bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrasensitive DNA hypermethylation detection using plasma for early detection of NSCLC: A validation study in Chinese patients.
Authors: Chen Chen , Huang Xiaojie , Song Mingzhe , Yin Wei , Hulbert Alicia , Brock Malcolm , Herman James , Yu Fenglei , Liu Wenliang
Published: March 2020

8522

Background: Our previous study revealed that high diagnostic accuracy for early stage lung cancer could be obtained in plasma samples with ultrasensitive DNA hypermethylation detection methods called MOB-qMSP. In this study, we sought to validate and also improve the diagnostic accuracy of lung cancer screening with modified MOB-qMSP approach in Chinese patients. We also develop a lung cancer specific gene panel for Chinese patients. Methods: We included patients with small lung nodules (less than 3cm in diameter) on CT scan screening and conducted a case-control study. Cases (n=138) had pathological confirmation of Non-Small Cell Lung Cancer (NSCLC) lesions staged IA or IB. Controls (n=65) had pathological confirmation of non-cancerous lesions. Plasma samples were obtained pre-operatively. Promoter methylation of eight lung cancer-specific genes (CDO1, TAC1, SOX17, HOXA7, HOXA9, GATA4, GATA5 and PAX5B) was detected using nanoparticle-based DNA extraction (MOB) followed by qMSP. Results: DNA methylation was detected in plasma more frequently in cases compared to controls (p<0.001) for 5 out of 8 genes. The sensitivity and specificity for lung cancer diagnosis using the best individual gene was 64-85% and 55-79% respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 92% and 78%. Area under the Receiver Operating Curve (AUC) for this panel was 0.90, 95% CI (0.86-0.96). Cross validation combining gene methylation with clinical information correctly predicted lung cancer in 86% of subjects using plasma detection. Furthermore, we analyzed the sensitivity and specificity of the same three-gene combination in cases subgroups regarding the tumor size and the results are as follow: in subgroup with tumor size of 2-3cm, the sensitivity and specificity were 94% and 87%, and the AUC was 0.96, 95% CI (0.91-0.99); in subgroup with tumor size of 1-2 cm, the sensitivity and specificity were 92% and 80%, and the AUC was 0.90, 95% CI (0.84-0.96); in subgroup with tumor size less than 1cm, the sensitivity and specificity decreased to 66% and 87%, and the AUC was 0.77, 95% CI (0.64-0.88). Conclusions: This study validates our previous study but in Chinese patients that it is possible to obtain high diagnostic accuracy for early stage NSCLC using a panel of methylated promoter genes in plasma samples with ultrasensitive MOB-qMSP, especially in patients with tumor of larger size. These epigenetic biomarkers could potentially be used to identify patients with high risk of lung cancer development.
Randomized phase Ⅱ trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage Ⅲ non-squamous non-small-cell lung cancer: NJLCG1001.
Authors: Watanabe Kana , Toi Yukihiro , Nakamura Atsushi , Fukuhara Tatsuro , Chiba Ryosuke , Akiyama Masachika , Sakakibara-Konishi Jun , Tanaka Hisashi , Yoshimura Naruo , Miyauchi Eisaku , Nakagawa Taku , Igusa Ryotaro , Minemura Hiroyuki , Mori Yoshiaki , Fujimoto Keisuke , Matsushita Haruo , Takahashi Fumiaki , Inoue Akira , Sugawara Shunichi , Maemondo Makoto
Published: March 2020

8527

Background: It is unknown which regimen is the best in concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC). Our previous randomized phase Ⅱ study, NJLCG0601, showed that chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy with acceptable toxicities. In this trial, this regimen was compared to a regimen with pemetrexed and cisplatin for stage Ⅲ non-squamous NSCLC. Methods: Patients with inoperable stage Ⅲ non-squamous NSCLC were randomized to UFT 400 mg/m2 on days 1–14 and 29–42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) was administered from day 1 to a total dose of 66 Gy radiotherapy in 33 fractions. Consolidation chemotherapy after CCRT was not planned for this study. The primary endpoint was 2-year overall survival (OS), with expected rates of 55% and a lower limit of 35% (alfa 0.05, beta 0.2). Secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), OS, and toxicity profile. Results: From November 2010 to June 2017, 86 patients were enrolled from 11 institutions. Of the 85 eligible patients, the rate of 2-year OS was 78.6% (95% CI: 62.8–88.3%) in the UP arm and 85.5% (95% CI: 70.5–93.2%) in the PP arm. The ORR was 76.7% in the UP arm and 81.0% in the PP arm. With a median follow-up of 54 months, median PFS and OS were 12.3 and 64.2 months in the UP arm, and 26.2 months and not reached in the PP arm, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP arm than in the PP arm (14.0%, 2.0%, respectively). Grade 3/4 pneumonitis occurred in 7.0% and 4.8% of patients in UP and PP arms, respectively. Conclusions: Both regimens with IFRT achieved the expected 2-year survival rate. PP had more favorable results than UP in terms of OS and PFS. We selected the PP arm for the next step.
T cell repertoire analysis of non-small cell lung cancer patients treated with neoadjuvant nivolumab alone or in combination with ipilimumab (NEOSTAR trial).
Authors: Reuben Alexandre , Zhang Jianjun , Lin Heather Y. , Little Latasha , Gumbs Curtis , Tran Hai T. , Wang Linghua , Haymaker Cara L. , Mehran Reza J. , Rice David C. , Walsh Garrett L. , Lee J. Jack , Wistuba Ignacio Ivan , Swisher Stephen , Vaporciyan Ara A. , Futreal Andrew , Sepesi Boris , Heymach John , Gibbons Don Lynn , Cascone Tina ,   NEOSTAR Study Group
Published: March 2020

