bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective study to measure the impact of MMprofiler on treatment intention in newly diagnosed multiple myeloma patients (PROMMIS).
Authors: Hari Parameswaran , Lentzsch Suzanne , Siegel David Samuel DiCapua , Usmani Saad Zafar , Dhakal Binod , Rossi Adriana C. , Rosenbaum Cara Ann , Leng Siyang , Bhutani Divaya , Biran Noa , Vesole David H. , Bhutani Manisha , Stork-Sloots Lisette , De Snoo Femke , Dumee Belinda C. , Van Vliet Martin , Niesvizky Ruben
Published: March 2020

8030

Background: Multiple Myeloma (MM) is recognized as a heterogeneous group of patients with varying response and outcome of their disease, associated with various risk factors including genetic aberrations. Risk adapted treatment strategies are beginning to emerge (e.g. mSMART), which include gene expression signatures. SKY92, a 92-gene prognostic signature, classifies MM patients as “high” or “standard” risk. It has been reported to be a robust predictor for Overall and Progression Free Survival (Kuiper 2012, 2015). Here we report the preliminary impact of SKY92 on risk classification and treatment intention decisions in newly diagnosed MM patients enrolled in the PRospective Observational Multiple Myeloma Impact Study (PROMMIS). Methods: Patients with MM had their BM aspirate analyzed using the MMprofiler with SKY92. The physician completed questionnaires with his/her treatment intention, before and after knowing SKY92 results. Results: 39 MM patients were enrolled from 5 US centers. The SKY92 signature classified 15 patients (38%) as high risk. Prior to knowing SKY92 results, physicians regarded 20 (51%) patients as clinically high risk, for whom SKY92 indicated 12 patients to be standard risk. Upon revealing SKY92, 8 patients were then considered standard risk by the physician. For 2 patients with concordant high risk classification results, the confirmation of the risk classification was considered helpful. The impact of treatment intention decisions in clinical high risk patients was 40% (8 out of 20). In the 19 patients (49%) that were regarded clinically standard risk prior to knowing SKY92, SKY92 indicated 7 patients to be high risk. Physicians agreed to this classification. For 4 patients with concordant risk classification, the confirmation was found helpful. The impact of treatment intention decisions in clinical standard risk patients was 37% (7 out of 19). Conclusions: Preliminary results from the PROMMIS trial indicate that SKY92 impacts the physician’s treatment intention for 38% of patients with newly diagnosed MM. Moreover, the physicians found the SKY92 result useful for 54% of the patients. This underlines the relevance and need for assessment of SKY92 in MM patients, and associated risk stratified treatment paradigm. Clinical trial information: NCT02911571.
Upstaging the R-ISS classification of newly diagnosed multiple myeloma (NDMM) patients (pts) by quantifying circulating clonal plasma cells (cPCs) via multiparametric flow cytometry (MFC).
Authors: Gonsalves Wilson I. , Jevremovic Dragan , Dispenzieri Angela , Buadi Francis , Dingli David , Lacy Martha , Kapoor Prashant , Lin Yi , Kourelis Taxiarchis , Muchtar Eli , Lust John Anthony , Russell Stephen J. , Go Ronald S. , Hayman Suzanne R. , Leung Nelson , Zeldenrust Steven R. , Kyle Robert A. , Gertz Morie A. , Rajkumar S. Vincent , Kumar Shaji
Published: March 2020

8031

Background: Our prior studies identified the prognostic significance of ≥400 cPCs/150,000 analyzed events quantified by MFC in NDMM. We evaluated if a similar quantification of cPCs using MFC can add prognostic value to the current R-ISS classification of NDMM pts. Methods: We evaluated all NDMM pts seen at the Mayo Clinic, Rochester from 2009-2017 who had their peripheral blood samples evaluated by 6-color MFC prior to therapy. The cPCs detected were reported as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 566 consecutive pts with NDMM with a median age of 66 years (27-95). The distribution of the R-ISS classification of this cohort is as follows: Stage 1- 128 (23%) pts, Stage 2- 369 (65%) pts and Stage 3- 69 (12%) pts. The median number of cPCs was 59 (0-46,412) / 150,000 events. The median time-to-next-treatment (TTNT) and overall survival (OS) for pts with ≥400 cPCs (n = 140, 25%) was 19 months and 46 months compared with 34 months and 77 months for those with < 400 cPCs respectively (n = 426, 75%) (p < 0.001 for both). The median TTNT and OS for pts based on their R-ISS classification as well as with and without the presence of ≥400 cPCs by MFC was as follows in the following Table. Conclusions: Quantifying ≥400 cPCs/150,000 analyzed events by MFC can potentially upstage the R-ISS classification of a subset of NDMM pts with stage I and II disease and identify those pts with a worse than expected survival outcome.[Table: see text]
S1206: A dose-finding study followed by a phase II randomized placebo-controlled trial of chemoradiotherapy (CRT) with or without veliparib in stage III non-small cell lung cancer (NSCLC).
Authors: Argiris Athanassios , Miao Jieling , Cristea Mihaela C. , Chen Allen M. , Sands Jacob , Decker Roy H. , Gettinger Scott N. , Daly Megan Eileen , Faller Bryan A. , Albain Kathy S. , Yanagihara Ronald H. , Garland Linda L. , Byers Lauren Averett , Wang Ding , Koczywas Marianna , Redman Mary Weber , Kelly Karen , Gandara David R.
Published: March 2020

