bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole body PD-1 and PD-L1 PET with 89Zr-nivolumab and 18F- BMS-986192 in pts with NSCLC.
Authors: Niemeijer Anna-Larissa N. , Smit Egbert F. , Dongen G.a.M.S. van , Windhorst A.D. , Huisman Marc C. , Hendrikse N. Harry , Leung David K. , Smith Ralph Adam , Hayes Wendy , Velasquez Linda M. , Bonacorsi Samuel J. , Donnelly David J. , Morin Paul E. , Thunnissen Erik , Poot Alex J. , Vugts Danielle J. , De Langen Joop
Published: September 2018

e20047

Background: Tumor PD-L1 IHC relates moderately with treatment outcome following anti-PD-(L)1 monotherapy in pts with NSCLC. Aim: 1. To assess safety of the PET procedures. 2. To quantify PD-1 and PD-L1 expression in tumors with 89Zirconium-labeled nivolumab (89Zr-nivo) and 18F-labeled BMS-986192 (18F-PD-L1) PET. 3. To assess intra- and inter-patient tracer uptake differences in tumors. 4. To correlate PET results with IHC and treatment outcome. Methods: NSCLC pts eligible for treatment with nivolumab were included. Pts received a dynamic and static whole body 18F-PD-L1 and a static 89Zr-nivo PET scan. A baseline tumor biopsy was required and up to two additional biopsies were allowed in case PET showed heterogeneous tumor uptake. SUVpeak was calculated for all delineable tumor lesions and related to PD-(L)1 IHC (28.8 assay) and response after 6 wks of nivolumab treatment. Results: 7 pts (5 ≥1%, 2 ≥50% and 2 negative by PD-L1 IHC) were enrolled and 11 lesions analyzed. No toxicity related to radiotracer administration was identified. Tumor uptake of both tracers was visualized in all pts. There was substantial variability among pts for 18F-PD-L1 (mean SUV 5.4, range 2.2 - 14.4) and 89Zr-nivo (mean SUV 5.0, range 1.6 - 9.7). Intra-patient tracer uptake heterogeneity was also seen: mean 2.5-fold (±0.96) and 2.3-fold (±0.86) differences between lesions for 18F-PD-L1 and 89Zr-nivo SUV, respectively. For lesions with < 50% PD-L1 IHC mean 18F-PD-L1 SUV was 3.4 (±2.9) as compared to 7.1 (±6.0) for lesions with ≥50% PD-L1 IHC (p = 0.22). For lesions with low PD-1 expression mean 89Zr-nivo SUV was 6.9 (±2.7) as compared to 8.1 (±2.0) for lesions with high PD-1 expression (p = 0.44). Five pts were evaluable for response evaluation: 1 PR, 2 SD and 2 PD with 18F-PD-L1 SUV values (most PET avid lesion) of 14.4 (PR), 2.0 and 5.4 (SD) and 6.4 and 6.6 (PD). Conclusion: 1.PET-imaging with both tracers is safe and feasible, with good tumor-to-normal tissue contrast. 2. Tumor uptake demonstrated substantial heterogeneity among pts and among tumors within the same pts. 3. Although higher 18F-PD-L1 tumor uptake was seen in pts with ≥50% tumor PD-L1 IHC and the highest 18F-PD-L1 SUV was measured in the responding pt, the dataset is still very small. Clinical trial information: 2015-004760-11.
KRAS mutants to regulate PD-L1 expression through NF-ƘB and HIF-1α pathways in non-small cell lung cancer cells.
Authors: Guo Rong , Li Yong , Bai Hua , Wang Jie
Published: September 2018

e20049

Background: PD-L1 (programmed death ligand 1) is expressed in various kinds of human tumors including non-small cell lung cancer (NSCLC) and is of critical importance for the immune escape of tumor cells by inhibiting T cell function via its coinhibitory receptor, programmed death 1 (PD-1). Some driver gene mutations including KRAS have been reported to be involved in intrinsic regulation of PD-L1 expression. However, the potential role and precise mechanism of KRAS mutants in regulation of PD-L1 expression in NSCLC cells remain obscure. Methods: We first examined the expression of PD-L1 and key molecules of KRAS signaling pathway in a panel of NSCLC cells with wild-type or mutant KRAS gene. Additionally, KRAS mutant transfection and pharmacological inhibitors of MEK/ERK, PI3K/AKT, and NF-κB were employed to elucidate the regulation mechanism of PD-L1 expression by KRAS mutant in NSCLC cells. We further analyzed KRAS status and protein levels of PD-L1 and hypoxia inducible factor 1 alpha (HIF-1α) in 82 cases of NSCLC tissue. Results: Examination of the KRAS signaling cascades in NSCLC cells revealed an apparent association of PD-L1 overexpression with activation of MEK/ERK and PI3K/AKT pathways. Moreover, NSCLC cells transfected with KRAS mutants and subsequently treated with pharmacological inhibitors showed strong accordance between PD-L1 expression and two transcription factors, NF-κB and HIF-1α. Further transfection or depletion of HIF-1α increased or decreased PD-L1 expression in NSCLC cells accompanied by enhanced or reduced p-IκBα level, respectively, indicating the central role of HIF-1α in upregulating PD-L1 expression in a mechanism parallel to and partially dependent on activation of the NF-κB pathway. Moreover , PD-L1 expression was detected in 31.7% of 82 NSCLC tissues and showed positive correlation with the rate of HIF-1α expression (52.4%). Conclusions: Taken together, KRAS mutants were identified to regulate PD-L1 expression by activating PI3K/AKT and MEK/ERK pathways via NF-κB and HIF-1α, suggesting the correlation between driver gene mutation and tumor immune escape in NSCLC.
Multiregion gene-expression profiling to reveal heterogeneity in molecular subtypes and immunotherapy response signatures in lung cancer.
Authors: Lee Won-Chul , Diao Lixia , Wang Jing , Zhang Jianhua , Roarty Emily , Chow Chi-Wan , Fujimoto Junya , Behrens Carmen , Cascone Tina , Peng Weiyi , Kalhor Neda , Moran Cesar , Johnson Faye M. , William William N. , Swisher Stephen , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun ,   Gene Expression ITH Study Team
Published: September 2018