8532

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) are being explored in resectable non-small cell lung cancer (NSCLC). Here, we studied the composition and changes in the T cell repertoire in a cohort of NSCLC patients (n = 44) treated with neoadjuvant nivolumab (N) alone or in combination with ipilimumab (NI) followed by surgery (NEOSTAR trial). Methods: Sequencing of the variable CDR3β chain of the T cell receptor (TCR) involved in antigen binding was performed in pre-treatment and surgical tumors, matched adjacent uninvolved lung specimens, as well as paired longitudinal blood at baseline, prior to each dose of therapy, prior to surgery, and within 8 weeks post-surgery. T cell repertoire density, diversity, and clonality (reactivity) were evaluated in addition to tumor PD-L1 expression pre- and post-neoadjuvant treatment. Results: Median T cell diversity in the blood post-therapy was 3.3-fold higher in NI- compared to N-treated patients (40,993 [NI, n = 3] vs 12,177 [N, n = 4] unique TCR rearrangements, n.s.). However, median T cell clonality in the blood was 3.5-fold higher in N- than NI-treated patients post-therapy (0.093 [N, n = 4] vs 0.026 [NI, n = 3], n.s.). Median clonality was 3.8-fold higher in the tumor post-therapy in patients receiving NI than in those receiving N (0.076 [NI, n = 7] vs 0.020 [N, n = 5], n.s.). Interestingly, diversity in the blood at baseline and in the tumor post-therapy were positively correlated ([n = 7], r = 0.82; p = 0.023), which may reflect an influx of cells from the periphery following ICIs. Importantly, higher baseline T cell clonality in the blood was associated with a lower % of viable tumor at time of surgery in both treatment arms ([n = 7], r = -0.77; p = 0.04). Conclusions: Our study is the first to assess the TCR repertoire in NSCLC patients treated with combination neoadjuvant NI and highlights potential mechanistic differences compared to N alone. Neoadjuvant NI is associated with higher clonality in tumors and lower clonality in blood post-therapy, suggesting increased T cell trafficking into the tumor. Finally, lower pre-treatment clonality in the periphery was correlated with higher % viable tumor post-neoadjuvant ICIs. Clinical trial information: NCT03158129.
Development of a prognostic risk model for small cell lung cancer: Identification of high-, intermediate-, and low-risk cohorts based on clinical-genomic data.
Authors: Ardeshir-Larijani Fatemeh , Wildey Gary , Fu Pingfu , Dowlati Afshin
Published: March 2020

8554

Background: Although many clinical prognostic factors for SCLC outcome have been described, there are no models that incorporate the combination of clinical and genomic details into a risk model defining high and low risk patients. Methods: From a total of 791 SCLC patients seen between 2013-2018, 91 were evaluated by exome sequencing. Using the univariate Cox regression model, 19 genes were prognostic for survival and included RET, ERBB4 MAP3K1, ABL1, CCND1, TSC1, PRKCI, FGFR3, JAK3, ZNF217, BRCA1, GPR124, LRP1B, GNAS, TAF1, FGF3, STAT3, CD79A and FLT. LASSO, elastic-net Cox and traditional Cox model with stepwise selection along with traditional clinical factors (age and stage) were further used to build the final model. The final risk groups were defined based upon the prognostic index from multivariable Cox model involving age, stage (extensive/limited) and 6 genes ( MAP3K1, ABL1, CCND1, PRKCI, BRCA1, GNAS). Results: The overall survival (OS) for the entire cohort was 11.2 (95% CI: 9 – 13.4) months and the median age was 65 (range: 39 - 90) years. Eighty percent (N = 74) of evaluated patients had extensive stage (ES) disease. The HR for death of age and stage (ES/LS) was 1.06 (CI: 1.03-1.08, p < 0.0001) and 4.33 (CI: 2.23-8.41, p < 0.0001) respectively. ABL1 demonstrated the highest HR of 10.14 (2.81-36.6, p = 0.0004) followed by PRKCI (HR: 5.05, CI: 1.43-17.8 , p < 0.012), CCND1 (HR: 4.52, CI: 1.23-16.57, p < 0.023), MAP3K1 (HR: 3.38, CI: 1.37- 8.33, p = 0.008) and GNAS (HR: 2.21, CI: 1.11-4.43, p < 0.025). Interestingly, BRACA1 mutation was protective as patients with BRACA1 mutation had significantly better overall survival (HR: 0.3, CI: 0.1- 0.85, p < 0.023). Our model categorized patients into three groups of low risk ( N= 31), intermediate risk ( N= 30) and high risk ( N= 30) with significantly different survival outcomes ( p < 0.0001). Those with low risk had the median OS of 27.4 (95% CI: 16.8-55.5) months, intermediate risk with median OS of 10.8 (95% CI: 7 – 14.7) months and high risk with median OS of 5.4 (95% CI: 3.9- 9) months. Conclusions: This clinical-genomic risk group stratification represents a useful model to estimate SCLC survival outcome and may have value in future clinical trials.
Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C).
Authors: Noronha Vanita , Joshi Amit , Patil Vijay Maruti , Chougule Anuradha , Mahajan Abhishek , Janu Amit , Purandare Nilendu , Kumar Rajiv , More Sucheta , Goud Supriya , Kadam Nandkumar , Daware Nilesh , Shah Srushti , Yadav Akanksha , Dutt Amit , Trivedi Vaishakhi , Behel Vichitra , Banavali Shripad Dinanath , Prabhash Kumar
Published: March 2020

