bluuebunny/crossref_metadata_2025_split huggingface dataset:
Costs and values of nivolumab in second-line cancer.
Authors: Guirgis Helmy M. 
Published: September 2018

e20629 Background: Nivolumab (Nivo) has been approved in 2nd-line treatment of melanoma, squamous (sq) and non-sq- non-small cell-lung (NSCLC), renal cell, and sq-cell of head and neck (SCCHC). Our objective was to screen and compare values (V) of Nivo in cancer. Methods: Nivo median overall survival gain over control (OS), hazard ratios (HR), doses and frequency were extracted from previously published clinical trials. Data and prices posted by the parent company were utilized. Probability of survival (PoS) was calculated as (1.0- HR). Costs (C) were computed at 4 week (w), V as 4wC/PoS (4wV) and year-C/life-year gain (C/LYG). Relative values (RV) were expressed as $100,000/C/LYG. Adverse events C were not accounted for. Results: Estimated Nivo 4wC in early 2016 was $10,021. Conclusions:HR- based platform was proposed to screen and compare V of Nivo. At 0.42 HR in melanoma and >150 day-OS in renal cell, the results suggested that Nivo was fairly-priced for its V. In non-enriched non-sq-NSCLC and SCCHN, the PD-L1 enrichment was necessary to enhance V significantly and justify C. [Table: see text]
PD-L1 immunohistochemistry in clinical diagnostics: Inter-pathologist variability is as high as assay variability.
Authors: Micke Patrick , Johansson Anna , Westbom-Fremer Anna , Backman Max , Djureinovic Dijana , Patthey Annika , Isaksson-Mettävainio Martin , Gulyas Miklos , Brunnstrom Hans 
Published: September 2018

e20637 Background: Several checkpoint inhibitors targeting the PD1 axis are now approved for the treatment of non-small cell lung cancer (NSCLC). The best predictor for therapy response is PD-L1 expression on tumor cells assessed by immunohistochemistry (IHC). However, the PD-L1 assays have been developed independently for each available drugs. In this study, we evaluated the different assays to determine the comparability between the assays and the concordance between pathologists under conditions reflecting the clinical situation. Methods: We tested four IHC assays (28-8, 22C3, SP263 and SP142) and one in-house protocol (28-8 on the Ventana system) on a tissue microarray (TMA) including 55 resected tissue specimens of NSCLC patients. The TMAs were independently annotated by seven pathologists with regard to the percentage of tumor cell membrane staining using a six-grade scale ( < 1%; 1-≤5%; 5%-≤10%; 10-≤25%; 25-≤50%; ≥50%). Results: The staining scores were comparable for the three assays with clones 28-8, 22C3 and SP263 as well as the in-house 28-8 protocol (κ-value: 0.75-0.91). The use of the SP142 clone resulted in a lower percentage of positive tumor cells and positive cases (κ: 0.44-0.63). When a reference score was defined based on the majority of scores, the proportion of positive cases (≥1%) were 38% for 28-8, 29% for 22C3, 42% for SP263, 37% for 28-8 in-house and 16% for SP142%. With ≥1% cut-off 3-8 of the 55 cases (5-15%) were differently classified as positive or negative when comparing any two assays excluding SP142. Analysing the scoring of the seven pathologists a clear inter-rater variability (κ: 0.71-0.96) was observed independent from the assay. With a ≥1% cut-off, 20% of cases were annotated differently by at least one pathologist. Conclusions: The concordance between the three antibody clones 28-8, 22C3 and SP263 was acceptable and was in the similar range as inter-rater variability of different pathologists. The results suggest that assessment of tumor cell staining for Nivolumab, Pembrolizumab and Durvalumab might be performed with only one of these assays. The assessment of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.
Response to crizotinib in advanced ALK-rearranged NSCLCs with different variants and abundance of ALK-fusion alleles.
Authors: Ying Jianming , Li Yan , Zhang Tongtong , Li Wenbin , Xing Pu-Yuan , Zhang Jing , Junling Li 
Published: September 2018

