bluuebunny/crossref_metadata_2025_split huggingface dataset:
A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan).
Authors: Murakami Haruyasu , Umemura Shigeki , Shinoda Masahiro , Shingyoji Masato , Ogawa Yukari , Takeda Koji , Nosaki Kaname , Okamoto Norio , Aono Hiromi , Hara Satoshi , Kuyama Shoichi , Sato Akiko , Kanaji Nobuhiro , Okimoto Tamio , Kataoka Yuki , Matsumoto Shingo , Udagawa Hibiki , Yoh Kiyotaka , Tsuchihara Katsuya , Goto Koichi 
Published: September 2018

8518 Background: Recent genomic studies of small-cell lung cancer (SCLC) have identified promising therapeutic strategies for this highly lethal form of cancer. Thus, we established a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) to identify SCLC patients harboring targetable genomic alterations for the development of novel targeted therapies. Methods: The samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 2016, 133 institutions were participating and 295 patients had been enrolled. The median age was 69 years (range, 14-90 years). Two hundred seventeen (74%) were male and most patients (93%) were smokers. Among 268 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 198 (74%) /82 (31) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 10 (4%) /13 (5) /4 (1) of cases, respectively. The NGS analysis also showed that 62 (23%) of cases had at least one targetable genomic alterations, including 7 EGFR activating mutations (3%), 6 KRAS activating mutations (2%), and 8 FGFR1 copy number gains (3%). No case was positive for ALK or ROS1 fusions. Never-smokers (71% vs. 5%, p<0.001) were significantly frequent in the EGFR type compared to the others. The KRAS type showed significantly poor progression free survival (PFS) of the first-line chemotherapy compared to the others (median PFS 1.2 vs. 6.1 months, respectively; p<0.001). Mutations in the PI3K/AKT/mTOR pathway were detected in 22 (8%) of the tumors: 10 PIK3CA mutations (4%), 9 PTEN inactivating mutations (3%) and 3 TSC2 inactivating mutations (1%). Among them, a case with PTEN mutation was enrolled in the investigator initiated phase II study of gedatolisib named “EAGLE-PAT” (UMIN 000020585). Conclusions: We identified a series of targetable genomic alterations in SCLC. This nationwide screening system is helpful for identifying targetable genomic alterations and their clinical features, contributing to the development of novel targeted therapies for this disease. Updated screening results will be presented at the 2017 ASCO Annual Meeting.
Analysis of circulating tumor DNA in localized lung cancer for detection of molecular residual disease and personalization of adjuvant strategies.
Authors: Chaudhuri Aadel , Chabon Jacob J. , Lovejoy Alexander F. , Newman Aaron M. , Stehr Henning , Azad Tej D. , Carter Justin N. , Merriott David J. , Liu Chih Long , Kurtz David Matthew , Dudley Jonathan C. , Padda Sukhmani Kaur , Shrager Joseph B , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Alizadeh Ash A. , Diehn Maximilian 
Published: September 2018

8519 Background: Identifying localized non-small cell lung cancer (NSCLC) patients with residual disease following curative intent therapy is difficult due to normal tissue changes caused by surgery or radiation and an inability to detect microscopic disease. Analysis of circulating tumor DNA (ctDNA) might enable identification of molecular residual disease (MRD) and personalization of adjuvant treatment approaches but has not been explored in lung cancer. Methods: We applied CAPP-Seq, an ultra-sensitive next-generation sequencing based ctDNA quantitation method, to pre- and post-treatment blood samples from a cohort of 41 patients treated with chemoradiation, radiotherapy or surgery for stage I-III primary lung cancer. Detection of ctDNA at a single MRD time-point within 4 months of treatment completion was compared with surveillance by cross-sectional imaging. Furthermore, we developed an approach for identification of tumor mutation burden based on mutations detected in plasma, leveraging whole exome sequencing data from 1,177 NSCLCs sequenced by TCGA. Results: Median follow-up time was 35 months. Pre-treatment ctDNA was detected in 38 (93%) patients and 19 (46%) had detectable post-treatment ctDNA MRD. MRD+ patients displayed significantly inferior 3-year freedom from progression (0% vs. 92%; HR 38; P < 0.0001) and 3-year overall survival (8% vs. 75%; HR 12; P < 0.0001) than MRD- patients. Detection of ctDNA MRD had positive and negative predictive values for disease progression of 100% and 93%, respectively. Furthermore, we non-invasively identified activating EGFR mutations or high mutational burden (≥5 CAPP-Seq non-synonymous mutations, corresponding to > 200 non-synonymous mutations per exome or > 4 single nucleotide variants per megabase of exome) in 47% of patients with detectable ctDNA MRD, suggesting potentially favorable responses to TKIs and immune checkpoint inhibitors, respectively. Conclusions: Our results indicate that ctDNA analysis accurately detects MRD in localized lung cancer patients and could facilitate personalized adjuvant treatment at early time-points when disease burden is minimal.
Phase 1/2 study of veliparib (V) combined with carboplatin (Cb) and etoposide (E) in patients (pts) with extensive-stage disease (ED) small cell lung cancer (SCLC) and other solid tumors: Phase 1 results.
Authors: Atrafi Florence , Groen Harry J.M. , Byers Lauren Averett , Garralda Elena , Lolkema Martijn P. , Sangha Randeep S. , Viteri Ramirez Santiago , Chae Young Kwang , Camidge D. Ross , Gabrail Nashat Y. , Waskiewicz Tina , Hu Beibei , Xu Tu , Nuthalapati Silpa , Hoening Elizabeth , Komarnitsky Philip , Calles Blanco Antonio 
Published: September 2018