9001

Background: Standard first-line therapy for EGFR mutant advanced non-small cell lung cancer (NSCLC) is an EGFR-directed oral TKI. We evaluated whether adding pemetrexed-carboplatin to oral TKI would improve outcomes. Methods: Phase III randomized trial in advanced chemotherapy-naïve NSCLC harboring EGFR sensitizing mutation (exon 19, 21 or 18) with performance status (PS) 0 to 2 planned for palliative therapy. Patients were stratified for PS and EGFR mutation and randomly assigned (computer-generated randomization by independent biostatistician) 1:1 to gefitinib 250 mg orally daily (gef) or gefitinib 250 mg orally daily with pemetrexed 500 mg/m2 IV and carboplatin AUC 5 IV every 3 weeks for 4 cycles, followed by maintenance pemetrexed 500 mg/m2 IV every 3 weeks (gef+C). Restaging was every 2 to 3 mths; therapy continued until progression or intolerable toxicity. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), toxicity and response rate. Survival endpoints were assessed in the intention-to-treat population. Results: Between Aug 2016 and Aug 2018, 350 patients were randomly assigned to gef (n = 177) and gef+C (n = 173). Median age was 54 yrs, 48% were females, 84% never-smokers, 21% were PS 2 and 18% had brain metastases. Median follow-up in surviving patients was 17 months (range, 7 to 30). Radiologic response rates were 81% and 69% in gef+C and gef respectively, P = 0.012. 234 patients (67%) have had events for PFS, 98 in gef+C and 136 in gef. Estimated median PFS was significantly longer with gef+C than gef (16 months, [95% CI, 13.7 to 18.3] vs. 8 months [95% CI, 7.1 to 8.9]; hazard ratio for disease progression or death, 0.5; 95% CI, 0.39 to 0.65; P < 0.001). 120 patients (34%) have died, 42 in gef+C and 78 in gef. Estimated median OS was significantly longer with gef+C than gef (not reached vs. 18 months [95% CI, 14.28 to 21.72]; hazard ratio for death, 0.45; 95% CI, 0.31 to 0.66; P < 0.001). Clinically relevant ≥ grade 3 toxicities occurred in 51% and 25% of patients in gef+C and gef arms respectively, P < 0.001. Conclusion: Adding pemetrexed-carboplatin chemotherapy to gefitinib significantly prolonged progression free and overall survival but also increased toxicity. Pemetrexed-carboplatin-gefitinib represents a new standard first-line therapy for EGFR mutant NSCLC. Clinical trial information: CTRI/2016/08/007149.
A phase I study to evaluate safety, tolerability, pharmacokinetics and antineoplastic activity of BPI-7711 in patients with EGFR/T790M mutation advanced or recurrent NSCLC.
Authors: Shi Yuankai , Fang Jian , Shu Yongqian , Wang Donglin , Yu Huiqing , Zhao Yanqiu , Zhang Liangming , Zhu Bo , Li Xingya , Chen Gongyan , Shi Jianhua , Zheng Rongsheng , Huang Jian'An , Yang Sheng , Long Jieran , Gao Wen , Greco Michael , Wang Jing , Li Xiao
Published: March 2020

9034

Background: BPI-7711 is a 3rd generation irreversible EGFR-TKI that is selectively against EGFR TKI–sensitizing mutations and the T790M resistance mutations. We are conducting a phase I study to determine the safety and efficacy of BPI-7711 in patients with advanced or recurrent EGFRm+/T790M+ NSCLC. Methods: NSCLC patients who had documented disease progression after 1st/2nd generation EGFR-TKI treatment and with EGFRm+/T790M+ confirmed by central lab were enrolled in the multicenter trial (NCT03386955) into “3+3” dose escalation or expansion cohorts. BPI-7711 was orally administered at doses of 30~240 mg in capsules. Patients in dose-escalation cohorts firstly received a single dose of BPI-7711 followed by a 7-day pharmacokinetic (PK) evaluation period then received the same dose daily until disease progression or intolerable toxicity(ies) per CTCAE V4.03. Treatment efficacy per RECIST 1.1 was evaluated every 6 weeks since daily treatment commence. Once efficacy was observed in a dose, its expansion cohort was opened to enroll patients for daily treatment. Results: As of 23 December 2018, 82 patients (median age 55, 27 males, 55 females) were enrolled into 5 dose escalation cohorts (30/60/120/180/240 mg) and 4 dose expansion cohorts (30/60/120/180 mg). No DLT was observed and MTD was not reached. For all safety-evaluable patients, most common treatment emergent adverse events (TEAEs) (≥10%) were white blood cell count decreased (21.3%), neutrophil count decreased (17.3%), upper respiratory tract infection (17.3%), vomiting (12.0%) and diarrhea (10.7%), and all were Grade 1 or 2. Grade 3~4 TEAEs were occurred in 8.0% patients and 4.0% of them were treatment-related per investigators’ judgement. SAEs were reported in 4.0% of patients, and 1.3% were treatment-related. For all efficacy-evaluable patients, the overall ORR of all doses was 54.5% (30/55) including 1.8% CR and 52.7% PR. The disease control rate (DCR) was 96.4%. For patients in 120/180 mg cohorts, the ORR was 64.1% (25/39) and DCR was 97.4%. PK analyses showed BPI-7711 exposure increased in a dose-proportional manner from 30 to 180 mg after single and multiple doses. Conclusions: BPI-7711 was well tolerated and highly effective in acquired T790M+ NSCLC patients. Phase II trials are under preparation. Clinical trial information: NCT03386955.
The efficacy of immune checkpoint inhibitors and PD-L1 status in patients with advanced non-small cell lung cancer harboring oncogenic driver alterations: Immuno-oncology biomarker study in LC-SCRUM-Japan.
Authors: Yoh Kiyotaka , Matsumoto Shingo , Kunimasa Kei , Kodani Masahiro , Nishi Koichi , Nakagawa Taku , Sugawara Shunichi , Kato Tomohiro , Sakakibara-Konishi Jun , Hayashi Yuichiro , Tsuta Koji , Motoi Noriko , Ishii Genichiro , Goto Koichi
Published: March 2020

