 61.5; 133 patients (81%) stage IV; 100 (62%) had adenocarcinoma and 46 (29%) squamous cells carcinoma; 35 (22%) were KRASmut, 13 (8%) EGFRmut and 3 (2%) ALKpositive. PDL1 expression was positive in 43 (75%), negative in 14 (25%) and unknown in 78. 132 (82%) patients received PD1 inhibitors; the median of prior lines was 1 (1-11). dNLR > 3 and LDH > upper normal limit (UNL) were independent factors for poor OS (HR 4,67, p = 0.011 and HR 2,65, p = 0.002, respectively) and poor PFS (HR 4,71, p = 0.001 and HR 1,68, p = 0.042 respectively). The median follow-up (FU) was 12 months (m) [95% CI 11-14], the median PFS 3m [2-4] and the median OS 10m [8-13]. In the V cohort, with a median FU of 11m [8-14], dNLR > 3 and LDH > UNL were significantly associated with poor OS (both p = 0.001), with a trend toward association with PFS (p = 0.06, p = 0.08, respectively). A Lung Immune Predictive Index (LIPI) was tested considering dNLR > 3 and LDH > UNL, with three groups. In D cohort, the median OS for good (no factor), intermediate (one factor) and poor (two factors) was 34m [17-NR], 10m [8-NR], 3m [1-NR], respectively (p = 0.0001), and PFS was similarly correlated (p = 0.001). Same results were demonstrated in the V cohort. Conclusions: Baseline dNLR > 3 and LDH > UNL can predict the benefit of ICI in advanced NSCLC patients. The LIPI at baseline is an easy tool to identify the candidates to immunotherapy. Confirmation cohorts are ongoing to validate the predictive role of the LIPI.
Re-challenge with BRAF-directed treatment: A multi-institutional retrospective study.
Authors: Valpione Sara , Carlino Matteo S. , Mangana Joanna , Mooradian Meghan , McArthur Grant A. , Schadendorf Dirk , Hauschild Axel , Long Georgina V. , Arance Ana M. , Ascierto Paolo Antonio , Maio Michele , De Rosa Francesco , Larkin James M. G. , Park John J. , Goldinger Simone M. , Flaherty Keith , Xu Wen , Livingstone Elisabeth , Weichenthal Michael , Lorigan Paul ,   Project Collaborators' Group (Gaba L, MD; Rajat R, MD; Sullivan R, MD; Di Giacomo AM, MD; Dummer R, MD)
Published: September 2018

9512

Background: Most patients treated with BRAF inhibitors (BRAFi) +/- MEK inhibitors (MEKi) eventually progress on treatment. Along with genetic acquired resistance, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse outcomes for patients (pts) retreated with BRAF-directed therapy. Methods: 116 pts who received BRAFi based therapy and, after a break, were re-challenged with BRAFi +/- MEKi treated at 14 centres in Europe, US, and Australia were analysed for progression free survival (PFS) and response rate (RR), as well as factors predicting overall survival (OS) (demographics, disease stage, treatment, LDH level, duration of first BRAFi treatment, reason for first BRAFi discontinuation and interval between BRAFi stop and re-challenge). Multivariate Cox regression, regression trees and Kaplan Meier method were used. Results: Median duration of 1st BRAFi +/- MEKi treatment was 9.4 months (mts) and 7.7 mts for the subsequent treatment after discontinuation (immunotherapy 72%, other 17 %, drug holiday 11%). Brain metastases were present in 51 pts (44%). RR to re-challenge with BRAFi +/- MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease 24% and progressive disease (PD) 30%, 4% missing. Of 80 pts who previously discontinued BRAFi for PD, 31 (39%) responded (30 PR and 1 CR). Median OS from retreatment was 9.8 mts. Independent prognostic factors for survival at re-challenge included number of metastatic sites (HR = 1.32 for each additional organ with metastases, p < .001), LDH (HR = 1.37 for each multiple of the upper normal limit, p < .001), while combination of BRAFi+MEKi conferred a better prognosis vs BRAFi alone (HR = 0.5, p = .006). Pts with < 3 metastatic sites treated with BRAFi and MEKi had a better survival (median OS not reached) and pts with ≥ 3 metastatic sites and raised LDH treated with BRAFi alone had the worse outcome (median OS 4 mts). Number of metastatic sites (HR = 1.44, p < .001) and combination of BRAFi and MEKi (HR = 0.45, p < .001) were independent prognostic factors for PFS (median 5.0 mts). Conclusions: Re-challenge with BRAFi +/- MEKi induces a clinically significant response and should be considered for selected cases.
Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO1 to predict outcomes to anti-PD-1 in metastatic melanoma (MM).
Authors: Johnson Douglas Buckner , Bordeaux Jennifer , Kim Ju Young , Vaupel Christine , Rimm David L. , Ho Thai Huu , Joseph Richard Wayne , Daud Adil , Conry Robert Martin , Gaughan Elizabeth M , Dimou Anastasios , Balko Justin M. , Smithy James William , Witte John S , McKee Svetlana B , Dominiak Nicole , Dabbas Bashar , Hall Jeff , Dakappagari Naveen ,   Navigate BioPharma Leadership
Published: September 2018