e20651 Background: Anaplastic lymphoma kinase ( ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants and abundance levels using next-generation sequencing (NGS). Methods: Among 89 ALK-rearrangement patients treated with crizotinib, 47 patients were identified with tumor specimens that could be evaluated by NGS. We retrospectively evaluated the clinical efficacy of crizotinib in different ALK variants and the abundance of ALK-fusion alleles. Results: The median PFS of the 89 ALK-rearrangement patients was 14.1 months (95%CI: 11.27-18.43 months). Among the 47 patients with NGS results, the most frequent variants were variant 3a/b (29.79%, 14/47), variant 1 (25.53%, 12/47) and variant 2 (14.89%, 7/47). Rare EML4- ALK variants were detected in 6 cases (12.77%). Other new fusion partners were detected in 8 cases (17.02%). Patients with EML4- ALK variant 2 appeared to have longer PFS than other EML4- ALK variants with a borderline p value. Patients were categorized into three groups based on the abundance of ALK-fusion alleles: low-abundance group ( < 35%), middle-abundance group (≥35% and < 55%), and high-abundance group (55%). Middle-abundance group had a better PFS than both low-abundance group and high-abundance group (P = 0.01). After adjusting for other baseline characteristics, abundance levels of ALK-positive alleles and ALKvariant type were identified as important factors for predicting clinical efficacy of crizotinib. Conclusions: Our results indicate prolonged PFS in patients with EML4- ALK variant 2 versus other EML4- ALK patients. The abundance of ALK-fusion alleles also correlated with the extent of benefit from crizotinib treatment.
Circulating tumor DNA (ctDNA) to monitor treatment response and progression in patients treated with tyrosine kinase inhibitors (TKIs) and immunotherapy for EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: Henick Brian S. , Goldberg Sarah B. , Narayan Azeet , Rossi Chiara , Rodney Simon , Kole Adam J , Politi Katerina A. , Gettinger Scott N. , Herbst Roy S. , Patel Abhijit 
Published: September 2018

e20652 Background: Detection of EGFR mutations in ctDNA can help determine appropriateness of TKI therapy for patients with NSCLC. We investigated whether longitudinal monitoring of ctDNA levels can be used to assess response to therapy and disease progression, with a focus on EGFR mutation-positive patients treated with immunotherapy. Methods: Serially collected blood from patients with EGFR mutation-positive NSCLC treated with TKIs and/or immunotherapy was analyzed using an ultrasensitive 24-gene next-generation sequencing assay. Clinical characteristics and outcomes were analyzed retrospectively by chart review. Results: We studied quantitative changes in ctDNA levels during treatment by analyzing somatic mutations in 91 plasma samples from 8 patients with EGFR-mutant NSCLC, including samples collected around the time of disease progression for a subset of patients. Two patients treated with PD-1 inhibitor monotherapy experienced a rise in ctDNA harboring EGFR-sensitizing mutations prior to radiographic progression. A third patient was started on anti-PD-1 monotherapy following disease progression on erlotinib. Plasma levels of L858R, T790M, and TP53 mutations were detectable on treatment initiation and decreased with radiographic response. The levels of these mutations rose at progression,fell with response to EGFR-directed therapy, and increased again before disease progression. Another patient was found to have mutations in EGFR, T790M, and TP53 that fell upon treatment with combination TKI therapy. The remaining four patients studied were treated with concurrent TKI and immunotherapy. In all of these cases, sensitizing EGFR mutations were present in plasma at low levels during response to treatment. Two of the four patients had a rise in ctDNA level at the time of radiographic progression; the other two patients had durable responses with persistently low ctDNA levels. Analysis of additional cases is ongoing. Conclusions: Monitoring quantitative changes in ctDNA may enable assessment of response or disease progression in immunotherapy- and TKI-treated EGFR-mutant NSCLC patients.
An updated analysis of ICOGEN to demonstrate utility of a blood-based proteomic test to predict outcomes in EGFR TKI treated patients.
Authors: Shi Yuankai , Han Xiaohong , Zhang Li , Ding Lieming , Dupuis Nicholas , Nickel Alex , Feng Lana , Chuang Yishan , Pestano Gary Anthony , Liu Xiaoqing , Zhou Caicun , Zhang Li , Zhang Shucai , Wang Dong , Li Qiang , Qin Shukui , Hu Chunhong , Chen Jianhua , Tan Fenlai , Sun Yan 
Published: September 2018