8523

Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were randomized to receive concurrent CRT with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) with V at 120 mg or placebo (P) twice daily during CRT followed by 2 cycles (every 21 days) of consolidation carboplatin (AUC 6), paclitaxel (200 mg/m2) with V at 80 mg or P (per randomized arm) orally on days 1-7 of each cycle. Progression-free survival (PFS) was the primary endpoint. The accrual goal was 132 patients. Results: The dose-finding study results were previously presented (ASCO 2016;A8537). V 120 mg twice daily was the recommended phase II dose. A total of 31 eligible and evaluable patients were enrolled in the phase II randomized trial: 17 on V and 13 on P (1 patient in the V arm withdrew prior to starting any treatment, thus was not evaluable). The study was closed to accrual early due to the positive results from the PACIFIC trial that changed standard practice. Median follow-up among alive patients was 16 months. During CRT, the following grade (G) 3-4 adverse events (AE) were seen with V vs P: any G3 AE (6 vs 6), any G4 AE (2 vs 3), G3 pneumonitis (0 vs 1), G3 esophagitis (1 vs 1), G3 oral mucositis (1 vs 0), G3 anorexia (1 vs 1), G3 hyponatremia (0 vs 3), G3 anemia (1 vs 0), G3 neutropenia (3 vs 1), G3 thrombocytopenia (1 vs 0), G4 hypoglycemia (0 vs 1). Also, 2 patients per arm had G4 lymphopenia. During consolidation (11 evaluable patients with V; 10 with P), G3 anemia (1 vs 0), G3 anorexia (1 vs 0), G3 weight loss (0 vs 1), G3 dehydration (1 vs 0), G3 dysphagia (2 vs 0), G3 fatigue (1 vs 0), G3 hypomagnesemia (0 vs 1), G3 nausea (1 vs 0), G4 hyperglycemia (0 vs 1), G3-4 neutropenia (3 vs 0), G3 thrombocytopenia (1 vs 0), G3-4 lymphopenia (2 vs 1); a G5 pneumonitis occurred in the P arm. Response rates were 56% (95% CI, 31-78%) and 69% (95% CI, 38-91%) on the V and P arms, respectively. PFS at 1 year was 47% (95% CI, 23% - 68%) with V and 46% (95% CI, 19% - 70%) with P. Overall survival (OS) at 1 year was 89% (95% CI, 61%-97%) with V and 54% (95% CI, 25%-76%) with P. Adding the 6 patients treated at 120 mg in the phase I part, 1-year with V was 91% (95% CI, 69%-98%). Conclusions: V in combination with CRT was tolerable with expected toxicities that relate to the backbone regimen. In the small number of randomized patients there was a suggestion of promising survival with V that may provide rationale for future trials of PARP inhibitors with CRT. Clinical trial information: NCT01386385.
Oncologic outcomes of segmentectomy versus lobectomy for radiologically aggressive small-sized lung cancer.
Authors: Kamigaichi Atsushi , Tsutani Yasuhiro , Mimae Takahiro , Miyata Yoshihiro , Imai Kentaro , Ito Hiroyuki , Nakayama Haruhiko , Ikeda Norihiko , Okada Morihito
Published: March 2020

8525

Background: Despite increasing evidence of favorable outcomes after segmentectomy for indolent lung cancer, such as ground glass opacity-dominant tumors, the adaptation of segmentectomy for radiologically aggressive lung cancer remains controversial. We attempted to elucidate oncologic outcomes after segmentectomy for radiologically aggressive lung cancer. Methods: Data from a multicenter database of 1353 patients with completely resected clinical Stage IA1–IA2 lung cancer at three institutions were retrospectively analyzed to identify radiologically aggressive lung cancer and compare outcomes of segmentectomy versus lobectomy in patients with radiologically aggressive lung cancer using propensity score matching. Results: Multivariable analysis showed that consolidation to maximum tumor (C/T) ratio on preoperative high-resolution computed tomography ( P= 0.037) and maximum standardized uptake value (SUVmax) on 18-fluorodeoxyglucose positron emission tomography/computed tomography ( P= 0.029) were independent predictors of recurrence-free survival (RFS). The criteria for radiologically aggressive lung cancer were determined as C/T ratio ≥ 0.8 or SUVmax ≥ 2.5, for which 522 patients were identified. RFS and overall survival (OS) were significantly worse in patients with aggressive lung cancer (5-year RFS, 83.3%; 5-year OS, 89.4%) than in those without the same (5-year RFS, 97.0%; P< 0.0001; 5-year OS, 97.3%; P< 0.0001). Among patients with aggressive lung cancer, no significant difference in RFS and OS was found between those undergoing lobectomy (n = 392) (5-year RFS, 81.3%; 5-year OS, 88.3%) and segmentectomy (n = 130) (5-year RFS, 90.0%; P= 0.33; 5-year OS, 92.3%; P= 0.76). Among the 111 pairs propensity matched for age, sex, smoking history, solid tumor size, C/T ratio, SUVmax, tumor location, clinical stage, and histology, similar RFS and OS were found between those undergoing lobectomy (5-year RFS, 83.3%; 5-year OS, 88.3%) and segmentectomy (5-year RFS, 90.9%; P= 0.92; 5-year OS, 94.5%). Conclusions: For radiologically aggressive small-sized lung cancer, oncologic outcomes of segmentectomy were equivalent to those of lobectomy.
Identifying actionable somatic mutations in lung cancer using cell-free DNA from bronchial washing fluid.
Authors: Zhang Xin , Zhang Xinyu , Wang Weiran , Huang Jian'An , Zhou Min , Li Chun , Ye Maosong , Zhao Yancheng , Gong Yuhua , Xu Yaping , Hu Qin , Guan Yanfang , Yang Ling , Xia Xuefeng , Zhang Hua , Ren Tao , Shen Qian , Wang Kai , Hou YY , Yi Xin
Published: March 2020