9517

Background: Although PD-1/L1 axis directed therapies induce durable responses in some mm patients (pts), biomarkers of response remain elusive. We hypothesized that quantifying key immune suppression mechanisms within the tumor microenvironment would provide superior predictors of response to anti-PD-1 compared with single marker assessment. Methods: Pre-treatment tumor biopsies from 124 mm pts treated with anti-PD-1 at 7 academic centers were fluorescently stained with multiple immune markers in discovery (n = 24) and validation (n = 100) cohorts. Selected biomarker signatures, PD-1/PD-L1 interaction score (proportion of PD-1+ cells co-localized with PD-L1) and IDO1/HLA-DR co-expression were evaluated for anti-PD-1 treatment response and survival. Slides were imaged using Vectra; biomarker positive cells and their co-localization were objectively quantified in pathologist-selected regions using novel Automated Quantitative Analysis (AQUA) algorithms. Results: In the discovery cohort, high levels of PD-1/PD-L1 interaction score and/or IDO1/HLA-DR coexpression was strongly positively associated with response to anti-PD-1 (p = 0.0005). In contrast, other individual biomarkers (PD-1, PD-L1, CD8) were not associated with response or survival (p > 0.10). This finding was replicated in the validation cohort: pts with high PD-1/PD-L1 and/or IDO1/HLA-DR were more likely to respond to treatment (p = 0.009). These pts also experienced a three-fold increase in progression free survival (hazards ratio (HR) = 0.33; p = 0.003) and overall survival (HR = 0.34; p = 0.004). Multivariate analyses revealed that these findings were independent of BRAF mutation, stage, LDH and prior therapy. In the combined cohort (n = 124), 80% of responding pts had higher levels of PD-1/PD-L1 interaction scores and/or IDO1/HLA-DR. In contrast, PD-L1 expression alone (≥1% or ≥50%) was not predictive of PFS or OS (p > 0.1). Conclusions: This novel multiplexed method profiling key tumor-immune suppression pathways identified mm pts likely to respond to anti-PD-1 therapy. This method could help stratify patients for PD-1 monotherapy and be useful in guiding future clinical trials.
Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: Safety, efficacy, and recommended phase 2 dose (RP2D).
Authors: Schuler Martin H. , Ascierto Paolo A. , De Vos Filip Yves Francine Leon , Postow Michael Andrew , Van Herpen Carla M.L.- , Carlino Matteo S. , Sosman Jeffrey A. , Berking Carola , Long Georgina V. , Weise Amy , Gutzmer Ralf , Kaatz Martin , McArthur Grant A. , Schwartz Gary , Daud Adil , Maharry Kati , Yerramilli-Rao Padmaja , Zimmer Lisa , Bozon Viviana , Amaria Rodabe Navroze
Published: September 2018