e20077

Background: Intra-tumor heterogeneity (ITH) may be present in all molecular levels. Genomic ITH at the exome level has been reported in many cancer types, but comprehensive gene expression ITH has not been well studied. Methods: We collected 35 samples from 10 NSCLC patients (3 or 4 regions/tumor) including lung adenocarcinoma (n = 6), squamous cell carcinoma (n = 2), large cell carcinoma (n = 1) and pleomorphic carcinoma (n = 1). Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for each sample. Diverse gene expression signatures associated with clinical outcomes were tested for ITH. Results: Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of ITH. The analysis of various clinically relevant gene expression signatures including molecular subtype, EMT and immunotherapy response signatures also revealed heterogeneity between different regions of the same tumor. The gene expression ITH we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Conclusions: Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression ITH.
Brigatinib (BRG) in crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): Updates from ALTA, a pivotal randomized phase 2 trial.
Authors: Ahn Myung-Ju , Camidge D. Ross , Tiseo Marcello , Reckamp Karen L. , Holmskov Hansen Karin , Kim Sang-We , Huber Rudolf M. , West Howard Jack , Groen Harry J.M. , Hochmair Maximilian J. , Leighl Natasha B. , Gettinger Scott N. , Langer Corey J. , Paz-Ares Luis G. , Smit Egbert F. , Kim Edward S. , Reichmann William , Kerstein David , Kim Dong-Wan
Published: September 2018

e20503

Background: Most ALK+ NSCLC patients (pts) receiving CRZ eventually experience disease progression. Based on promising activity in a phase 1/2 trial, a randomized phase 2 trial of the ALK inhibitor BRG in pts with CRZ-refractory, advanced ALK+ NSCLC (ALTA; NCT02094573) was initiated. Responses and adverse events (AEs) varied with starting dose; therefore, ALTA was designed to evaluate 2 distinct BRG regimens. Methods: Pts were stratified by presence of baseline (BL) brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Results: In 222 pts (arm A/B, n=112/n=110), median age was 51/57 y; 71%/67% had brain metastases. As of May 31, 2016, 51%/56% (A/B) continued to receive BRG; median follow-up was 10.2/11.0 mo. Table shows efficacy. In pts with measurable BL brain metastases (A/B, n=26/n=18), confirmed intracranial ORR was 46%/67%. Most common treatment-emergent AEs (A/B) were: nausea 36%/43%, diarrhea 21%/39%, cough 23%/36%, headache 28%/30%, vomiting 28%/26%; grade ≥3 AEs included increased CPK 3%/10%, hypertension 6%/6%, pneumonia 3%/5%, increased lipase 5%/3%. A subset of pulmonary AEs with early onset (median: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); 7/14 pts were successfully retreated. Dose reductions (8%/23%, A/B) and discontinuations (3%/10%) due to AEs were reported. Conclusions: BRG showed substantial activity, robust PFS, and acceptable safety at both dose levels, with numerically improved efficacy (particularly PFS and intracranial ORR) at 180 mg (with lead-in). Clinical trial information: NCT02094573. [Table: see text]
Prognostic value of circulating tumor cells in non-small cell lung cancer.
Authors: Agelaki Sofia , Fiste Oraianthi , Grapsa Dimitra , Politaki Eleni , Stoupis Ioannis , Mavroudis Dimitrios , Syrigos Konstantinos N.
Published: September 2018

e20520

Background: Quantitative analysis of circulating tumor cells (CTCs) is increasingly investigated as a novel predictor of prognosis in non-small cell lung cancer (NSCLC). The primary aim of this study was to further investigate the prognostic value of CTCs enumeration in patients with advanced NSCLC. Methods: The medical records of patients with chemotherapy-naïve, advanced NSCLC and at least one available measurement of CTCs were retrospectively reviewed. The presence of CTCs was evaluated using the CellSearch system. A cut-off point of 2 CTCs ( < 2 vs ≥2 ) was used to discriminate between negative and positive samples, respectively. The detection of CTCs was correlated with the clinicopathological features of patients and outcome. Results: Our study population comprised a total of 43 patients (mean age 67.1±9.9 years; male/female ratio: 39/4). Eight out of 43 patients (18.6%) harbored CTCs. No significant associations were found between treatment response and baseline count of circulating tumor cells (CTCs) (p = 0.067). Positive CTC count was associated with the presence of five or more metastatic sites (p = 0.018). Neither PFS nor OS were found to differ significantly between CTC-positive and CTC-negative cases (log-rank p = 0.079 and 0.549, respectively). The presence of five or more metastatic sites and worse PS were recognized as independent predictors of reduced PFS [HR = 2.9, p = 0.042 and HR = 2.7, p = 0.035, respectively], and reduced OS [HR = 7.8, p = 0.003 and HR = 16.9, p < 0.001, respectively]. Conclusions:CTCs were detected in a relatively small percentage of our patient population and their presence was associated with increased metastatic burden. In contrast, we failed to observe any significant associations between baseline CTC count and the prognostic variables evaluated. Our results support the suggested role of CTCs in the metastatic dissemination of cancer and underline the need for more efficient methods of CTCs detection.
Comparison of circulating tumor DNA (ctDNA) sequencing and tumor-based genotyping for the detection of EGFR mutations in non-small cell lung cancer (NSCLC).
Authors: Li Allen , Dacic Sanja , Burns Timothy Francis , Socinski Mark A. , Abberbock Shira , Villaruz Liza Cosca
Published: September 2018