9046

Background: The efficacy of immune checkpoint inhibitors (ICI) and PD-L1 status in patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic alterations has not been fully investigated. We initiated this immuno-oncology biomarker study as part of nationwide genomic screening by LC-SCRUM-Japan (LC-SCRUM-IBIS). Methods: Lung cancer patients enrolled in LC-SCRUM-IBIS underwent targeted next-generation sequencing (NGS) with Oncomine Comprehensive Assay, PD-L1 immunohistochemistry (IHC) assays and further whole-exome sequencing (WES) to determine tumor mutation burden. According to subtype of oncogenic alterations, the efficacy of ICI and PD-L1 status were analyzed. Results: Between Feb 2017 and May 2018, 1017 lung cancer patients were enrolled. Of these, 832 NSCLC patients had adequate tumor samples and were included in this analysis. Targeted NGS showed that major oncogenic alterations included 157 EGFR, 83 KRAS, 33 MET, 30 HER2, 25 FGFR, 22 PIK3CA, 19 ALK, 15 ROS1, 10 RET, 5 BRAF and 13 others. High expression of PD-L1 ( > 50% of tumor cells by 22C3) were observed in RET (70%), MET (67%), ROS1 (53%), KRAS (41%) and BRAF (40%) positive tumors. One-hundred five patients were evaluable for the efficacy of ICI, including 80 non-squamous and 25 squamous histology. Among them, 104 were treated with PD-1/PD-L1 monotherapy and only 1 in combination therapy of ICI. Median treatment line was 2 (range, 1-9). The response rate was 19% (20/105) and median progression-free survival (PFS) and overall survival (OS) were 3.3 and 18.3 months. In 50 patients harboring at least one oncogenic alterations, the response rate, PFS and OS were 18% (9/50), 3.3 and 24.8 months. Among 9 responders to ICI, 3 had KRAS, 2 had MET and 1 each had ALK/EGFR/HER2/RET. Six (26%) of 23 patients with both high PD-L1 expression and at least one oncogenic alterations responded to ICI. Conclusions: PD-L1 status seemed to vary among patients with advanced NSCLC harboring oncogenic alterations. New biomarker for ICI therapy in this population should be moreover explored. Updated results on WES analysis will be presented at the meeting.
Clinical outcomes of EGFR+ NSCLC pts treated with immune checkpoint inhibitors (ICI).
Authors: Piotrowska Zofia , Cobb Rosemary G. , Banwait Mandeep , Marcoux Nicolas , Mooradian Meghan , Dagogo-Jack Ibiayi , Lin Jessica Jiyeong , Heist Rebecca Suk , Shaw Alice Tsang , Gainor Justin F. , Sequist Lecia V.
Published: March 2020

9069

Background: ICIs have limited efficacy in EGFR+ NSCLC with ORR ~10% if PDL1 > 25% in ATLANTIC, yet ICIs are often used in later lines of therapy as pts and providers feel there may be little risk. The impacts of ICI in this setting are poorly understood. We describe our institutional experience of ICI use in EGFR+ NSCLC. Methods: MGH pts with advanced EGFR+ NSCLC treated with ICI (any line) were retrospectively reviewed for demographics, PDL1, treatment duration and patient outcomes. Disease flare was defined as hospital/hospice admission due to progression or death (Chaft CCR 2011) within 30d of ICI. Results: 40 pts with EGFR+ NSCLC (22 del19, 11 L858R, 5 ins20, 2 other) received ICI between 7/2012-12/2018. 13 were on a clinical trial. 4 had SCLC transformation. Median # of prior therapies = 3 (range, 0-8). Of 16 with PDL1 quantified, 8 had PDL1 > 25%. ICI regimens were: nivolumab (nivo; n = 16), pembrolizumab (pembro; 9), atezolizumab (atezo; 3), ipilimumab/nivo (7), carboplatin/pemetrexed (pem)/pembro (3), pem/pembro (1), paclitaxel/atezo (1). 18 pts stopped TKI ≤21d prior to ICI start. Median duration of treatment (DOT) was 25 days (range, 1-1482). DOT was > 1 yr for 2 pts (5%), treated with 1st-line nivo/erlotinib (erlo) and 3rd-line nivo. All 8 pts with PDL1 > 25% had DOT < 2 mos. Disease flare within 30d of ICI occurred in 16/40 (40%) overall, 8/18 (44%) who stopped TKI ≤21d of ICI start, and 14/26 (54%) who received ICI in 4thline or later. 8 pts had concurrent TKIs (4 erlo/nivo, 2 erlo/pembro, 1 erlo/atezo, 1 osimertinib (osi)/nivo); 3/8 discontinued ICI for toxicity (all 3 treated first-line). 5 pts received osi immediately post-ICI. There was no pneumonitis on osi post-ICI; 1 pt developed gr3 LFTs and gr4 hypoNa. Conclusions: In this real world cohort of EGFR+ NSCLC, clinical benefit from ICI (assessed by DOT) was rare, including pts with high PDL1. 5% had durable benefit (both pts received ICI in earlier lines of therapy). A previously underappreciated negative outcome of ICI is that admission to hospital, hospice or death within 30d of ICI occur in up to 54% pts. This may be related to disease flare or hyperprogression and suggests that use of ICI in heavily pretreated EGFR+ NSCLC may negatively impact outcomes at end-of-life and should be used with caution.
Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis.
Authors: Neal Joel W. , Hausrath Daniel , Wakelee Heather A. , Cunanan Kristen , Liu Stephen V. , Banwait Mandeep , Sequist Lecia V. , Stirling Kevin , Piotrowska Zofia
Published: March 2020