9519

Background: Simultaneous inhibition of MEK and CDK4/6 may suppress MAPK pathway activation and cell-cycle checkpoint dysregulation in NRAS-mutant melanoma, resulting in enhanced antitumor activity. Phase 1b data are reported. Methods: The phase 1b primary objective was to determine maximum tolerated dose (MTD)/RP2D. A 28-d cycle of oral ribociclib (RIBO) once daily (QD) for 21 d + oral binimetinib (BINI) twice daily (BID) for 28 d, and a 21-d cycle of RIBO QD + BINI BID, both for 14 d per cycle, were evaluated. Secondary objectives were to evaluate efficacy, safety and pharmacodynamics. Results: Based on dose escalation (van Herpen, ESMO 2015), MTD was 600mg RIBO/45mg BINI for the 21-d and 200/45 for the 28-d regimens. Due to promising activity, the 28-d cycle was selected as RP2D(unconfirmed partial response [PR] with limited follow-up occurred in 35% of pts). This finding was supported by comparable and manageable safety and the Bayesian logistic regression model.As of Jan 2017, the RP2D was received by 16 pts in phase 1b (ECOG PS 0/1/2, 63%/31%/6%; elevated lactate dehydrogenase, 44%; stage IVM1c disease, 50%; prior ipilimumab [ipi], 44%; prior anti–programmed death [PD]-1/PD-L1, 31%). Median (range) exposure was 4 (0–13) mo. Common adverse events (AEs) were increased blood creatine phosphokinase, elevated AST, peripheral edema, acneiform dermatitis, diarrhea and fatigue. Common grade 3/4 AEs were elevated AST and ALT (19%/6%), nausea (19%/0%), rash (19%/0%), vomiting (6%/6%) and neutropenia (12%/0%). Confirmed PR (cPR) occurred in 4 pts (25%; time to response, 48–168 d), stable disease in 7 pts (44%), disease progression in 3 pts (19%); 2 pts (12%) were not evaluable. Among cPR pts, 3 had prior ipi and/or anti–PD-1/PD-L1. Median progression-free survival (mPFS) was 6.7 (95% CI, 3.5–9.2) mo. Sequence analysis of synchronous non- RAS genetic alterations will be presented. Conclusions: Combined RIBO/BINI at the selected RP2D had a manageable safety profile and favorable efficacy (based on mPFS) for NRAS-mutant melanoma in phase 1b. Based on these promising data, the phase 2 expansion is underway to assess antitumor activity at the RP2D. Clinical trial information: NCT01781572.
Immune-related tumor response dynamics in melanoma patients (pts) treated with pembrolizumab: Identifying markers for clinical outcome and treatment decisions.
Authors: Nishino Mizuki , Giobbie-Hurder Anita , Manos Michael P , Bailey Nancy , Buchbinder Elizabeth Iannotti , Ott Patrick Alexander , Ramaiya Nikhil H. , Hodi F. Stephen
Published: September 2018