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.
Expansion study of ADI-PEG 20, pemetrexed and cisplatin in patients with ASS1-deficient malignant pleural mesothelioma (TRAP).
Authors: Phillips Melissa , Szyszko Teresa , Hall Peter , Cook Gary J. R. , Khadeir Ramsay , Steele Jeremy P. C. , Spicer James F. , Feng Xiaoxing , Hategan Mirela , Rashid Sukaina , Johnston Amanda , Bomalaski John S. , Shamash Jonathan , Pacey Simon , Sheaff Michael , Szlosarek Peter Wojciech 
Published: September 2018

8553 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) cells are sensitive to arginine deprivation with pegylated arginine deiminase (ADI-PEG20), which also potentiates the cytotoxic effect of pemetrexed (PEM). In the phase I dose-escalation TRAP study (NCT02029690) we showed that ADI-PEG20 with first-line PEM and cisplatin (CIS) chemotherapy (ADIPEMCIS) produced a 100% disease control rate (DCR) in patients (pts; n = 9) with ASS1-deficient thoracic cancers, with no additional toxicity (Beddowes et al 2017). Here, we present the TRAP expansion cohort experience in MPM. Methods: Good performance (ECOG 0-1) MPM pts with non-resectable disease and measurable by modified RECIST, were enrolled in a phase I TRAP expansion cohort at the maximum tolerated dose (MTD) of ADIPEMCIS, using tumoral ASS1 loss as a selection biomarker. PEM (500mg/m2) and CIS (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for a maximum of 6 cycles with maintenance ADI-PEG20 in responding pts. Primary endpoint was tumor response rate (modified RECIST), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We measured plasma arginine and citrulline concentrations, ADI-PEG20 antibodies, and biopsied patients on progression to explore resistance mechanisms. Results: 31 ASS1-deficient MPM pts (median age 67) were enrolled (11 epithelioid, 10 biphasic and 10 sarcomatoid) out of 92 screened pts. Plasma arginine decreased with a reciprocal increase in plasma citrulline. The partial response rate was 35.5% (95% CI 19.2%-54.6%) with a DCR of 93.5% (95% CI 78.6%-99.2%). Median PFS was 5.6 months (95% CI 4-6) and median OS was 10.1 months (95% CI 6.7-17.7). 10/31 pts (32.3%) experienced grade 3/4 treatment-related toxicities, the most common being neutropenia (16.1%). Upregulation of ASS1 expression was observed in 2/3 biopsies on progression. Conclusions: The ADIPEMCIS regimen is active in ASS1-deficient MPM pts, including non-epithelioid disease. Based on these data the ATOMIC-meso phase 2/3 trial has opened comparing ADIPEMCIS versus PEMCISPlacebo, focusing on pts with non-epithelioid MPM. Clinical trial information: NCT02029690.
Progression after the next line of therapy (PFS2) and updated OS among patients (pts) with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥50% enrolled in KEYNOTE-024.
Authors: Brahmer Julie R. , Rodriguez-Abreu Delvys , Robinson Andrew George , Hui Rina , Csõszi Tibor , Fülöp Andrea , Gottfried Maya , Peled Nir , Tafreshi Ali , Cuffe Sinead , O'Brien Mary , Rao Suman , Hotta Katsuyuki , Leiby Melanie A. , McLean Jessica , Shentu Yue , Rangwala Reshma A. , Reck Martin 
Published: September 2018