9083

Background: First generation EGFR TKIs are well tolerated with chemotherapy (chemo), and have evidence of improved efficacy in EGFR-mutant NSCLC. Osimertinib (osi) is a 3rd-generation EGFR TKI with improved T790M and CNS activity. Safety and outcome data combining osi and concurrent chemo are limited. Methods: EGFR-mutant pts who received osi with chemo between 12/2015 and 8/2018 were retrospectively identified at two institutions. Pt demographics, toxicities and outcomes were collected by chart review. Results: 35 pts received osi + chemo, 29/35 pts had CNS mets. 16/35 had > = one prior chemo and/or immunotherapy, 34/35 previously received a 1st/2nd gen EGFR TKI (25/35 T790M+ at progression), and all 35 had prior progression on osi. 47 osi + chemo regimens were abstracted: carboplatin/pemetrexed+/-bevacizumab (n = 17), cisplatin/pem (1), carbo/taxane (2), pem+/-bev (7), taxane (7), gemcitabine (8), irinotecan (3), vinorelbine (2); 32/35 pts had platinum. Osi was dosed at 80 mg QD (32), 160 mg QD (2), or 80mg QOD (1). Toxicities (table) occasionally led to treatment delay (n = 5), osi dose-reduction (2) and discontinuation (3). Median overall survival (mOS) from metastatic diagnosis was 48.4 mo (95% CI 30.7-NR); mOS from first osi was 19.6 mo (95% CI 16.1-32.6). Median duration of treatment (mDOT) for first regimen of chemo + osi was 5.3 mo (95% CI 4.1-9.5); stratifying by chemo, mDOT for platinum doublet + osi was 6.1 mo (95% CI 4.7-NR) and mDOT for osi + single agent was 3.2 mo (95% CI 2.4-5.3). In the 29 pts with brain mets receiving their first regimen of osi + chemo, 6 had CNS progression but only 2 required radiation at progression. Conclusions: Osimertinib is tolerable in combination with many standard chemo regimens for EGFR-mutant NSCLC. mDOT for platinum doublet and single agent are similar to historical controls, but CNS disease control appears better than expected for chemotherapy alone. Adding chemotherapy at the time of progression on osimertinib may be considered for selected pts, particularly those with known CNS mets. [Table: see text]
Cancer cachexia, sarcopenia and hand-GRIP strength (HGS) in the prediction of outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): A prospective, observational study.
Authors: Agelaki Sofia , Rounis Konstantinos , Papadaki Chara , Monastirioti Alexia A , Vamvakas Lampros , Gioulbasanis Ioannis , Mavroudis Dimitrios , Makrakis Dimitris A
Published: March 2020

9099

Background: Cancer cachexia syndrome, affecting up to 80% of patients (pts) with NSCLC, is characterized by systemic inflammation, negative protein and energy balance and poor patient outcome. HGS has been independently correlated with outcome in pts with advanced cancer. We investigated the potential association between cachexia, sarcopenia and HGS with outcome in pts with advanced NSCLC treated with ICIs. Methods: Fifty-five pts with NSCLC treated with ICIs were included in the analysis. Patient and disease characteristics and data on outcome measures were prospectively collected. Cancer cachexia was defined as weight loss > 5% in the last 6 months, BMI < 20% (or baseline skeletal muscle index at the level of the 3rd lumbar vertebra consistent with sarcopenia) and any degree of weight loss > 2%. Baseline HGS was measured using the JAMAR analogue dynamometer. Results: Median age was 69 years, 50% of pts had non-squamous histology, 69% had PS 0-1, 61% had cancer cachexia and mean HGS was 27 kgs. Partial response, stable disease and progressive disease was recorded in 16%, 33% and 51% of pts, respectively. Median PFS was 4 months and median OS was 7.8 months. There was no association of cachexia or HGS with tumor burden, number of metastatic sites, LDH or neutrophil/lymphocyte ratio. Cachexia had a negative impact on HGS (p = 0,001). Pts with cachexia had lower response rates (4% vs 37%, p = 0.002), disease stabilization rates (32% vs 81%, p = 0.003) and shorter PFS (3.7 vs 8.2 months, p = 0.008) compared to non-cachectic pts. In multivariate analysis, cachexia independently predicted for shorter PFS (HR = 2.7, CI: 1.15 – 6.46, p = 0.023). Data on sarcopenia are being analyzed and will be presented at the meeting. Conclusions: Cancer cachexia is associated with lower response rates and disease stabilization rates and independently predicts for shorter PFS in pts with NSCLC treated with ICIs. To our knowledge this is the first report demonstrating a between the host’s immune and metabolic responses. The study of cancer cachexia may offer a new platform for the development of novel biomarkers of resistance to ICIs.
The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.
Authors: Shoukier Mahran , Kantarjian Hagop M. , Cortes Jorge E. , Jabbour Elias , Ravandi Farhad , Garcia-Manero Guillermo , Kadia Tapan M. , Matthews Jairo , Verstovsek Srdan , Borthakur Gautam
Published: March 2020