9521

Background: PD-1 inhibitors have shown marked efficacy in advanced melanoma and are associated with unique response patterns. We aimed to characterize the tumor burden dynamics and identify quantitative imaging markers for overall survival (OS) in melanoma pts treated with pembrolizumab. Methods: The study included 107 advanced melanoma pts (63 males; median age: 63) treated with pembrolizumab monotherapy at DFCI. Tumor burden dynamics were assessed on serial CT scans during therapy by irRECIST, which uses unidimensional measurements and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. The relationships between tumor burden dynamics and OS were studied. Results: Among 107 pts, 96 pts had measurable tumor burden at baseline and 11 had non-target lesions alone at baseline. Among the 96 pts, maximal tumor shrinkage ranged from -100% to 567% (median:-18.5%). Overall response rate was 44% (42/96; irCR in 5, irPR in 37). Tumor burden remained < 20% increase from baseline throughout therapy in 57 pts (55%). Using a 3-month landmark analysis, pts with < 20% tumor burden increase from baseline at 3 months had longer OS than pts with ≥ 20% increase (12-month OS rate: 82 vs. 53%). In extended Cox models, pts with < 20% tumor burden increase during therapy had significantly reduced hazards of death (HR = 0.19, 95%CI: 0.08–0.43, p < 0.0001 univariate; HR = 0.18, 95%CI: 0.08-0.41, p < 0.0001, multivariable). Five pts (5%) experienced pseudoprogression; 3 pts had increase of target lesions with subsequent response, which was noted after confirmed irPD on consecutive scans. Two pts with no measurable tumor burden progressed with new/non-target lesions that subsequently regressed. Conclusions: Tumor burden increase of < 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical prognostic marker to guide treatment decisions. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response assessment. Evaluations of non-measurable tumor burden may require further attention in the clinical setting of immuno-oncology.
Updated 5-y landmark analyses of phase 2 (BREAK-2) and phase 3 (BREAK-3) studies evaluating dabrafenib monotherapy in patients with BRAF V600–mutant melanoma.
Authors: Chapman Paul B. , Ascierto Paolo Antonio , Schadendorf Dirk , Grob Jean Jacques , Ribas Antoni , Kiecker Felix , Dutriaux Caroline , Demidov Lev V. , Lebbe Celeste , Rutkowski Piotr , Blank Christian U. , Gutzmer Ralf , Millward Michael , Kefford Richard , Huang Yingjie , Zhang Ying , Squires Matthew , Mookerjee Bijoyesh , Hauschild Axel
Published: September 2018

9526

Background: Prior analyses of phase 2 (BREAK-2; NCT01153763) and phase 3 (BREAK-3; NCT01227889) trials showed that durable clinical benefit and tolerability lasting ≥ 3 y are achievable with the BRAF inhibitor dabrafenib in some patients (pts) with BRAFV600–mutant metastatic melanoma. Here, we report 5-y landmark analyses for BREAK-2 and BREAK-3. Methods: BREAK-2, a single-arm, phase 2 study, evaluated dabrafenib 150 mg twice daily in pts with stage IV BRAF V600E/K–mutant MM. BREAK-3, an open-label, randomized (3:1), phase 3 study, assessed dabrafenib 150 mg twice daily vs dacarbazine 1000 mg/m2 every 3 weeks in pts with previously untreated BRAFV600E–mutant unresectable stage III or stage IV MM. Updated analyses were performed to describe ≥ 5-y outcomes in each study. Results: BREAK-2 enrolled 92 pts (V600E, n = 76; V600K, n = 16), of whom most (90%) had prior systemic anticancer therapy. At data cutoff (17 Jun 2016), all pts had discontinued, mostly due to progression (84%). In V600E pts, 5-y progression-free survival (PFS) was 11%, and 5-y overall survival (OS) was 20%. Postprogression immunotherapy was received by 22% of enrolled pts. In BREAK-3 (data cutoff, 16 Sep 2016), median follow-up was 18.6 mo for the dabrafenib arm (n = 187) and 12.8 mo for the dacarbazine arm (n = 63). Follow-up for the 37 dacarbazine-arm pts (59%) who crossed over to receive dabrafenib was based on the initial assignment of dacarbazine. The 5-y PFS was 12% vs 3% and 5-y OS was 24% vs 22% for the dabrafenib and dacarbazine arms, respectively. A subset of pts in each respective arm received postprogression anti–CTLA-4 (24% vs 24%) and/or anti–PD-1 (8% vs 2%) therapy, whereas 31% vs 17% did not receive any further therapy following study treatment. No new safety signals were observed in either study with long-term follow-up. Additional characterization of pts using cfDNA analysis will be presented. Conclusions: These data provide the longest reported PFS and OS follow-up for BRAF inhibitor monotherapy in BRAF V600–mutant MM. Both BREAK-2 and BREAK-3 showed that 11%-12% of pts initially treated with single-agent dabrafenib remained progression free at 5 y. Clinical trial information: NCT01153763; NCT01227889.
Intra-patient escalation dosing strategy with IMCgp100 results in mitigation of T-cell based toxicity and preliminary efficacy in advanced uveal melanoma.
Authors: Sato Takami , Nathan Paul D. , Hernandez-Aya Leonel Fernando , Sacco Joseph J , Orloff Marlana M. , Truscello Jessica , McAlpine Cheryl , Hulstine Ann-Marie , Lanasa Mark C. , Coughlin Christina Marie , Carvajal Richard D.
Published: September 2018