8528

Background: Bronchial washing is the most common technique for sampling the components of the alveolar space. Here, we evaluated the potential use of bronchial washing fluid (BWF) in liquid biopsy in lung cancer. Methods: This study enrolled 65 lung cancer patients. BWF (separated supernatant and precipitate) samples, peripheral blood lymphocytes (PBL) and formalin-fixed paraffin-embedded tissues were obtained and subjected to next-generation sequencing using a 1021-gene panel. Results: Mutations were identified in 58 (89.2%) of BWF precipitate (BWFp) samples and 64 (98.5%) of BWF supernatant (BWFs) samples, comparing with 61 (93.8%) of tumor tissues. In total, 461 somatic mutations were identified in tissues, of which 331 (71.8%) and 381 (82.6%) were detected in the matched BWFp and BWFs samples. In addition, there were 44.6% of patients carrying actionable variants identified in tissue DNA, including EGFR, ALK, ROS1, RET, etc. (Table). Similarly, there were 40.0% of BWFp samples and 44.6% of BWFs samples identified actionable variants. Moreover, tumor mutation burden (TMB) was also calculated. Nearly 9% of BWFp samples and 23% of BWFs samples were TMB-H (more than 9 mutations per megabase), comparing with 20% of tissues. Significantly, the combined results of three types of samples showed that, 49.2% of patients carrying actionable variants and 24.6% of patients with TMB-H, which suggested more patients benefit from targeted therapy or immunotherapy. Conclusions: In summary, liquid biopsy using BWF showed high potential to identify actionable mutations and to calculate TMB grade of patients with lung cancer, which might be implemented and standardized into clinical use. [Table: see text]
Neutrophil-to-lymphocyte ratio and subsequent recurrence of non-small cell lung cancer patients in remission.
Authors: Chan Abigail Sy , Bentzen Søren , Adashek Michael L , Friedberg Joseph , Culligan Melissa , Khashab Tamara , Miller Kenneth David
Published: March 2020

8533

Background: Baseline neutrophil-lymphocyte ratio (NLR), a surrogate marker for systemic inflammation and immunosuppression, is a well-established prognostic marker in non-small cell lung cancer (NSCLC). This study tests if interim NLR is prognostic in NSCLC patients in remission. Methods: This single-center, retrospective cohort study analyzed 131 NSCLC patients treated from 2010-2015 who achieved complete remission. Patient data included demographics, histologic subtypes, stage, and treatment type. NLR was calculated at baseline and from the first available blood sample during remission. Kaplan-Meier estimates of overall survival (OS) and time to recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox proportional hazards model. Results: Of 131 cases, 63 had subsequently recurred at the last follow up. Mean age was 64 ± 10 years. Histology: adenocarcinoma (60%), squamous cell (33%), and unspecified (7%). Ninety percent were smokers. Thirty-five percent had stage I, 24% had stage II, and 41% had stage III disease. Treatment modalities varied from surgery (28%), chemotherapy (2%), or radiation therapy (10%) alone, or combined (50%). The time from end of treatment, median (range), to the interim NLR was 9.2 months (2.2, 66.7). The baseline and interim median NLR were 2.6 (0.6, 34.0) and 3.1 (0.5, 20.5), respectively. The median follow-up duration was 44 months (5.9, 101). For the univariate analysis interim NLR was binned into tertiles. In multivariable analysis remission NLR remained strongly prognostic for OS (P<0.001) as did patient’s age (P=0.002), but not stage, race, sex, and baseline NLR. Conclusions: Our study found that interim NLR, obtained in remission, was strongly prognostic for OS and recurrence. The results may indicate that even subclinical disease promotes immunosuppression or alternatively that immunosuppression increases recurrence risk. NLR during remission may help identify NSCLC patients at high risk of recurrence and may thus be of value in surveillance of lung cancer survivors. [Table: see text]
Interim safety analysis of consolidation nivolumab and ipilimumab versus nivolumab alone following concurrent chemoradiation for unresectable stage IIIA/IIIB NSCLC: Big Ten Cancer Research Consortium LUN 16-081.
Authors: Yan Melissa , Durm Greg Andrew , Mamdani Hirva , Ganti Apar Kishor , Hrinczenko Borys , Jabbour Salma K. , Feldman Lawrence Eric , Kloecker Goetz H. , Leal Ticiana , Almokadem Salah , Naidoo Jarushka , Fujioka Naomi , Hanna Nasser H.
Published: March 2020

8535

Background: Consolidation PD-1 inhibition after chemoradiation (chemoRT) for unresectable stage IIIA/IIIB NSCLC improves overall survival. The efficacy and safety of combining a CTLA-4 inhibitor with a PD-1 inhibitor in this setting are unknown but may further improve efficacy in this patient population. Methods: In this randomized, multi-center, phase II study, 105 pts with unresectable stage IIIA/IIIB NSCLC will receive chemoRT, then randomize 1:1 to either nivolumab 480mg IV q4 wks (nivo) or nivolumab 3mg/kg IV q2 wks + ipilimumab 1mg/kg IV q6 wks (nivo/ipi), for up to 24 wks. In this interim analysis, we assess the safety of the first 20 patients treated. Results: From 9/2017 to 11/2018, 20 patients were accrued. Characteristics of those treated on the nivo arm (n = 10) were: median age 62 years, stage IIIA/B 7/3; non-squamous/squamous 7/3; and the nivo/ipi arm (n = 10): median age 61 years; stage IIIA/B 6/4; non-squamous/squamous 7/3. Most toxicities were grade 1 or 2 and the most frequently noted grade 2 AEs included fatigue (25%), pneumonia (25%), extremity pain (20%). Adverse events reported in the Nivo only arm included 81 total events with only four grade 3 events and a single grade 4 thromboembolic event. The Nivo/Ipi arm reported 101 total AEs, with only 3 grade 3 events and a single grade 4 toxicity (amylase elevation). With respect to immune-related adverse events (irAEs), in the nivo arm there were two cases of grade 2 pneumonitis and no grade 3/ 4 events. In the nivo/ipi arm, there was one grade 2 pneumonitis, three grade 3 irAEs (pneumonitis, colitis, pancreatitis), and one asympomatic grade 4 amylase elevation. No treatment-related deaths were observed in either arm. Conclusions: There were no unexpected safety signals in the first 20 patients treated on BIG10CRC LUN 16-081. The incidence of grade 3 or higher irAEs was higher in the nivo/ipi arm, as expected, but this was manageable with the use of established guidelines. The study currently remains open to accrual (32 of 105 have been randomized as of 2/8/19). Clinical trial information: NCT03285321.
The spatiotemporal evolution of early-stage non-small-cell lung cancer.
Authors: Wang Siwei , Zhang Jingyuan , Xu Weizhang , Bao Hua , Fan Xiaojun , Jiang Yunlong , Wu Xue , Wang Xiaonan , Shao Yang , Xu Lin , Yin Rong
Published: March 2020