e20586

Background: Therapy for NSCLC is based on detection of actionable oncogenic drivers. Conventionally, targetable mutations are detected by tissue biopsy, which may be insufficient for molecular testing. Repeat biopsy is often required at the time of disease progression. Guardant360™ (G360) utilizes digital next-generation sequencing (NGS) to analyze ctDNA in plasma. Limited data exists on clinical outcomes of 3rd generation EGFR tyrosine kinase inhibitors (TKIs) against T790M-mediated resistance detected by digital NGS in ctDNA. We hypothesize that G360 has high concordance in detecting actionable oncogenic drivers and similar clinical outcomes compared with tumor-based genotyping. Methods: G360 (Guardant Health, Inc.) was performed in 20 advanced NSCLC patients (pts) with matched tumor-based genotyping by either Sanger sequencing (N = 10) or Ion Torrent ApliSeq v.2 NGS (N = 10; Life Technologies, Fisher Scientific). Matched genotypes were done at diagnosis (N = 12) or at time of acquired resistance (N = 8). Sensitivity, specificity, and response to EGFR TKIs (RECIST V1.1) were determined. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method. Objective response rates (ORR) were calculated by MedCalc(r) software. Results: Compared with tumor-based testing, G360 has high concordance for EGFR exon 19 deletion, T790M and L858R (90%, 85% and 100%, respectively) and high specificity (100%, 93.3%, and 100%, respectively). OS of pts with T790M or L858R were similar between those detected by G360 and by tumor-based testing (p > 0.99). Pts who received 3rd generation EGFR TKIs (4 osimertinib, 1 PF-06747775) after detected T790M in plasma (N = 4) had similar ORR (50% vs 25% with difference of 25%, 95% CI (-0.45 to 0.75)) and median PFS (7.5 vs 6.0 mos, p = 0.63) as those detected by tumor-based testing (N = 4). Conclusions: G360 showed high concordance for EGFR actionable mutations. Clinical outcomes of 3rd generation EGFR TKI treatment in T790M+ disease were similar between those detected by G360 and those detected by tumor testing. G360 represents a viable option for pts who are not candidates for solid tumor biopsies.
The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer.
Authors: Watanabe Hiromi , Kubo Toshio , Ninomiya Takashi , Ohashi Kadoaki , Ichihara Eiki , Sato Akiko , Hotta Katsuyuki , Tabata Masahiro , Kiura Katsuyuki
Published: September 2018

e20601

Background: Central nervous system (CNS) metastases (mets) occur in 30% of patients with advanced non-small cell lung cancer (NSCLC) and are associated with poor overall survival (OS). Although nivolumab, a programmed death-1 immune checkpoint inhibitor antibody, has demonstrated a longer survival benefit compared with docetaxel in previously treated NSCLC patients (CheckMate 017 and 057; N Engl J Med, 2015), patients with symptomatic or untreated CNS mets were excluded in these trials. In CheckMate 012 Arm M, 2 of 12 patients (16.7%) with untreated CNS mets showed intracranial responses, but the effect of nivolumab treatment for CNS mets was not fully investigated. Methods: To investigate the effect and safety of nivolumab for CNS mets in NSCLC patients, we retrospectively analyzed 48 patients with NSCLC who were treated with nivolumab from February 2016 to December 2016 at Okayama University Hospital. Results: Twenty-nine patients (60%) had no CNS lesions (group A) and 19 patients (40%) had brain mets (BM) (group B). In group B, 15 patients (79%) received radiotherapy (RT) for BM, including 5 patients who received RT just before nivolumab treatment. The responses of extra-CNS lesions to nivolumab are shown in the table. The PFS was longer in group A than in group B (p=0.14). In group B, the PFS of patients who received prior RT tended to be longer than in those without RT (p=0.42); OS was not reached in either group. In group B, the effects of nivolumab treatment for CNS mets were evaluated in 12 patients: SD occurred in 3 patients (25%), PD in 4 patients (33%), and NE in 5 patients (42%). All 4 patients with PD in the CNS lesion also showed PD in the extra-CNS lesion. In group A, no patients showed progression only in the CNS lesion. Conclusions: In this retrospective study, there were no patients treated only with nivolumab who showed a response to CNS mets. RT prior to nivolumab might be more effective, so future investigations should involve additional cases and prospective studies. [Table: see text]
Dynamic predictions of patient survival using longitudinal tumor size in non-small cell lung cancer: Approach towards personalized medicine.
Authors: Al-Huniti Nidal , Onishchenko Dmitry , Dunyak James , Masson Eric , Helmlinger Gabriel , Zhou Diansong , Xu Hongmei , Tomkinson Helen , Abdallah Kald , Stanski Donald
Published: September 2018