e18539

Background: Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic phase (CP) chronic myeloid leukemia (CML). Up to have patients with CML may develop grade ≥3 thrombocytopenia, leading to treatment interruptions and dose reductions. Similarly, management of thrombocytopenia in myelofibrosis (MF) can be challenging because the condition may result in dose adjustments and interruptions of ruxolitinib. Methods: We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia during therapy with a TKI or ruxoltinib. We enrolled 15 CML patients with persistent grade ≥3 thrombocytopenia (platelets ≤50 x 109/l) and six MF patients with platelets < 100 x 109/l after at least 3 months of therapy with a TKI or ruxolitinib. Patients received eltrombopag at a starting dose of 50 mg daily, with dose escalation to a maximum of 300 mg daily according to platelet response. Patients were followed with a weekly complete blood count until a stable platelet count was achieved. The target response was a complete response, defined as a platelet count ≥50 x 109/l for CML and ≥100 x 109/l for MF in at least 30% of subjects, sustained for 3 months while continuing TKIs or ruxolitinib therapy. Results: We enrolled 21 patients (CML = 15, MF = 6), with a median age of 60 years (range, 31-99 years). The median platelet count was 44 (range, 3-49) in patients with CML and 62 (range, 25-91) in those with MF. After a median duration of treatment of 18 months (range, 5-77 months), 11 of the 15 patients with CML achieved a complete platelet response at eltrombopag doses of 50–300 mg per day. The median peak platelet count among responders was 133 (range, 6-1225) x 109/l. Nine patients with CML experienced an improvement in cytogenetic response. In 5 patients with CML, the TKIs dose was increased and maintained while continuing eltrombopag. None of the 5 patients with MF had a sustained increase in platelet count to ≥100 x 109/l. No progression of disease was documented in any patient. Therapy was generally well tolerated. One patient (CML) discontinued therapy secondary to toxicity (persistent transaminitis with an accompanying lack of response). Conclusions: Eltrombopag demonstrated clinical efficacy in some patients with CML who were treated with TKIs. No similar benefit was observed in patients with MF who were treated with ruxolitinib. Eltrombopag might be a useful adjunct for patients with CML experiencing persistent thrombocytopenia. Clinical trial information: NCT01428635.
Feasibility of brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in children and adolescents (< 18 years) with early relapse Hodgkin lymphoma.
Authors: Fernandez Karen S. , Mavers Melissa , Chang-Halpenny Christine N. , Titapiwatanakun Ruetima , Baker Katherine , Pugmire Brian , Tcheng Wendy , Agarwal-Hashmi Rajni
Published: March 2020

e19012

Background: High-dose therapy followed by autologous stem-cell transplantation (ASCT) is standard of care for patients with relapsed Hodgkin lymphoma (HL). Approximately 50% of relapsed HL patients are cured after ASCT. However, most patients with unfavorable risk factors (refractory disease, early relapse < 12 months and extranodal involvement prior to ASCT) progress after ASCT. Brentuximab Vedotin (BV) improves progression-free survival (PFS) when given as early consolidation after ASCT in adults. In pediatrics, the use of consolidative BV for relapsed HL has not been studied. Methods: Retrospective review of relapsed HL patients who received post ASCT consolidative BV from January 2016 to January 2017. We evaluated time of relapse, sites of involvement, presence of extranodal disease, clinical response after salvage therapy, response, PFS and BV toxicity. Results: During the study period 6 patients (age 12 -18 years) had relapsed HL. Of those, five had high risk (IIIB n = 1 , IVA n = 2, IVB n = 2) and one intermediate risk (IIA) disease. All had disease progression 0 – 3 months after completion of frontline therapy. High risk patients received ABVE-PC regimen and intermediate risk received Stanford V. Four patients received radiation therapy (RT) based on anatomical response as per protocol. Following relapse, 2 cycles of salvage Gemcitabine and Vinorelbine was given to 5 patients. Due to partial response, two of these patients received 2 additional cycles of BV-Bendamustine. One patient was re-induced with BV-Gemcitabine. FDG-PET/CT status prior to ASCT was negative for all 6 patients (Deauville score equal to or less than 3). High dose therapy prior to ASCT consisted of BEAM or BEC. Four patients received additional RT. All patients received consolidative BV every 3 weeks up to 16 cycles. Two patients experienced grade 3 motor and sensorial neuropathy and discontinued BV after 12 cycles. Two patients experienced grade 3 neutropenia. At present the PFS for the six patients is 12, 16, 23, 24, 28 and 30 months. Conclusions: Early consolidation with BV after ASCT is feasible in patients less than 18 years of age. Toxicity included grade 3 peripheral neuropathy and neutropenia. Larger studies are needed to determined safety and efficacy of consolidative BV post ASCT.
A phase I/II study of the anti-programmed cell death-1 (PD-1) antibody AK105 in patients with relapsed or refractory classic Hodgkin lymphoma (cHL).
Authors: Song Yuqin , Zhu Jun , Lin Ningjing , Zhang Chen , Jin Xiaoping , Xu Shuping , Li Baiyong , Xia Yu
Published: March 2020