8539

Background: Lung cancer is a genetically heterogeneous disease. The genomic basis of tumorigenesis and cancer cell spread, as well as intratumor heterogeneity (ITH) and subclonal evolutionary patterns might correlate with patients’ clinical outcomes. In this prospective study, we aimed to investigate such associations through comprehensive spatiotemporal genomic profiling in early-stage non-small cell lung cancers (NSCLCs). Methods: We performed deep targeted sequencing (GeneseeqPrime, 425 genes) of 503 primary tumor regions and 141 metastatic lymph node tumors from surgery and 378 longitudinal plasma biopsies (pre- and post-operation) across 128 Stage I-III NSCLC patients. ITH and phylogenetic tree for each patient were analyzed and correlated with clinical outcomes. Longitudinal and phylogenetic ctDNA analyses were further performed. Results: Spatial ITH varied among patients and was associated with clinical phenotypes. Geographical stratification of clonal structure, with localized confinement of subclones, was linked with slower tumor progression. In contrast, early expansion of subclones to multiregions was associated with rapid tumor growth and lymph node metastases. EGFR and TP53 mutations were nearly always clonal, whereas subclonal mutations in PI3K, WNT and TGF-beta pathway that occurred later in evolution were found in more than 50% of the patients. By tracking these phylogenetic events, we identified five evolutionary subtypes with distinct clinical outcomes, including a rare subtype characterized by independent origin of multiple EGFR driver mutations. ctDNA profiling could capture the spatial ITH to a certain extent with additional unique signatures. Further longitudinal and phylogenetic ctDNA analyses indicated early detection of relapse and adjuvant chemotherapy resistance. Conclusions: ITH is a key factor associated with clinical outcomes of early-stage NSCLC patients, which show diverse evolutionary subtypes underpinning the disease progression such as lymph metastasis and relapse. ctDNA sequencing can be used to capture spatial ITH, predict recurrence and track drug resistance.
Retrospective study of capecitabine and temozolomide in advanced lung neuroendocrine neoplasms.
Authors: Al-Toubah Taymeyah E. , Morse Brian , Strosberg Jonathan R.
Published: March 2020

8542

Background: Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently showed significant activity in patients with pancreatic NETs, but data in lung NETs are limited. Methods: We retrospectively reviewed the records of patients treated at a large NET referral center to identify patients seen between 1/2008 and 9/2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Patients who were not seen at the center within the first month of treatment were excluded. Small cell lung cancer patients were also excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression free survival, overall survival, and toxicity. Results: 20 patients were identified who received treatment with capecitabine/temozolomide. 14 (70%) were typical lung NETs, 5 (25%) atypical carcinoids, and 1 (5%) was defined as a large cell neuroendocrine carcinoma. 6 patients (30%) exhibited a best response of PR per RECIST 1.1 criteria, 11 (55%) SD, and 2 (10%) PD. 1 patient died 2 months after starting treatment. 11 eventually progressed (radiographically or clinically), only 6 of whom exhibited progression per RECIST 1.1 criteria. Median PFS was 11 months (95% CI, 6 – 16 months). Median OS was 68 months (95% CI, 35 – 101 months). Toxicity profile was mild with mainly grade 1, expected toxicities. 6 patients required dose reduction due to toxicity (2 for diarrhea and nausea, 1 for hand foot syndrome, 3 for thrombocytopenia). Conclusions: We identified a group of patients with metastatic lung NENs who received treatment with the CAPTEM regimen and exhibited a favorable response rate to treatment with a relatively tolerable toxicity profile. This regimen warrants further exploration in a prospective clinical trial.
Lung cancer diagnosed by an incidental lung nodule program or lung cancer screening.
Authors: Smeltzer Matthew , Stevens Walter , Faris Nicholas Ryan , Kethireddy Jennifer , Meadows Meghan Brooke , Ray Meredith , Epperson Amanda , Adams Kim , Fulford Angela , Wagh Ajay , Machin Jim , Tokin Keith , Optican Rob , Wright Jeffrey , Robbins Edward T , Osarogiagbon Raymond U.
Published: March 2020