e20606

Background: Tumor burden has long been used for the clinical diagnosis, staging, prognosis and treatment of non-small cell lung cancer (NSCLC), as described, for example, in the 7th edition of the AJCC/UICC NSCLC staging guidelines. Previous longitudinal tumor size approaches have used fixed tumor kinetic parameters or tumor shrinkage at a given timepoint, to correlate PFS and OS in a stepwise fashion. Here we describe a joint modeling approach which allows for individual, patient-level predictions of survival during NSCLC treatment. Joint modeling simultaneously fits OS and tumor size dynamics, converting full information from individual tumor assessments into a personalized prediction of survival - thereby avoiding dichotomization of response measure in a patient. Methods: Clinical data from IPASS Phase 3 study of Iressa (gefitinib) in NSCLC were used to fit a joint model of OS and tumor size. The data from a follow-up study (IFUM, Phase 4) for the same drug in a narrower population were used to validate the model on an independent set of subjects. This part included simulating clinical trials from the model and comparing the simulated survival with the observed data. The survival estimation method for individual patients followed from a Bayesian formulation and was implemented in R packages JM and JMbayes. Results: A joint model for overall survival and tumor size was developed and validated using clinical trial simulations. Individual survival estimates were obtained for subjects in a subsequent study based on early data cut-off for tumor assessments. Patient-level predictions were shown to be accurate as well as study-level survival estimates. The model was able to update individual survival predictions in real time. Conclusions: Joint tumor size / survival modeling provides a promising area of investigation for prediction of survival in individual patients. It can be used as a quantitative tool for estimating time-evolving risk of death based on early tumor size measurements. A clinically validated version of such a tool may allow physicians to better choose between treatment continuation and change, following tumor size measurements from standard clinical care.
Population pharmacokinetics (popPK) and exposure-response (ER) analyses bridge J-ALEX to the global population with an alectinib (ALC) 600mg bid dosing regimen.
Authors: Hsu Joy C. , Jaminion Felix , Guerini Elena , Tanaka Tomohiro , Golding Sophie , Balas Bogdana , Zeaiter Ali Hassan , Morcos Peter N. , Frey Nicolas
Published: September 2018

e20616

Background: J-ALEX showed superiority of ALC 300mg BID vs crizotinib (CRIZ) in Japanese ALK inhibitor naïve ALK-positive NSCLC patients (pts). PopPK and ER analyses were used to bridge J-ALEX data to the global population to confirm the appropriateness of ALC 600mg BID dose, used in global trials. Methods: The previous popPK analysis (Hsu et al, ASCO 2016) was updated to include PK data from J-ALEX and the ongoing global ALEX study to confirm any significant covariates influencing PK of ALC and major metabolite, M4, using Bayesian feedback analysis. ER analyses from J-ALEX (n=96) investigated the relationship between ALC and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis and key safety events using logistic regression. Results: The popPK models previously developed for pts who have progressed on, or are intolerant to CRIZ were able to adequately predict ALC and M4 PK in J-ALEX and ALEX. Body weight remained the only significant covariate influencing ALC and M4 PK. Administration of ALC 600mg BID in the global population ensures that ALC and M4 exposures across the body weight range are not inferior to those seen in Japanese pts receiving ALC 300mg BID, while lower doses would result in lower exposures. CPH analysis demonstrated a statistically significant relationship between ALC exposure and PFS in J-ALEX such that one third of pts in J-ALEX may benefit from a higher exposure of ALC (Table). ALC 600mg BID ensures the distribution of achieved exposures maximize the expected PFS benefit while lower ALC exposures could result in reduced efficacy. No significant exposure-safety relationships were identified in J-ALEX consistent with previous analyses conducted following ALC 600mg BID. Conclusions: ALC 600mg BID is the appropriate dose in the global ALK inhibitor naïve population. Clinical trial information: JapicCTI-132316. [Table: see text]
Incidence of pneumonitis with use of PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of trials.
Authors: Khunger Monica , Pasupuleti Vinay , Rakshit Sagar , Jain Prantesh , Mazzone Peter J. , Stevenson James , Pennell Nathan A. , Hernandez Adrian V , Velcheti Vamsidhar
Published: September 2018

e20647

Background: PD-1/PD-L1 inhibitors show clinical activity in non-small cell lung carcinoma (NSCLC). However, these agents are sometimes associated with potentially fatal immune related pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis associated with PD-1 and PD-L1 inhibitors. In this meta-analysis, we sought to determine the overall incidence of pneumonitis, and differences by type of inhibitor and prior chemotherapy use. Methods:We systematically searched databases (PubMed-Medline, Embase, Scopus) and conference proceedings until December 2016 for clinical trials using PD-1/PD-L1 inhibitors. Rates of pneumonitis of any grade and grade 3 or higher from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors, as well as between treatment naïve and previously treated patients (pts). Results: 19 distinct published trials (12 with PD-1 inhibitors [n = 3232] and 7 with PD-L1 inhibitors [n = 1806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis as compared to PD-L1 inhibitors (3.6%, 95%CI 2.4%-4.9% vs 1.3%, 95%CI 0.8%-1.9%; p = 0.001). There was also a higher incidence of grade 3 or greater pneumonitis with PD-1 inhibitors (1.1%, 95%CI 0.6%-1.7% vs 0.4%, 95%CI 0%-0.8%, p = 0.02). Pts who received PD-1 or PD-L1 inhibitors in the front line setting experienced more grade 1-4 pneumonitis as compared to previously treated pts (4.3%, 95%CI 2.4%-6.3% vs 2.8%, 95%CI 1.7%- 4%, p = 0.03, however the rates of grade 3 or greater pneumonitis were not significantly different in treatment naïve and previously treated pts. Conclusions: Pneumonitis was more frequently associated with use of PD-1 inhibitors than PD-L1 inhibitors. There was a higher incidence of all grade pneumonitis with PD-1 inhibitors in treatment naïve patients as compared to previously treated patients.
Matching-adjusted indirect comparison (MAIC) of relative efficacy for brigatinib vs. ceritinib and alectinib in crizotinib-resistant anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC).
Authors: Reckamp Karen L. , Lee Joseph , Huang Joice , Proskorovsky Irina , Reichmann William , Krotneva Mira , Kerstein David , Huang Hui
Published: September 2018