e20655 Background: ICOGEN was a randomized Phase III clinical trial comparing two EGFR tyrosine kinase inhibitors (TKI), icotinib (I) and gefitinib (G), in EGFR gene mutation status unknown non-small-cell lung cancer (NSCLC) patients previously treated with platinum doublet chemotherapy. Plasma samples from study patients were retrospectively analyzed with a commercially-available blood-based proteomic test which has been shown to have prognostic and predictive properties in NSCLC. This study represents an updated analysis of ICOGEN to evaluate the ability of the test to predict outcome based on therapeutic regimen. Methods: Available pre-treatment plasma samples from ICOGEN were retrospectively analyzed with the proteomic test which classifies subjects as Good or Poor. Progression free survival (PFS ) and over-all survival (OS) were analyzed within treatment (TX) arms and test classification. Results: 352 subjects were evaluated, with 277(78.7%) classified as Good and 75(21.3%) classified as Poor. Among all patients evaluated with the proteomic test, the median PFS was 4.9 mo. and 2.3 mo. (HR [95% CI] 0.61 [0.46 – 0.81]; p = 0.0004) and median OS was 16.6 mo. and 5.5 mo. (HR [95% CI] 0.39 [0.29 – 0.50]; p < 0.0001) for the Good and Poor sub-groups, respectively. Association between test result and PFS was significant in patients treated with I (6.0 mo vs. 1.9 mo, HR = 0.43, p < 0.0001), but not significant in patients treated with G (3.7 mo vs. 2.5 mo, HR = 0.85, p = 0.429). Further evaluation demonstrated that the proteomic test predicted differential therapeutic benefit between icotinib and gefitinib for PFS (pint = 0.036). In OS, a significant association between test result and outcome was shown in both the I (16.3 mo vs. 4.0 mo, HR [95% CI] 0.27[0.19-0.39]; p < 0.0001) and G (16.6 mo vs. 7.0 mo, HR [95% CI] 0.51[0.35-0.76; p = 0.0008) arms, which trended towards prediction of differential therapeutic benefit between icotinib and gefitinib for OS (pint = 0.086). Conclusions: For ICOGEN’s primary study endpoint, the proteomic test was predictive of differential therapeutic benefit between icotinib and gefitinib in EGFR mutations status unknown NSCLC patients.
Icotinib as first-line or maintenance therapy in patients with advanced lung adenocarcinoma with positive EGFR mutation and the influence of cytokines shift on survival.
Authors: Sun Shengjie , Jiao Shun Chang , Fang Jian , Sun Qiong , Han Jindi , Liu Wei , Bai Chunmei , Tan Fenlai , Ding Lieming 
Published: September 2018

e20658 Background: To compare the efficacy of first-line icotinib or chemotherapy plus icotinib maintenance in EGFR-mutated NSCLC patients, and analyze the correlation between changes in cytokine levels and survival. Methods: Treatment-naive patients with EGFR-mutated NSCLC were enrolled and randomly assigned to recieve icotinib or 2- or 4-cycle chemotherapy (pemetrexed + platinum [PP] or docetaxel + platinum [DP]) with icotinib maintenance. The primary endpoints were progression-free survival (PFS). Plasma samples were collected at baseline and after 6-week treatment. Cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), transforming growth factor (TGF), programmed death (PD) 1, PD-ligand (PD-L) 1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and hypoxia-inducible factor-1 (HIF-1), were tested by ELISA. Results: 66 eligible patients were enrolled (November, 2011 to June, 2016), in which 56 patients were treated, including 20 patients receiving icotinib [PFS: 8.17 months (5.5-13.97)], 11 patients receiving 2-cycle chemotherapy (DP) followed by icotinib maintenance [PFS: 12.07 (6.2-12.83)], 10 patients receiving 2-cycle chemotherapy (PP) followed by icotinib maintenance [PFS: 15.37 (4.03-NR)], 4 patients receiving 4-cycle chemotherapy (DP) followed by icotinib maintenance [PFS: 15.37 (7.13-NR)], 9 patients receiving 4-cycle chemotherapy (PP) followed by icotinib maintenance [PFS: 13.82 (1.5-22.93)]. Samples were collected from 20 patients. The shift of level was seen in all cytokines and multivariate analysis showed that the change of IL-6, HIF, PD-L1, and PD1 were associated with significantly longer survival in patients with EGFR-mutated NSCLC. Conclusions: First-line chemotherapy plus icotinib maintenance seems to offer better efficacy in advanced NSCLC patients with EGFR mutation. The shift of level of IL-6, HIF-1, PD 1, and PD-L1 in peripheral blood correlates with a better prognosis, however, further study with larger size is warranted to detect the potential role of immune response in regulating survival of patients with EGFR-mutant NSCLC. Clinical trial information: NCT01665417.
Fibroblast kinase 1-3 inhibitor BGJ398 in patients with FGFR1 amplified squamous non-small cell lung cancer treated in a phase I study: Evaluation of tumor tissue and response at a single center.
Authors: Nogova Lucia , Malchers Florian , Bitter Elisabeth , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Scheffler Matthias , Gardizi Masyar , Brandes Vanessa , Scheel Andreas H. , Kambartel Karl-Otto , Krüger Stefan , Serke Monika Heidi , Isaacs Randi , Porter Dale , Buettner Reinhard , Thomas Roman K. , Wolf Juergen 
Published: September 2018