8546

Background: Early detection reduces lung cancer (LC) mortality. We prospectively evaluated LC patients diagnosed through Lung Cancer Screening (LCS) or an Incidental Lung Nodule Program (ILNP) (‘early detection’ programs) compared to routinely diagnosed LC patients in a multidisciplinary program (MDP). Methods: We compare demographics, tumor characteristics, and survival between the three groups diagnosed within the same healthcare system from 2015-2018. The ILNP prospectively tracks patients with suspicious lung lesions on routinely-performed studies flagged by radiologists using a standard macro text. LCS used Medicare eligibility criteria. Statistical methods include the chi-square test, Kruskal-Wallis test, and proportional hazards models with hazard ratios (HR) and 95% confidence intervals. Results: ILNP detected 201 lung cancers from 4713 scans (4.3%), LCS yielded 35 lung cancers from 1540 low-dose CT scans (2.3%), while MDC had 926 LC cases not detected by LCS or ILNP. Mean age at diagnosis for ILNP/LCS/MDC was 70/69/67 years (p = 0.0083); African Americans were under-represented in LCS (25%/11%/32%, p = 0.0104). LCS had the highest proportion with commercial insurance (46%/54%/43%, p = 0.3442). Early detection groups were more likely to have adenocarcinoma histology (ILNP/LCS/MDC: 61%/57%/49%, p = 0.0113). Smoking exposure was highest in LCS cohort (mean pack years: 48/64/52, p = 0.0500); 11% of ILNP, 8% MDC patients were never-smokers. Only 36% ILNP and 39% MDC patients were eligible for LCS by NLST criteria and 30%/40% by NELSON criteria. Reasons for ineligibility included smoking status in 73-90% and age in 7-27% of patients. Stage I/II distribution was (66%/58%/21%, p < 0.0001), stage IV 15%/20%/36%; surgical resection rates were (56%/55%/31%, p < 0.0001). Overall survival was longer in early detection groups (LCS HR: 0.31 [0.11,0.82]; ILNP HR: 0.51[0.33,0.81]) compared to MDC (p = 0.0011). Conclusions: The majority of LC patients were ineligible for LCS, but the ILNP identified LC in a high proportion of such patients, with similar stage re-distribution, curative-intent treatment, and survival rates. Structured ILNP complement LCS for early LC detection, such programs need to be built out.
Phase II study of consolidation amrubicin after concurrent chemoradiotherapy for patients with limited-stage small cell lung cancer.
Authors: Yoshida Hironori , Kim Young Hak , Ozasa Hiroaki , Sakamori Yuichi , Nishimura Takashi , Tomii Keisuke , Mio Tadashi , Hirai Toyohiro
Published: March 2020

8555

Background: Concurrent chemoradiotherapy (CCRT) using etoposide and cisplatin has been the gold standard for limited-stage small-cell lung cancer (LS-SCLC) for decades; however, approximately three out of four cases treated by CCRT inevitably relapse. Amrubicin (AMR), a synthetic anthracycline with a structure similar to doxorubicin, has demonstrated strong antitumor activity against relapsed SCLC and has been the standard second-line treatment for SCLC in Japan. We consider consolidation AMR following CCRT to be a potential treatment for patients with LS-SCLC. Methods: In this single-arm, multicenter phase II study, all patients enrolled were treated using induction CCRT consisting of four cycles of etoposide at 100 mg/m2 on days 1-3 and cisplatin at 60 mg/m2 on day 1 every 3 weeks, plus concurrent thoracic radiotherapy (1.5 Gy twice daily, total 45 Gy) concomitant with the first cycle of chemotherapy. Then, eligible patients received three cycles of AMR at 40 mg/m2 on days 1-3 every 3 weeks as consolidation treatment. The primary endpoint was the 2-year progression-free survival (PFS) rate in patients who received consolidation AMR, and the secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), and safety. This study was terminated early due to slow patient accrual. Results: Of the 36 patients who underwent induction CCRT (ITT population), 28 (78%) received AMR as consolidation therapy (consolidation population) and 24 (67%) completed all planned treatments. The 2-year PFS rate and ORR were 35.7% and 86% (8 CR and 16 PR), respectively, in the consolidation population. The median PFS and median OS were 14.3 months (95%CI, 10.8-46.6) and 60.9 months (95%CI, 29.8-NR), respectively, in the consolidation population. In the ITT population, the median PFS and the median OS were 13.4 months (95%CI, 7.5-19.0) and 60.9 months (95%CI, 29.8-NR), respectively. Grade 3/4 toxicities during the consolidation phase included neutropenia (39%), thrombocytopenia (14%), and febrile neutropenia (7%). There were no treatment-related deaths in the ITT population. Conclusions: Consolidation AMR following standard CCRT consisting of etoposide and cisplatin plus concurrent thoracic radiotherapy was feasible, and demonstrated promising efficacy for LS-SCLC. Clinical trial information: 000002352.
Thoracic twice-daily radiotherapy and brain metastasis in patients with small cell lung cancer.
Authors: Zeng Haiyan , Li Rui , Hu Chen , Qiu Guoqin , Ge Hong , Yu Huiming , Zhang Kaixian , Hu Miaomiao , Zeng Peng , Xiao Dan , Miao Chuanwang , Wei Chuqing , Ni Meng , Shen Jingyi , Li Hui , Hu Xudong , Kong Feng-Ming Spring , Yuan Shuanghu , Yu Jinming
Published: March 2020