e20675

Background: Brigatinib (BRG), ceritinib (CER), and alectinib (ALEC) are second-generation ALK inhibitors developed for crizotinib (CRZ)-resistant ALK+ NSCLC. No randomized trial has directly compared the efficacy of these treatments. The goal of this analysis was to use an MAIC to indirectly compare progression-free survival (PFS) and overall survival (OS) for BRG vs CER and BRG vs ALEC in CRZ-resistant ALK+ NSCLC patients (pts). Methods: This analysis used pt-level data from arm B (180 mg qd with a 7-day lead-in at 90 mg, n=110) of the ALTA trial for BRG and published summary data from ASCEND-1/ASCEND-2 and NP28673 trials for CER and ALEC, respectively. PFS and OS curves from published data were digitized to generate virtual pt-level data for estimation of event rates. Pts in ALTA were assigned weights so that their weighted mean baseline characteristics matched baseline characteristics in each of ASCEND-1, ASCEND-2, and NP28673. Relative treatment effects pre- and post-matching were estimated using Cox proportional hazards models. Results: Prior to matching, baseline imbalances were noted in ECOG PS 2, prior chemotherapy, Asian race, smoking status, and best prior response to CRZ among trials. Weighting reduced effective sample sizes (ESSs) for ALTA pts in the matched comparisons. Relative efficacy results were robust and did not appreciably change after adjusting for the prognostic factors (Table 1). Conclusions: Both before and after matching, BRG had significantly longer PFS compared to CER and ALEC, significantly longer OS than CER, and a trend toward longer OS than ALEC. [Table: see text]
Randomized cross-over study of patient preference for oral or intravenous vinorelbine in the treatment of advanced NSCLC: A phase IV study.
Authors: Dazzi Claudio , Gamboni Alessandro , Delmonte Angelo , Rosetti Francesco , Verlicchi Alberto , Papi Maximilian , Scarpi Emanuela , Zingaretti Chiara , Nicolini Mario , Giovanis Petros , Casanova Claudia , Cappuzzo Federico
Published: September 2018

e20676

Background: Elderly and patients with ECOG PS ≥ 2 often present with medical and physiological characteristics that make the selection of their treatment more challenging. Single-agent vinorelbine improves survival and quality of life compared with best supportive care. At constant effectiveness between two treatments formulations patient preference must be taken into account. Methods: Stage IIIB or IV NSCLC patients candidates to receive a first line chemotherapy with Vinorelbine alone due to age ≥ 70 and Eastern Cooperative Oncology Group (ECOG) Performance status ≤2 or age ≤ 70 but ECOG PS ≥ 2, could enter the study. Patients were randomized to receive: • Arm A: first cycle of IV vinorelbine (30 mg/m2) and second cycle of oral vinorelbine (60mg/m2) • Arm B: first cycle of oral vinorelbine followed by a second cycle of IV vinorelbine. In both arms vinorelbine was administered at day 1 and day 8 every 3 weeks. From the third cycle onwards patients had to choose to continue with oral or intravenous vinorelbine. The dosage of oral vinorelbine could be subsequently increased to 80 mg/m2 at physician’s choice. Treatment continued until disease progression, intolerable toxicity or patient refusal. The primary objective of the study was the patient preference for oral or intravenous vinorelbine. Results: Ninety-three patients entered the study and were randomized. Sixty-two were able to complete the first two cycles and to express a preference (32 in Arm A and 30 in Arm B). Forty-five out of 62 were males and 17 females. Median age was 80 (72-89). Nineteen patients had an ECOG PS of 0, 39 a PS of 1 and 4 a PS of 2 (30.7%, 62.9% and 6.4% respectively). Eighteen patients (29%) decided to continue with IV vinorelbine while 44 patients (71%) expressed a preference for oral vinorelbine p = 0.001 (Gart's test). Regarding secondary enpoints, median OS was 5.7 (4.7-7.7) and 5.5 (3.8-9.1) months and median PFS was 3.5 (2.4-4.4) and 3.5 (3.5-5.0) for arm A and arm B respectively. Conclusions: The study has clearly demonstrated that elderly or frail patients with NSCLC prefer to receive an oral rather than an intravenous chemotherapy. The reasons for the choice were expressed in a questionnaire still in evaluation. Clinical trial information: nct01848613.
OrienX010 oncolytic viral therapy in phase Ic trial of intralesional injection in liver metastases among patients with stage IV melanoma after standard treatment.
Authors: Cui Chuanliang , Lian Bin , Chi Zhihong , Si Lu , Sheng Xinan , Li Dan , Li Si Ming , Tang Bixia , Mao Li Li , Wang Xuan , Zhou Li , Yan Xieqiao , Bai Xue , Guo Jun
Published: September 2018