e19017

Background: AK105 is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1 allowing T-cells to recognize and kill tumor cells. Key attributes of AK105 include antibody engineering to eliminate Fc mediated effector function, and a slower off-rate on antigen binding resulting in improved receptor occupancy. These features were designed to offer more robust biological effect and enhance anti-tumor activity of AK105. Methods: A multicenter, Phase I/II, single-arm study in relapsed/refractory cHL (NCT03722147) began in July, 2018, evaluating the safety and efficacy of AK105 administered IV q2w till disease progression (response assessed by Lugano 2014 criteria). Eligible pts had relapsed/refractory cHL after most recent therapy with progression after autologous hematopoietic stem cell transplantation, or at least 2 lines of prior chemotherapy. Enrollment for Phase I part of the study was completed, and Phase II at the RP2D of AK105 200 mg q2w is ongoing. Results: As of 1 Feb, 2019, in the Phase I part, 6 Chinese patients (pts) median age 26.5 years [19–38], female 33%, ECOG 0/1 ([67%/33%]), had received a median of 7 (3–12) doses of AK105 200mg q2w. No DLT and SAE were reported. No immune-related grade 2 (G2) or higher adverse reactions were reported. Treatment-related adverse events (TRAEs) occurred in 83% (5/6) of pts (G3 in 17% [1/6], no G4, none leading to treatment interruption or discontinuation). Most frequent TRAEs (≥2 pts) were hypothyroidism (33%, 2/6) and ALT increased (33%, 2/6). PK profile for Chinse pts is consistent with that in Caucasian pts. Of 5 evaluable heavily pretreated pts, ORR was 100% (5/5, 3 CR and 2 PR). All 3 pts achieved CR at the first tumor assessment (i.e., week 8) and remained in CR at the last assessment (i.e., week 24) prior to data cutoff. The other 2 pts achieved PR at week 8 and the responses are still ongoing. Conclusions: The reported safety profile and encouraging early antitumor activity of AK105 supports continued clinical development, which include: pivotal studies in relapsed/refractory cHL and metastatic nasopharyngeal carcinoma, phase 2/3 combination studies with chemotherapy in NSCLC and combination study with anlotinib, a multi-targeting tyrosine kinase inhibitor in hepatocellular carcinoma. Clinical trial information: NCT03722147.
NHL and rituximab biosimilar: How have prescribing behaviours changed in EU5 in 15 months?
Authors: Franceschetti Alessandra
Published: March 2020

e19054

Background: 15 months after EMA approval of the first rituximab biosimilar to treat NHL – and 12 months on from our presentation on its initial impact at the Biosimilars Special Clinical Symposium of ASCO 2018 – this study tracks the real world impact of official endorsement on prescribing behaviour and biosimilar adoption for NHL. Methods: The Ipsos Global Oncology Monitor – an online multi-country, multi-centre medical chart review of NHL patients, where 138 geographically representative physicians provided de-identified data on 3,239 patients treated with anti-cancer drugs in France (565), Germany (379), Italy (622), Spain (684) and UK (989) from July 2017 to Sept 2018. Physicians provided diagnosis date, current and historic treatment and reasons for prescribing treatment. Data on patients treated with and without a rituximab biosimilar were compared using descriptive statistics. Results: While prescribing of the rituximab molecule was stable over the study period, prescribing of rituximab biosimilars significantly increased – from 7% to 35% (p < 0.01), most notably in Germany and UK. By Q3 2018, for those patients treated with a rituximab-including regimen (N = 483), prescribing of any EMA-approved rituximab biosimilar was 72% in Germany and 63% in UK; France, Italy and Spain reported 47%, 32% and 30%, respectively. Physicians were significantly more likely to state “Well tolerated” and “Proven efficacy” as reasons for prescribing rituximab biosimilars in Q3 2018 vs Q3 2017 (p < 0.01). Prescribing of branded rituximab in the SC formulation significantly increased, from 21% to 33% (p < 0.01). Rituxan prescribing may be partially driven by availability of the SC mode of administration (MoA) not available for biosimilars. Conclusions: Over time, prescribing of rituximab biosimilars has significantly increased in the EU5, mainly in Germany and UK. Growth is less evident in Italy and Spain, perhaps as Southern physicians are historically more averse to ‘generic’ versions. Physicians’ ongoing experience of mAb biosimilars has resulted in higher associations with “Well tolerated” and “Proven efficacy”. The rise in prescribing Rituxan with the SC MoA has likely contained an even higher prescribing of rituximab biosimilars.
Cause-specific mortality in survivors of lymphoplasmacytic lymphoma (LPL) and waldenstrom macroglobulinemia (WM).
Authors: Dalal Nicole H. , Dores Graca , Curtis Rochelle E. , Linet Martha S. , Morton Lindsay M.
Published: March 2020

e19056

Background: LPL and WM are rare, indolent mature B-cell lymphomas. While recent studies reveal improving survival after LPL/WM, cause-specific mortality has not been comprehensively studied. Methods: We identified 6659 adults with first primary LPL (n = 2866) or WM (n = 3793) within 17 US population-based cancer registries from 2000 to 2015. Patients were followed for vital status (mean follow-up = 5.07 years), and causes of death were determined from death certificates. Standardized mortality ratios (SMRs) estimated relative risk of death compared to the general population. We estimated cumulative mortality and absolute excess risk (AER) per 10,000 person-years. Results: We observed 2826 deaths overall, of which 43%, 13%, and 42% were due to lymphoma, cancers excluding lymphoma, and non-malignant causes, respectively. There was a 20% higher risk of death due to non-malignant causes compared to the general population (n = 1194, SMR = 1.2, 95% confidence interval [CI] = 1.1 to 1.2). The most common non-malignant causes included infectious (n = 162, SMR = 1.8, 95% CI = 1.5 to 2.1, AER = 21.0), respiratory (n = 131, SMR = 1.2, 95% CI = 1.0 to 1.5, AER = 7.4), and digestive (n = 76, SMR = 1.9, 95% CI = 1.5 to 2.4, AER = 10.7) diseases. Cause-specific mortality varied by time since and age at LPL/WM diagnosis. Risks were highest in the first year after LPL/WM for non-malignant causes (SMR = 1.4, AER = 34.3), particularly infections (SMR = 2.4, AER = 34.4) and non-neoplastic hematologic diseases (SMR = 17.3, AER = 20.7). In contrast, risk of death due to cancers excluding lymphoma increased with time since diagnosis (SMR< 1y = 1.2, SMR≥5y = 1.7; AER< 1y = 15.1, AER≥5y = 60.0). Analyses by age, focused on AERs, showed generally similar risks across age groups (cancers excluding lymphoma: AER< 65= 26, AER65-75= 28, AER≥75= 31; non-malignant causes: AER< 65= 52, AER65-75= 66, AER≥75= 23). Cumulative mortality from non-malignant causes (23.7%) exceeded that from lymphoma (22.9%) beginning 9 years after LPL/WM diagnosis. Conclusions: Using population data, we identified areas to improve survivorship care of LPL/WM patients, particularly for non-malignant causes of death.
The presence of bone marrow fibrosis is associated with poorer prognosis in newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors.
Authors: Paul Barry , Loitsch Gavin , Feinberg Daniel , Barak Ian , Li Zhiguo , Wang Endi , Zhao Yue , Dupuis Megan , Kang Yubin
Published: March 2020