8560

Background: Although thoracic twice-daily radiotherapy (TDRT) is one of standards of care for small cell lung cancer, its impact on brain metastases remains unknown. This study aimed to compare TDRT with once-daily radiotherapy (ODRT) for the brain metastases rate after prophylactic cranial irradiation in patients with small cell lung cancer. Methods: Consecutive patients received TDRT (45Gy/30f)/ODRT(50-66Gy/25-33f), chemotherapy and prophylactic cranial irradiation were retrieved from eight hospitals’ databases between 2003 and 2016. The endpoints included brain metastases, progression-free survival and overall survival. Brain metastases rate was evaluated using competing risk analysis. A 1:1 propensity score matching approach was used to control confounding between these two groups. Confounding covariates included eight demographic variables and eight treatment related covariates. Results: Of the 778 eligible patients with median age of 55-year (IQR, 48-61), 204 (26.2%) were female. At a median follow-up time of 23.6 months (IQR, 14.2- 38.2), 131 (16.8%) experienced brain metastases. The rates in TDRT were significantly higher than ODRT (3-year, 26.0% vs. 16.9%; HR = 1.55, 95%CI 1.06-2.26, P = 0.03). Of the 338 matched patients (169 in ODRT vs. 169 in TDRT), 60 (17.8%) experienced brain metastases with 3-year rate of 14.9% in ODRT vs 26.0% in TDRT (HR = 1.71, 95%CI 1.02-2.88, P = 0.04). Progression-free survival was similar in both the whole cohort and the matched one. Overall survival in ODRT tended to be significantly longer after matching (median, 47.2 months in ODRT vs. 32.8 months in TDRT; HR = 1.41, 95%CI 0.99-2.01, P = 0.06). When jointly evaluated biologically effective dose (BED), start of any therapy to the end of radiotherapy (SER) and TDRT/ODRT in the multivariable analysis, the impact of ODRT/TDRT on overall survival become more significant (HR = 1.69, 95%CI 1.05-2.71, P = 0.03). Conclusions: Patients with small cell lung cancer who were treated with thoracic TDRT appeared to have higher risk of brain metastases than those with ODRT, which strongly supports the need for further prospective randomized clinical trials, especially in China or other parts of Asia.
Progression free survival and time to local failure after radiosurgery of pleural metastases in twenty-two patients with thymomas.
Authors: Pasquini Giulia , Chella Antonio , Menichelli Claudia , Lucchi Marco , Fabrini Maria Grazia , Maestri Michelangelo , Ricciardi Roberta , Cappelli Sabrina , Petrini Iacopo , de Rosa Anna , Guida Melania , Lucchesi Maurizio
Published: March 2020

8565

Background: Thymomas but not thymic carcinomas can benefit of cytoreductive surgery even if a complete resection is not achievable. Surgical resection of pleural metastases, the most common site of progression, can be performed in selected patients. We evaluated the outcome of stereotactic body radiation therapy (SBRT) for treatment of pleural metastases in patients’ not eligible for surgery. Methods: We retrospectively identified 22 patients treated with SBRT for pleural metastases between 2004 and 2019. According to RECIST criteria, time to local failure and progression free survival (PFS) were calculated using Kaplan-Meier estimation. Results: Twelve of the 22 patients were male. The median age was 40 years (range 29-73). There were 1 A, 3 AB, 3 B1, 3 B2, 3 B2/B3 and 9 B3 thymomas. The Masaoka stage at diagnosis was IIA in 2, IIB in 7, III in 5, IVA in 7 and IVB in 1 patient. Pleural metastases and primary tumor were synchronous in 8 patients. Thymectomy was performed in 21 patients. Seven patients received pre-operative chemotherapy and 12 post-operative radiotherapy. One patient received chemotherapy and radiotherapy after a macroscopically incomplete thymectomy. Five patients had a single pleural metastatic site and 17 presented multiple localizations. Sixteen patients received SBRT on multiple sites of pleural metastases. At the time of the analysis a patient received SBRT exclusively on one of 3 pleural metastases. The median dose of radiation was 30Gy (range 25-40) given in 3 fractions. Ten patients experienced a progression of treated lesions with a median time to local failure of 25.5 months (95%CI 20.9-30.1). The median PFS was 20.4 months (95%CI 10.7-30). There were not significant differences in PFS between patients diagnosed with synchronous and metachronous metastases (p=0.477), across those treated with chemotherapy or naive (p=0.189) and between those who received or not a previous surgical resection of the pleural metastases (p=0.871). Conclusions: SBRT of pleural metastases is feasible and offer an interesting local control of diseases. The impact of this treatment on patients’ survival is hardly predictable because of the heterogenous clinical behavior of thymomas.
A phase II study of talazoparib (BMN 673) in patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer (Lung-MAP Sub-Study, S1400G).
Authors: Owonikoko Taofeek Kunle , Redman Mary Weber , Byers Lauren Averett , Hirsch Fred R. , Mack Philip C. , Schwartz Lawrence Howard , Bradley Jeffrey D. , Stinchcombe Tom , Leighl Natasha B. , Al Baghdadi Tareq , Lara Primo , Miao Jieling , Kelly Karen , Ramalingam Suresh S. , Herbst Roy S. , Papadimitrakopoulou Vassiliki , Gandara David R.
Published: March 2020

9022

Background: This signal finding study was designed to evaluate the clinical efficacy of a PARP inhibitor, talazoparib, in advanced stage squamous cell lung cancer harboring HRRD. Methods: Eligible patients (pts) identified through the parent S1400 screening platform were required to have a deleterious mutation in any of the study-defined HRR genes [ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1) defined as the full eligible population (FEP). The primary analysis population (PAP) is defined by a subset of genes [ATM, ATR, BRCA1, BRCA2, PALB2]. Pts have platinum sensitive disease (at least stable disease on platinum doublet) and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, and not have been previously exposed to a PARP inhibitor and not be on systemic therapy within 21 days of registration. A 2-stage design with exact 93% power and 1-sided 0.07 level type I error required enrollment of 40 patients in the PAP in order to rule out an ORR of 15% or less if the true ORR is 35% or greater. At least 3 or more responses were needed in the first 20 pts in order to proceed to full enrolment of 40 pts in the PAP. The total accrual goal was 60 FEP assuming 67% of patients would be in the PAP. Results: The study enrolled 51 patients of whom 47 are eligible and analyzable for response (FEP) with 24 in the PAP. In the FEP, median age 66.7 yrs; M/F 39/8 (83/17%); 85% White and 15% Black; 77% of the pts received at least 1 prior line of treatment for stage IV. The study was closed for futility with only one response in the PAP. In the PAP (n = 24, median age 68 yrs), ORR was 4% (95%CI: 0, 21) and DCR was 54% (95%CI: 33, 74); median PFS of 2.4 months (95%CI: 1.5-2.8) and median OS was 5.2 months (95%CI: 3.8-10, 7). There were five responders in the FEP with ORR of 11%; DCR of 53% and median DoR was 1.8 months (95% CI: 1.3, 4.2); median PFS was 2.5 months (95%CI: 1.6-3.0) and median OS was 5.7 months (95% CI: 4.5-8.7). The most frequent grade ≥3 adverse event in the FEP were: Anemia (14.9%), thrombocytopenia (12.8%); lymphopenia (8.5%) and nausea (6.4%). Conclusions: S1400G failed to show sufficient level of efficacy for talazoparib in a biomarker defined subset of squamous lung cancer with HRRD. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Clinical trial information: NCT02154490.
Time from stereotactic body radiotherapy to immunotherapy as a predictor for outcome in metastatic non small cell lung cancer.
Authors: Wegner Rodney E , Abel Stephen , Hasan Shaakir , White Richard , Finley Gene Grant , Monga Dulabh , Colonias Athanasios , Verma Vivek
Published: March 2020