e21013

Background: The liver is one of the most common metastases in melanoma pts and associated with extremely poor prognosis. However, effective treatment has not been found. The safety and efficacy of OrienX010, a herpes simplex virus type 1-derived oncolytic immunotherapy with expression of gene encoding human GM-CSF, was tested in phaseⅠc trial of intralesional injection in liver metastases among patients with stage IV melanoma after standard treatment. Methods: We studied safety and efficacy of OrienX010 (8×107pfu/ml, 10ml per injection) q2w by ultrasound guided puncture. Efficacy was evaluated q8w by CT scan. The primary endpoint was toxicity. Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR) as well as PFS time. Treatment continued until intolerance, or disease progression per Immune Related Response Criteria. Results: From May 2016, 15 pts received OrienX010 intralesional therapy. The median age was 47 y (32, 61), and 53.3% were female. The primary anatomic sites were: 40.0% (6 pts) from ocular, 33.3% (5 pts) from acral, 26.7% (4 pts) from mucosal. Only 1 patient with c-Kit mutation, 14 pts were wide-type in genotype. All pts had received at least one prior therapy, 53.3% (8 pts) had received transcatheter hepatic arterial chemoembolization. 73.3% (11 pts) had multiple liver metastases, 60.0% (9 pts) had extrahepatic metastases such as lung, bone, abdominal, distant lymph node. 60.0% (9 pts) had an elevation of serum LDH. Mean injection times were 6 (4-18). Mean size of all injectable lesions was 30.4mm (10.0-59.0). AEs were all grade 1/2, pyrexia 80.0%, fatigue 33.3%, injection site pain 26.7%, nausea/vomiting 20.0%, hepatotoxicity 20.0%, leucopenia 6.7%. 12 pts were eligible for evaluation till Jan 2017, and the median follow-up time was 6.0 months. ORR was 8.3% (1 PR), DCR was 41.7% (1 PR, 4 SD). Time to response was 8-16 wks, median PFS was 13.3 wks (95%CI 8.3-18.4), OS was not reached. Conclusions: This is the first trial for evaluating OrienX010 of intralesional injection in liver metastases among melanomas. It appears to be tolerable and with a potentially beneficial effect. Phase 2 and combination trial are pending.
Efficacy and tolerability of vemurafenib in BRAF-mutant acral and mucosal melanoma.
Authors: Bai Xue , Si Lu , Chi Zhihong , Sheng Xinan , Cui Chuanliang , Kong Yan , Dai Jie , Mao Li Li , Wang Xuan , Li Si Ming , Tang Bixia , Lian Bin , Zhou Li , Yan Xieqiao , Guo Jun
Published: September 2018

e21017

Background: Vemurafenib has substantially impressive clinical efficacy in cutaneous melanoma (CM). However, compared with their cutaneous counterpart, acral melanoma (AM) and mucosal melanoma (MM) have distinct genetic patterns and worse prognosis. The efficacy and safety profiles of vemurafenib in AM and mm remain unclear. Methods: Clinical, pathological, and therapeutic data were collected and reviewed of patients (pts) with metastatic or unresectable BRAF-mutant AM and mm hospitalized and administrated vemurafenib during January 2011 and January 2017. Responses were evaluated by RECIST v1.1, survival data were analyzed by Kaplan-Meier survival curve, and adverse effects were assessed by CTCAE v4.0. Results: 24 pts were identified, 13 (54.2%) with AM, 11 (45.8%) with mm (1 patient without available radiology data). All 13 AM pts harbored BRAF V600E mutation (1 with simultaneous C-KIT E861K mutation); 10/11 (90.9%) mm pts carried BRAF V600E mutation (1 with simultaneous PDGFRA V824I mutation), 1/11 (9.1%) had BRAF D594N mutation. Median PFS were 5.4 (95%CI 3.5-8.7) and 4.5 (95%CI 1.5-15.0) months, median OS were 11.7 (95%CI 8.1-23.6) and 7.9 (95%CI 4.6-26.2) months; ORRs were 61.5% (8/13) and 40.0% (4/10), DCRs were 92.3% (12/13) and 90.0% (9/10) in AM and MM, respectively. Vemurafenib was well tolerated. The most common adverse effects (AEs) were hand-foot syndrome in AM and elevation of total cholesterol in MM, with the incidence of 23.1% (3/13) and 18.2% (2/11), respectively. Grade 3/4 AEs have not been observed. No patient discontinued vemurafenib because of treatment related toxicity. Conclusions: Vemurafenib yields substantial response in pts with AM and MM. Compared with in CM, vemurafenib has similar efficacy and safety profiles in BRAF-mutant AM and MM.
Can checkpoint inhibitor therapy improve response to chemotherapy?
Authors: Kirchberger Michael Constantin , Schilling Bastian , Haferkamp Sebastian , Bosserhoff Anja , Schuler Gerold , Heinzerling Lucie
Published: September 2018

e21024

Background: Even though immune checkpoint inhibitors (ICPI) are very effective with the wider use of single or combination treatment an increasing number of patients show resistance to treatment. If patients with metastatic melanoma progress and targeted therapy has also failed or is not feasible due to the lack of targetable mutations chemotherapy remains a treatment option. There is strong evidence that high mutational load leading to formation of so-called neoantigens is a major determinant of ICPI benefit. Additionally, chemotherapy has been described to modulate the microenvironment and the immune system. Here, we assess the efficacy of chemotherapy after checkpoint inhibitor failure in a series of advanced melanoma patients. Methods: We evaluated overall survival and response to chemotherapy of patients with progressive disease under previous treatment with the immune checkpoint inhibitors anti-CTLA4 and anti-PD1. Three skin cancer centers included a total of 17 patients. All BRAF-mutated patients had also progressed under previous BRAF/MEK-inhibitor therapy. Of all patients, 71% showed an elevated LDH, 41% had brain metastases and 35% an ECOG of 2 at initiation of chemotherapy. Results: Tumor control, defined as complete response, partial response, mixed response or stable disease was achieved in 53% (n = 9) of the patients who had previously been clearly progressive. The mean overall survival was 13.1 months with 65% (n = 11) of the patients still being alive. The choice of chemotherapy did not seem to influence the overall survival or tumor control rate. Conclusions: Immune checkpoint inhibitors could increase response to chemotherapy. The combination of chemotherapy and immunotherapy might be beneficial and increase tumor control.
Analysis of the impact of body mass index in the treatment of metastatic melanoma with ipilimumab.
Authors: Gomes Jessica Ribeiro
Published: September 2018