e20664 Background: Fibroblast growth factor receptor 1 ( FGFR1) amplification in squamous cell non-small cell lung cancer (sqNSCLC) has been described as potential oncogenic and targetable driver in cell lines and murine models. However, a phase I study evaluating FGFR 1-3 inhibitor BGJ398 showed moderate response rate of 11% in FGFR1amplified sgNSCLC treated with dose ≥ 100mg. To identify underlying mechanisms of resistance, we analyzed tumor tissues of selected patients. Methods: Within the phase I BGJ398 study, patients (pts) with FGFR1amplified sqNSCLC were treated orally with escalating dose (5 to 150mg) of BGJ398 once daily (QD) or 50mg twice a day. In the expansion phase, pts received BGJ398 either continuously QD or on a 3-weeks on/1-week off schedule. CT scans for response were performed every 8 weeks. Available tumor tissue of pts treated with BGJ398 at our center was analyzed using hybrid capture–based massively parallel sequencing (CAGE). Results: Twenty-one pts with FGFR1 amplified sqNSCLC were treated with ≥ 100mg BGJ398 at our site. As best response, 3 pts showed partial response (PR), 7 pts stable disease (SD) and 7 pts progressive disease (PD). Two pts withdrew their consents and 2 pts died ahead of first CT scan: one due to infection and one due to sudden death. We performed CAGE covering 256 genes on 9 patients: on 3 pts with PR, 2 pts with SD, 2 pts with PD and 2 pts who died before first CT scan. All analyzed patients harbored mutations in TP53. Additionally, we detected two CDKN2A (one patient with PR and one patient who died before first CT) and three MLL2 stop codon and frame shift mutations (two patients with SD and one patient with PD). Of interest, we identified three patients with two canonical (one patient with SD and one patient who died before first CT) and one non-canonical mutations in PIK3CA(one patient with SD). Conclusions: In our analysis, MLL2 and PIK3CA mutations seem to have a negative impact on response in FGFR1 amplified pts treated with BGJ398. Further analysis with higher patient number is needed to identify the role of MLL2 and PIK3CA mutations in FGFR1 amplified sqNSCLC. Clinical trial information: NCT01004224.
Survival impact of aggressive treatment on patients with oligometastatic non-small cell lung cancer (NSCLC).
Authors: Gauvin Camille , Blais Normand , Tehfe Mustapha , Florescu Marie 
Published: September 2018

e20669 Background: The new 2016lung cancer classification differentiates oligometastatic (M1b) better prognostic from plurimetastatic (M1c) disease. A prospective study presented at 2016 ASCO showed improved PFS in patients with oligometastatic brain disease treated aggressively compared to a more palliative treatment but OS data is pending. Methods: This study is a single-center retrospective study including 643 patients with metastatic lung cancer diagnosed in an University center (CHUM) from 2005-2015 and followed more than 6 months (median follow up 13.3mo) . Only 67 patients (10.4%) were found to have synchronous oligometastatic disease at diagnosis. Results: Amongst the 67 patients, the localization of metastatic disease was as follows: 74% brain (n = 50), 9% adrenal gland (n = 6), 7% contralateral pulmonary lobe (n = 5), 6% bone (n = 4) and 3% liver (n = 2). 29 patients received radical treatment to primary and metastatic site (group A) and 36 patients received non-aggressive treatments (group B). There was no statistically significant difference between the two groups in terms of demographic and histological characteristics. The radical treatment group A had a mOS of 26mo and a mPFS of 12.8m compared to mOS of 5mo (p = 0.0001) and mPFS of 4.8mo (p = 0.010) for group B. This difference was observed when stratifying according to stage of primary lung disease (stage I mOS 42mo vs 16mo, stage II mOS 34mo vs 6mo and stage III mOS 22mo vs 4mo) and according to to oligometastatic site. Interestingly, addressing aggressively the primary lung cancer improved median survival even when the oligometastasis was not resected (26mo v and 24mo respectively), but not when oligometastasis only was resected and primary was treated palliatively (5mo vs 3 mo). Adjuvant chemotherapy given after radical treatment did not improve mPFS or mOS (12.83 vs12.47 months, p = 0.860). Conclusions: Radical treatment of oligometastatic NSCLC in this unselected population improved mPFS and mOS compared to other treatment strategies. As overall survival data of the prospective trial presented at 2016 ASCO meeting is pending, the more radical approach should be emphasized when patients present with oligometastatic lung cancer disease.
Generalizability of clinical trials in metastatic melanoma.
Authors: Sam Davis , Gresham Gillian K. , Cheung Winson Y. 
Published: September 2018