9024

Background: Immunotherapy has changed the face of treatment for stage IV non small cell lung cancer (NSCLC), quickly becoming the standard of care. The appropriate timing of immunotherapy in the setting of other ablative therapies, namely stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), remains to be determined. We sought to use the National Cancer Database to examine trends in immunotherapy use as well as timing as it relates to SBRT/SRS in stage IV NSCLC patients. Methods: We queried the NCDB for patients with Stage IV NSCLC diagnosed between 2004-2015 that were treated with SRS or SBRT techniques (to any site) and had at least three months of follow up. Multivariable logistic regression was used to identify predictors of immunotherapy use. Receiver operator curve analysis was used to identify the optimal timepoint between SBRT and immunotherapy correlating with overall survival. Kaplan-meier curves were generated to determine overall survival. Multivariable cox regression was used to determine factors predictive of survival. A propensity score was generated and incorporated into Kaplan-meier and cox regressions to account for indication bias. Results: We identified 13,862 patients meeting the above eligibility criteria, 371 being treated with immunotherapy. The vast majority (75%) had chemotherapy as well. Patients with adenocarcinoma, treatment with chemotherapy, and more recent year of treatment were more likely to receive immunotherapy. Univariable Kaplan-meier analysis showed improved median survival with immunotherapy, 17 months vs. 13 months, p < 0.0001. On multivariable propensity-adjusted cox regression significant predictors for improved overall survival were younger age, lower comorbidity score, lower grade, private insurance, and female gender. Using a cutoff of 21 days after start of SBRT, patients treated thereafter were more likely to survive longer, median survival of 19 months vs 15 months, p = 0.0335. Conclusions: Immunotherapy use in Stage IV NSCLC after SBRT has increased over time, mostly in patients with adenocarcinoma and in the setting of chemotherapy. In this analysis, outcomes were improved when immunotherapy was given at least three weeks after start of SBRT.
Phase Ib study: Selective histone deacetylase (HDAC) inhibitor ACY-241 + nivolumab (Nivo) in advanced non-small cell lung cancer (NSCLC).
Authors: Awad Mark M. , Le Bruchec Yvan , Lu Brian , Miller Julieann , Dumitru Calin Dan , Spira Alexander I.
Published: March 2020

9029

Background: Identification of new regimens for patients (pts) with relapse/refractory NSCLC is an ongoing need. HDAC inhibitor monotherapy has cytostatic activity in pts with NSCLC. The HDAC6 inhibitor ACY-241 has immunomodulatory activity and may synergize with immune checkpoint inhibitors (ICI). This phase Ib study investigated ACY-241 + nivo in metastatic NSCLC. Methods: Previously platinum-treated, ICI-naïve pts with advanced NSCLC and ECOG PS ≤ 1 were eligible. In 3 + 3 dose-escalation, pts received ACY-241 (180, 360, or 480 mg PO; d 1-28) + nivo 240 mg on d 15 of cycle 1 and d 1,15 subsequently in 28-d cycles. Primary outcomes: safety and RP2D. Secondary outcome: antitumor activity. Exploratory outcome: biomarker analyses; peripheral blood samples and tumor biopsies were collected pre- and on-treatment. Results: As of Jan 17, 2019, 18 pts were treated. Median age 66 y; 56% male, 78% PS 1, 93% stage IV, 28% PD-L1–negative, and 89% adenocarcinoma (11% squamous). No DLTs were observed at ACY-241 180 or 360 mg, and 2 DLTs were observed at 480 mg (gr 3 nausea lasting > 72 h despite medication; gr 5 cardiac arrest); 360 mg was declared RP2D. Common all-grade AEs: fatigue (22%), arthralgia (17%), and cough (17%); 1 gr 3 cerebrovascular accident (related to brain metastasis unrelated to study drug) and 1 additional gr 5 AE (myasthenia gravis, possibly related to ACY-241 and nivo) occurred. Of 13 response-evaluable pts, 8 had clinical benefit (1 CR, 3 PR [1 PD-L1–negative], 1 unconfirmed PR [tumor shrinkage followed by new lesion], 3 SD); 5 had PD. At data cutoff, treatment was ongoing in 5 pts (12 – 30 cycles). Histone and tubulin acetylation levels were transiently increased after treatment. Circulating IL-2, IL-1β, MMP-9, and IL-10 levels increased, with undetectable TNF-α and IFN-γ modulation. Treatment-related changes in tumor-infiltrating Treg, MDSC, TCM, and macrophages varied between pts but revealed a trend of increased infiltrating cytotoxic T and NK cells. Conclusions: The ACY-241 + nivo combination is feasible and can be considered for further research as a potential NSCLC treatment option. Biomarker analyses may help identify an optimal population for the combination. Clinical trial information: NCT02635061.
The impact of sequential therapy of crizotinib followed by alectinib: Real-world data analysis of 840 ALK-inhibitor naïve patients with NSCLC harboring ALK-rearrangement (WJOG9516L).
Authors: Ito Kentaro , Yamanaka Takeharu , Watanabe Satomi , Hattori Yoshihiro , Nishino Kazumi , Kobayashi Haruki , Oya Yuko , Yokoyama Toshihide , Seto Takashi , Azuma Koichi , Fukui Tomoya , Kozuki Toshiyuki , Nakamura Atsushi , Okamoto Isamu , Hirano Katsuya , Yokoi Takashi , Daga Haruko , Sakata Shinya , Nakagawa Kazuhiko , Yamamoto Nobuyuki
Published: March 2020