e21044

Background: Recently observational and retrospective studies have been observing a higher incidence of melanoma among patients with over normal body mass index (BMI), as well as a higher melanoma-specific mortality. However, no study has analyzed the impact of BMI in patients with metastatic melanoma treated with immunotherapy. We aim to evaluate whether BMI could influence the treatment of patients with metastatic melanoma receiving Ipilimumab. Methods: Patients diagnosed with metastatic melanoma treated with Ipilimumab at Centro Oncológico Antônio Ermírio de Moraes - Brazil were identified. Patients were stratified according to BMI value at the beginning of Ipilimumab therapy (BMI ≥ 25 and BMI < 25). Progression free survival (PFS) was compared between the groups. Results: We evaluated 187 patients with metastatic melanoma treated with Ipilimumab. About fifty eight percent were male and median age was 58 years (range 27-89). About 88.8% had cutaneous melanoma (42.6% BRAF mutated), 5.3% mucosal melanoma, and 5.9% choroid melanoma. The overall PFS was 3.13 months (95% CI 2.84 – 3.41). Median BMI was 25.8% (range 15.2 - 47.9), and 37.4% of the patients had BMI < 25. The group with BMI ≥ 25 had higher median PFS when compared to those with BMI < 25 (3.5 versus 2.9 months, p = 0.037). In the group of BMI < 25, 16 (22.8%) and 4 (5.7%) patients had PFS > 6 months and 12 months, respectively, versus 35 (30%) and 16 (13.6%) patients in the group of BMI ≥ 25. Conclusions: We have observed a superior PFS on Ipilimumab among overweight patients with metastatic melanoma . Further studies are necessary to confirm whether activity of Ipilimumab is greater among patients with higher BMI.
Symptom distribution of terminally ill cancer patients in a palliative care unit of a developing country.
Authors: Tiwari Shristi
Published: September 2018

e21500

Background: Palliative care is new concept in developing countries like Nepal, It encompasses physical, psychosocial and spiritual aspects. Methods: This is a retrospective study of symptom patterns of 668 terminal cancer patients (median age: 51 years; 58% female), admitted to the Palliative Care Unit of Nepal Cancer hospital, Kathmandu Nepal from Jan 1st 2015 to Dec 31st 2016 Results: The most common primary cancer sites in these patients were lung (41%), GI (28%), ovarian (20%) and liver (10%). Physical and psychological symptoms were assessed using different scales. The median number of symptoms was 13.5 (range: 9-18) on admission, among which pain, nausea, vomiting, dyspnea, fatigue and depression were the most common. There was 23% mortality during palliative care ward stay. Anorexia-cachexia and dyspnea symptoms showed highest mortality association with in ward mortality Conclusions: A very rational approach in regards to socioeconomic beliefs and symptom presentation is required for relief of these incurable symptoms at the end stage of life for these patients.
Evaluating the utility of the QUAL-EC in the clinical care of patients with advanced cancer.
Authors: Wilkinson Anne , Slatyer Susan , Nowak Anna K. , Pienaar Cathy , Tandon Anil , Wallace Mark
Published: September 2018

e21507

Background: We piloted the Quality of Life at the End of Life (QUAL-E) in Australian palliative care in-patients (N = 52) and demonstrated feasibility, acceptability and face validity. An unexpected finding was the potential for the QUAL-E to prompt psycho-social-spiritual discussion when conducted as an interview, indicating opportunities for enhanced support. We compared a 17-item QUAL-E-Cancer (QUAL-EC) to the Distress Thermometer Screening Tool (DT) and participants’ experience when the QUAL-EC was conducted as an interview. Methods: A cross-sectional, mixed methods design was used. Convenience sampling recruited patients (N = 50) with advanced cancer and a prognosis of less than 12 months from a tertiary hospital. Participants completed the DT, followed by the QUAL-EC which was digitally recorded as an interview. Results: Correlational and thematic analysis found that 39.6% of participants reported severe distress (score ≥ 7) while 40% reported moderate distress (score 4-6) on the DT. Levels of distress significantly correlated with two QUAL-EC domains: symptom control ( r= 0.52, p < 0.001) and preparation for end of life ( r= 0.32, p < 0.05). Qualitative analysis identified six themes: the health care team; family issues; approaching death; worry; coping and QUAL-EC experience. Feasibility: completion of the QUAL-EC ranged from 3-14 minutes (M = 7.37 minutes, SD 3.05 minutes). Acceptability: Participants overwhelmingly found the questions to be clear and did not find the questions hard to understand, hard to answer or stressful. Ninety per cent of participants agreed or strongly agreed that they were glad they took part. Conclusions: Patient distress was associated with either symptom burden or concerns about their family/loved ones. When distress is identified on screening, the QUAL-EC offers good potential for nuanced, versus vague, assessment of globalised distress (e.g., DT) as an aid in targeting patient-centered clinical/psycho-social interventions.
Risk factors for hospitalizations (HOS) among older adults with gastrointestinal (GI) cancers receiving chemotherapy.
Authors: Li Daneng , Sun Can-Lan , Levi Abrahm , Klepin Heidi D. , Elias Rawad , Mohile Supriya Gupta , Tew William P. , Lim Dean , Chung Vincent M. , Chao Joseph , Owusu Cynthia , Muss Hyman B. , Lichtman Stuart M. , Gross Cary Philip , Chapman Andrew E. , Gajra Ajeet , Cohen Harvey Jay , Katheria Vani , Hurria Arti
Published: September 2018