e21004 Background: Results from clinical trials are not always generalizable to real world patients (pts). Clinicians may not adhere to the studies’ original inclusion/exclusion criteria because of differences in clinical circumstances or institutional variations in treatment policies. Our aims were to determine the pattern in which melanoma trial findings are applied in a population-based setting and to describe the treatment outcomes of these pts. Methods: We focused on melanoma as several novel therapies have been recently introduced. Pts with unresectable disease from 2013 to 2014 and referred to any 1 of 6 cancer centers in British Columbia were reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0-1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent cause of being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (adjusted HR 0.53, 95% CI 0.28-1.00 for Vem and adjusted HR 0.33, 95% CI 0.13-0.83 for Ipi). Conclusions: There was favorable uptake of new melanoma treatments, but a fair number of pts were considered TI, suggesting the need for trials with better external validity. Non-use of novel agents in TE pts was due to physician factors, pt preferences, and concerns about toxicities, highlighting areas that limit real world effectiveness of new melanoma drugs.
Long-term (LT) disease-free survival (DFS) of melanoma (MM) and renal cell cancer (RCC) patients following high-dose interleukin-2 (HD IL2).
Authors: Clark Joseph , Curti Brendan D. , Davis Elizabeth J. , Kaufman Howard , Amin Asim , Alva Ajjai Shivaram , Johnson Douglas Buckner , White Richard L. , Wiernik Peter H. , Dutcher Janice P. 
Published: September 2018

e21005 Background: HD IL2 treatment (Tx) produces durable complete responses (CRs) and surgical CRs. Patients (pts) achieving partial response (PR) and stable disease (SD) demonstrate improved survival compared with pts who progress. Methods: 7 HD IL2 Tx centers identified pts with survival > 5 years (yrs) after HD IL2. DFS was from end of IL2 to January 2017. Tx courses generally consisted of 2 1-week cycles of HD IL2, 600,000-720,000 U/kg IV every 8 hours. We collected data on pts Tx with HD IL2 alone, or HD IL2 plus local Tx (surgery or radiation (SRS) leading to CR) with survival > 5 yrs after HD IL2 Tx. Results: 72 pts are reported: 29 RCC (male 22, female 7) and 43 mm (male 26, female 17). Median age at Tx of RCC is 54 yrs (range, 47-67 yrs) and of mm is 50 yrs (range, 24-72 yrs). Sites of metastatic disease for 26 mm pts were lymph nodes (LN) -18, lungs-12, bone-6, liver-9, brain-3, other organs-10 and for 22 RCC pts were lung-17, LN-5, adrenal-4, bone-3, other organs-8. Number of IL2 courses received: 1-10 pts, 1.5-4 pts, 2-28 pts, 2.5-5 pts, 3-24 pts, 4-one pt. Among the 29 RCC pts, there are 24 CRs, 3 surgical CRs and 2 PRs with no further Tx. Among 43 mm pts, there are 34 CRs, 2 near CRs, and 7 Surgical/SRS CRs. DFS in these pts after HD IL2 Tx ranges from 5+ yrs to 30+ yrs, median 10.5+ yrs. 10 RCC and 16 mm are alive > 5 - < 10 yrs after IL2, and 19 RCC and 27 mm are alive > 10 yrs after IL2. LT toxicity among these 72 pts includes hypothyroidism-5 pts, arthralgias/arthritis-5 pts, vitiligo-3 pts, and 1 pt each: neuropathy, PVCs, and normal pressure hydrocephalus. Additional pts may be added as records become available. Conclusions: We document LT DFS ( > 5 yrs) after CR or PR from HD IL2 alone. Surgical or SRS conversion of PR to CR can produce durable CRs. LT DFS was observed in pts with visceral and bone metastases, not only those with LN or lung sites. Neither age, sex, nor number of courses of IL2 predicted LT DFS. Chronic toxicity due to IL2 is uncommon in LT survivors.