e19514

Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved significantly with the advent of the immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs). While the presence of bone marrow fibrosis (BMF) has previously been associated with poor prognosis in multiple myeloma (MM), these studies were small and conducted prior to the widespread use of IMiDs and PIs. Here, we determined the incidence of BMF in NDMM patients and correlated the degree of BMF with prognosis in a population enriched for IMiD and/or PI exposure. Methods: Bone marrow biopsies from 306 MM patients seen at Duke between 2003 and 2013 were screened for BMF using a reticulin stain. Samples were scored as absent, mild, moderate, or severe fibrosis based on the degree and intensity of staining. The association between presence and degree of BMF to progression free survival (PFS) and overall survival (OS) was calculated using Kaplan-Meier analysis. Results: Of the 306 patients evaluated, 248 (81.0%) were treated with an IMiD, 241 (78.8%) were treated with a PI, and 217 (70.9%) received both. Additionally, 160 (52.3%) patients went on to receive an autologous stem cell transplant (HSCT). A total of 193 patients (63.1%) were evaluable for BMF. Of these, 96 (49.7%) had detectable BMF, while 97 (50.3%) had no BMF. The degree of BMF was mild in 60 patients (62.5%), and moderate or severe in 34 patients (35.4%). Median PFS in patients without BMF was 30.4 months, and 21.8 months in patients with BMF present (log-rank p = 0.02). Median OS was 61.1 months in patients without BMF, and 46.3 months in patients with BMF (log-rank p = 0.048). Patients with moderate or severe BMF had a particularly poor prognosis with a PFS of only 18.8 months and an OS of 32.7 months. Conclusions: Our study represents the largest dataset to date examining the incidence of BMF in MM patients, and is the only one to examine the association of BMF with prognosis in the era of novel therapies and widespread use of HSCT. Our data suggests that BMF is common in NDMM, and MM patients with BMF (particularly those with more extensive BMF) have a poorer prognosis even when treated with IMiDs and PIs. These data emphasize the importance of determining the presence and degree of BMF at time of MM diagnosis, and suggest a role for adjunctive therapies that target BMF in MM patients with co-existing BMF.
Carfilzomib-lenalidomide-dexamethasone in the management of lenalidomide-refractory multiple myeloma.
Authors: Cerchione Claudio , Martinelli Giovanni , Nappi Davide , Pareto Anna Emanuele , Di Perna Maria , Ferrara Katia , Pane Fabrizio , Catalano Lucio ,   Myeloma Cerchione Team
Published: March 2020

e19522

Background: Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, whose prognosis is particularly severe. Methods: 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2-18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results: According to IMWG criteria, after a median follow-up of 9 months (r. 2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39% (16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients. Conclusions: Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT.
Postoperative radiotherapy for stage II or III non–small cell lung from 1988 to 2014.
Authors: Chen Dawei , Li Yintao , Jing Wang , Yu Jinming , Xing Ligang
Published: March 2020

e20013

Background: In 2006 ASCO, Brian E. Lally et al. reported the association between survival and postoperative radiotherapy (PORT) in patients with resected non–small-cell lung cancer (NSCLC). We now undertook a update analysis using the latest data. Methods: Updated data were obtained by the Surveillance, Epidemiology and End Results database. We analyzed stage II or III NSCLC patients diagnosed between 1988 and 2014. Results: A total of 20645 patients were selected, with a median follow-up time of 3.3 years. Predictors for the use of PORT included age less than 50 years, higher AJCC stage, T3-4 tumor stage, larger tumor size, advanced node stage, greater number of lymph nodes involved, and a higher ratio of lymph nodes involved to lymph nodes sampled. On multivariate analysis, male sex, older age, T3-4 tumor stage, N2 node stage, fewer sampled lymph nodes, higher positive lymph nodes and higher ratio of lymph nodes involved to lymph nodes sampled had a negative impact on survival. PORT had a significant adverse effect on survival, regardless of all patients (P < 0.001), or N0 subgroup ( P< 0.001) or N1 subgroup (P< 0.001). For N2 subgroup, PORT did not have a significant effect of on survival (P < 0.117). This is different from the result Brian E. Lally et al. reported in ASCO 2006. Conclusions: Postoperative radiotherapy is detrimental to resected N0 or N1 NSCLC patients and should not be used routinely for such patients. The role of postoperative radiotherapy in the treatment of N2 tumours is not clear and may warrant further research.