e21523

Background: Older adults undergoing chemotherapy for GI cancers are at increased risk of HOS due to treatment related toxicity; however, there are limited data regarding which individuals are at greatest risk. We therefore sought to identify risk factors for HOS among older adults with GI cancers receiving chemotherapy. Methods: We performed a secondary analysis of patients age ≥ 65 years with GI cancer who participated in either of 2 prospective studies used to develop (n = 500) and validate (n = 250) a geriatric assessment (GA) based chemotherapy toxicity score for older adults with cancer. The incidence of HOS within 30 days post treatment was determined. The following patient characteristics were captured pre-chemotherapy: demographics, cancer type, stage, laboratory values, chemotherapy type, and GA measures (functional status, comorbidity, psychological state, cognitive function, nutritional status, and social support). Univariate and multivariate logistic regressions were used to estimate the odds ratio (OR) to identify risk factors. Results: A total of 199 adults age 65+ (median 73; range 65-94) with GI cancers (colorectal 43%, gastric/esophageal 25%, pancreas/biliary 32%; Stage I-III 42%, stage IV 58%) receiving chemotherapy (67% poly-chemotherapy) were included. 5-FU chemotherapy was administered alone or in combination in 126 (63%) patients. Sixty five (33%) patients had ≥1 HOS (1 HOS: 55, 2 HOS: 9, 3 HOS: 1). In univariate analysis, hospitalized patients were more likely to be female (p = 0.02), have stage IV disease (p = 0.03), have a diagnosis of non-colorectal GI cancer (p = 0.04), have poly-pharmacy (≥ 5 medications, p < 0.01), decreased hearing (p = 0.05), cardiac comorbidity (p < 0.01), and low serum albumin (p = 0.05). On multivariate analyses, patients who were female (OR = 2.06, 95% CI: 1.05-4.06), with cardiac comorbidity (OR = 3.73, 95% CI: 1.78-7.83), or a diagnosis of stage IV non-colorectal GI cancer (OR = 3.75, 95% CI: 1.50-9.39) were more likely to be hospitalized. Conclusions: HOS during chemotherapy treatment are common among older adults with GI cancers. Female sex, cardiac comorbidity, and a diagnosis of stage IV non-colorectal GI cancer are risk factors for HOS.
Nutritional risk as predictor for short-term outcomes in a prospective cohort of elderly patients with cancer.
Authors: Costa Jose Iran , Telles O Lima Jurema , Bergmann Anke , Mello Maria Julia Gonçalves , Bezerra Mirella Rebello , Cavalcanti Zilda , Sales Letícia telles , Thuler Luiz Claudio Santos
Published: September 2018

e21533

Background: To determine if the nutritional risk according Mini Nutritional Assessment Short-Form (MNA®-SF) is an independent factor for short-term outcomes (infection, un programmed hospitalization and premature death) within the first six months after study entry. Methods:Prospective cohort study of elderly patients (≥ 60 years) with a recent diagnosis of cancer admitted to an outpatient oncology unit. At baseline sociodemographic and clinical variables were determined and comprehensive geriatric assessment (CGA) was conducted including MNA-SF. The outcomes were first Healthcare-associated Infection, un programmed hospitalization and death. Data were analyzed using multivariate Cox proportional hazards models; overall survival was estimated using the Kaplan–Meier method and survival curves were compared using the Log rank test. Results:The cohort consisted of 608 elderly patients followed for 180 days or until the censured data. Mean age was 71.9 years (range: 60‒96), 305 (50.2%) participants were at risk of malnutrition. During this period, 216 (35.5%) participants were hospitalized, 179 (29.4%) HAI and 100 (16.4%) died. After adjustment for age, site of cancer and cancer stage the multivariate regression Cox model showed that being undernourished was an independent predictor of infection (HR = 1.88, 95%CI 1.32-2.67, p < 0.001) hospitalization (HR = 1.5, 95% CI:1.10- 2.06, p = 0.012) and death (HR = 3.12, 95% CI: 1.74‒ 5.78, p < 0.001) Conclusions:Nutritional risk at admission was identified as a significant predictor of risk for premature death, infection, and need for hospitalization in elderly cancer patients. The use of MNA-SF should be incorporated into regular geriatric assessment of older patients with cancer
Integrative therapy use amongst patients and providers at an NCI-Designated Cancer Center.
Authors: Ross Masey Marie , Braun Sarah E. , Albrecht Tara A.
Published: September 2018

e21565

Background: Historically, use of integrative health (IH) therapies among patients with cancer is high. Less is known about provider use and provider perceptions. The study aim was to evaluate the use of IH approaches among patients and providers and to gauge provider knowledge, familiarity, and referrals. Methods: We conducted a single-institution patient and provider survey in the outpatient hematology/oncology clinics at a NCI designated cancer center. Results: In 145 patients surveyed (mean age 58±13, 64% female, 56% white), 66% reported use of at least one IH approach. Of these, the highest reported were vitamins/herbs/special diets (66%), physical activity (54%), and mindfulness/meditation/prayer (44%). In 53% of patients who used IH, the therapy was recommended by someone; of these, 58% of the recommendations came from their oncologist or PCP. In all, 37% of patients wished their provider would supply more information regarding IH approaches. In 87 providers surveyed (46% MD/DO, 30% RN, mean age 46±12, 61% male, 79% white), 89% reported prior personal use of an IH therapy. Seventy-four percent reported that they received IH inquiries from patients “sometimes” or more, with 9% receiving inquiries frequently. Thirty-six percent rated their knowledge of IH low, with 24% not feeling comfortable discussing IH approaches with patients. Provider comfort level with IH therapies was positively correlated with frequency of reported patient inquiries ( r= .391, p= .01). Overall, 85% of providers thought IH therapies had the potential to be beneficial and 77% had recommended their use. The highest reported barrier to referral was lack of knowledge (18%) followed by lack of resources (14%). Conclusions: Use of IH therapies among cancer patients and providers is high and most providers have recommended IH approaches to their patients. Patients would like more provider-directed education on IH, yet more than 1/3 of providers rate their knowledge of IH low with a correlation between provider comfort level and frequency of reported patient inquiries. These data suggest that efforts should be aimed at improving educational resources and programs for providers to increase their awareness and comfort level with IH approaches.