9038

Background: Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries. Methods: We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group. Results: Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P= 0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P= 0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P< 0.0001. Conclusions: The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown. Clinical trial information: UMIN000028605.
Anti-PD-1/PD-L1 plus chemotherapy versus chemotherapy alone in first-line treatment for patients with metastatic NSCLC that were PD-L1 negative or less than 1%.
Authors: Landre Thierry , Des Guetz Gaetan , Chouahnia Kader , Taleb Cherifa , Vergnenegre Alain , Chouaid Christos
Published: March 2020

9061

Background: Clinical efficacy of single agent anti-PD-1/PD-L1 in patients with Non-Small-Cell-Lung-Cancer (NSCLC) that were PD-L1 negative or < 1% is controversial. Recent studies have evaluated the combination of anti-PD-1/PD-L1 to chemotherapy (CT) for this population in the first line setting. Methods: We performed a meta-analysis (MA) of randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with undetectable PD-L1 expression or < 1%. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. Results: Four studies evaluated atezolizumab + CT (IMpower 130,131,132 and 150), three studies pembrolizumab + CT (Keynote 021, 189 and 407) and one study evaluated nivolumab + CT (CheckMate 227). The eight eligible studies included 2037 patients (1246 with PD-L1 negative and 791 with PD-L1 expression < 1%). Most of the patients were men and smokers, with a median age of 64 years. There were 1423 Non-squamous (69.8 %) and 614 Squamous tumors (30%). The combination (PD-1/PD-L1 inhibitor + CT) was significantly associated with improvement of OS (hazards ratio [HR], 0.75; 95% CI 0.63–0.89; p < 0.0001), PFS (HR, 0.72; 95% CI 0.65–0.80; p < 0.0001) and ORR (relative ratio [RR], 2.59; 95% CI 1.46–4.60; p < 0.0001). Moreover, median duration of response (DOR) was statistically longer with combination (8.1 months versus 4.9; p < 0.0008). Conclusions: For patients with untreated NSCLC with low ( < 1%) or undetectable PD-L1 expression, the anti-PD-1/PD-L1 combination with chemotherapy, compared with chemotherapy alone, is associated with significantly improved OS, PFS, and ORR.
Phase I/Ib study of pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Updated results.
Authors: Saltos Andreas Nicholas , Tanvetyanon Tawee , Haura Eric B. , Creelan Ben C. , Antonia Scott Joseph , Shafique Michael Rahman , Zheng Hong , Dai Wenjie , Chen Zhihua , Saller James Joseph , Tchekmedyian Nishan , Goas Kristen , Thapa Ram , Boyle Theresa A. , Chen Dung-Tsa , Beg Amer A , Gray Jhanelle Elaine
Published: March 2020

9073

Background: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may augment response to immune checkpoint inhibitors (ICI). We report updated results from a phase I/Ib trial testing the combination of oral HDACi vorinostat (V) with PD-1 inhibitor pembrolizumab (P) in mNSCLC. Methods: In phase I, pts with ICI-naïve or ICI-pretreated mNSCLC were treated with P (200mg IV q3 wk) + V (200 or 400 mg PO daily). In phase Ib expansion, pts were required to have progressed on prior ICI treatment. Primary endpoints were safety/tolerability; secondary endpoints included RR, PFS, DOR, and OS. Tissue and blood specimens from pre- and on-treatment were collected for correlative analyses to determine tumor gene expression changes, T cell density and levels of myeloid-derived suppressor cells. Results: Between 3/2016 - 12/2018, Phase I: 13 pts were treated (4 at 200mg, and 9 at 400mg V dose); and Phase Ib: 20 pts were treated. Median age: 68 (range 38-82); Females: 11 (33%); ECOG 1: 31 (94%); and never/former/current smokers: 3/22/8 (9%/67%/24%). PD-L1 expression was < 1% in 8/33 (18%), ≥1-49% in 7/33 (21%), ≥ 50% in 9/33 (27%) and unknown in 11/30 (33%). No DLTs or treatment related deaths were observed. The RP2D was P 200mg and V 400mg. Most common any grade AEs was fatigue (11%) and nausea/vomiting (8%). 2 (6%) patients had treatment discontinued due to toxicity. 30 pts are evaluable for response, 6 ICI-naïve and 24 ICI-pretreated. 4 (13%) had PR (2 confirmed), 16 (53%) had SD, and 10 (33%) had PD for a disease control rate of 67%. In the ICI-pretreated Ib cohort, 3 pts (1 confirmed; 2 unconfirmed) had a PR and 10 had SD (8 confirmed). For ICI-pretreated pts, mPFS was 3.2 and mOS was 7.3 months, and 1-year PFS was 17% (4 pts). For ICI-naïve, mPFS was 7.6 months and mOS was 16 months. CD8 T cell presence in tumor stromal regions was associated with benefit to P + V treatment. Conclusions: P + V were well tolerated. The combination demonstrates preliminary anti-tumor activity despite progression on prior ICI treatment and stromal CD8 T cells may be associated with benefit from P + V treatment. A randomized phase II portion of this study, examining P combined with V vs. placebo in immunotherapy naïve pts, is ongoing. Clinical trial information: NCT02638090.