9531

Background: IMCgp100 is a bispecific biologic capable of redirecting T cells against the melanocyte-associated antigen gp100. In the first-in-human (FIH) clinical trial, preliminary efficacy of IMCgp100 in advanced uveal melanoma (UM) was observed; however, cases of severe T cell-mediated toxicities with the first 2 doses limited dosing to 50 mcg QW. This phase 1 study was designed to implement intra-patient escalation to mitigate toxicity and maximize exposure of IMCgp100. Methods: Using a 3+3 design, HLA-A2+ pts with metastatic UM were treated with low weekly (QW) dosing of IMCgp100 iv at Cycle 1, Day 1 (C1D1) (20 mcg) and C1D8 (30 mcg), followed by the escalated cohort dose administered at C1D15 and beyond. Results: Nineteen metastatic UM pts with a median of 3 prior lines of therapy (range 0 - 8) were treated across 4 target dose cohorts (60, 70, 80, and 75 mcg). Fifteen of 19 pts remain on treatment at the data cutoff (25Nov16). Enrollment completed 15Sep16. DLT was observed in 1 of 6 pts in the 70-mcg cohort (LFT elevation), and 2 of 4 pts treated at 80 mcg QW (LFT and bilirubin elevation). The 80 mcg dose level was not tolerated and a 75 mcg cohort was enrolled. Six pts were treated at 75 mcg without DLT; this dose was identified as the MTD and RP2D. All 3 DLT resolved without corticosteroids and all pts resumed IMCgp100. Frequent related AE included pruritus (84%), pyrexia (84%), fatigue (74%), hypotension (74%) and peripheral edema (63%). Gr 3/4 drug-related AE include AST increased (15%), erythema (15%) and hypotension (15%). Preliminary efficacy data (RECIST v1.1) from 17 evaluable pts (2 pts had insufficient follow-up) showed no objective responses; 12 pts had a BOR of SD (63%) including 4 pts (24%) with a ≥10% reduction in target lesions. With median follow-up of 1.8 mo, the disease control rate (16 wks) was 32%. Conclusions: The intra-patient escalation regimen of IMCgp100 results in a 50% increase in dose above the FIH Phase 1, acceptable safety profile, and preliminary efficacy in UM pts. Considering the dismal prognosis of metastatic UM, the PFS observed in this study is encouraging. A Phase 2 expansion cohort and separate pivotal trial of IMCgp100 in advanced UM are ongoing. Clinical trial information: NCT02570308.
Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naïve & experienced metastatic melanoma patients.
Authors: Leung Abraham C.F. , Kummar Shivaani , Agarwala Sanjiv S. , Nemunaitis John J. , Gonzalez Rene , Drabick Joseph J. , Schmidt Emmett V. , Chartash Elliot , Xing Biao , Currie Graeme , Janssen Robert , Ribas Antoni
Published: September 2018

9550

Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 (NCT02521870), assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH > 1 ULN 27%, ≥ 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (≥20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade ≥ 3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. Additional follow up data through May 15, 2017 will be presented. Clinical trial information: NCT02521870.