9000 Background: In KEYNOTE-024 (NCT02142738), pembrolizumab (pembro) was superior to chemotherapy (chemo) as first-line (1L) therapy for advanced NSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR mutations or ALK translocations. After a median follow-up of 11.2 mo, HR was 0.50 for PFS by independent central radiologic review ( P< 0.001) and 0.60 for OS ( P= 0.005). Here we present PFS2 and updated OS. Methods: 305 pts were randomly assigned to pembro 200 mg Q3W (n = 154) or investigator (INV)-choice platinum-doublet chemo with optional pemetrexed maintenance for nonsquamous histology (n = 151). Pts in the chemo arm could cross over to pembro upon PD. Poststudy anticancer therapy and INV-assessed outcomes were collected. Kaplan-Meier PFS2 and OS were calculated in all allocated pts. PFS2 was defined as time from randomization to PD per INV after start of 2L+ therapy or death, whichever occurred first; pts alive and without 2L+ PD were censored at last known survival. Kaplan-Meier OS was defined as time from randomization to death. There was no adjustment for multiplicity (cutoff: Jan 5, 2017). Results: 2L+ therapy was received by 48 (31.2%) pts in the pembro arm and 97 (64.2%) in the chemo arm, including 80 pts who crossed over from chemo to pembro per protocol and 14 pts who received anti–PD-1 therapy outside of crossover. 56 (36%) 1L pembro pts were on 1L pembro therapy or in follow-up as of data cutoff. Updated median OS and PFS2 results are in the Table. Conclusions: Fewer pembro pts received 2L+ therapy vs chemo pts because of the significant improvement in PFS observed for pembro in the 1L setting. Median PFS2 was substantially improved for pembro (not reached [NR]) vs chemo (8.6 mo). Updated OS with median follow-up of 19 mo maintained consistent superiority of 1L pembro, despite increased crossover from 1L chemo. Clinical trial information: NCT02142738. [Table: see text]
Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study.
Authors: Gandara David R. , Von Pawel Joachim , Sullivan Richard N. , Helland Aslaug , Han Ji-Youn , Ponce Aix Santiago , Rittmeyer Achim , Barlesi Fabrice , Kubo Toshio , Park Keunchil , Goldschmidt Jerome H. , Gandhi Mayank , Yun Cindy , Yu Wei , Matheny Christina , He Pei , Sandler Alan , Ballinger Marcus , Fehrenbacher Louis 
Published: September 2018

9001 Background: Cancer immunotherapy (CIT) can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS). This effect can also result from unconventional CIT response due to tumor immune infiltration or delayed response, reducing reliability of RECIST v1.1 (RECIST) PD as an indicator of treatment failure. In the primary analysis (N = 850) of OAK, a study of atezo vs docetaxel (doc) in 2L/3L NSCLC, OS favored atezo (HR 0.73; 95% CI: 0.62, 0.87), despite similar PFS between arms (HR 0.95; 95% CI: 0.82, 1.10). Here we evaluate clinical benefit from TBP, defined by post PD tumor regression, OS and safety. Methods: Patients (pts) received atezo 1200 mg IV q3w until PD or loss of clinical benefit per investigator or doc 75 mg/m2 IV q3w until PD per RECIST. No crossover was allowed. Primary outcome measure: OS. Atezo TBP pts were evaluated for post PD tumor change and for safety pre and post PD. OS from time of PD per RECIST was evaluated in both arms (data cutoff, July 7, 2016; minimum follow-up, 19 mo). Results: Among 332 atezo pts with PD, 51% (n = 168) continued atezo TBP; 7% (12/168) achieved subsequent response in target lesions (≥ 30% reduction from new baseline at PD); 49% (83/168) had stable target lesions (best change between +20% and −30%). mOS was 12.7 mo (95% CI: 9.3, 14.9) post PD for pts on atezo TBP (Table). Atezo TBP was not associated with increased safety risk. Conclusions: This is the first report from a Phase III study of CIT in NSCLC to evaluate post PD OS in pts continuing treatment beyond RECIST PD. Atezo TBP was associated with high frequency of stable or decreased target lesions, mOS > 1 year and a tolerable safety profile, all supporting prolonged treatment benefit consistent with PPPS. NCT02008227 Clinical trial information: NCT02008227. [Table: see text]
Efficacy and safety results from AvaALL: An open-label, randomized phase III trial of standard of care (SOC) with or without continuous bevacizumab (Bev) treatment beyond progression (PD) in patients (pts) with advanced non-small cell lung cancer (NSCLC) progressing after first-line Bev and chemotherapy (chemo).
Authors: Bennouna Jaafar , De Castro Javier , Dingemans Anne-Marie C. , Griesinger Frank , Grossi Francesco , Langer Corey J. , Ohe Yuichiro , Syrigos Konstantinos N. , Thatcher Nick , Das-Gupta Ashis , Donica Margarita , Smoljanovic Vlatka , Gridelli Cesare 
Published: September 2018

9004 Background: The role of treatment with Bev beyond PD is unclear in the multiline treatment strategy of advanced NSCLC.AvaALL(NCT01351415), a multinational, open-label, randomized phase III trial, assessed continuous Bev and SOC beyond first PD (PD1) in pts with NSCLC following first-line treatment with platinum-based chemo plus Bev. Here we present efficacy and safety data from AvaALL. Methods: Pts with NSCLC who received 4–6 cycles of chemo + Bev and ≥2 cycles of maintenance Bev were randomized after PD1 to second-line SOC therapy (docetaxel, pemetrexed or erlotinib) ± Bev. After second PD (PD2) and third PD (PD3), pts received third-line or fourth-line SOC ± Bev treatment, respectively. Primary endpoint was overall survival (OS). Secondary endpoints were OS rates (6, 12, and 18-months [mos]), progression-free survival (PFS) from PD1 to PD2/from PD2 to PD3, overall response rate (ORR), disease control rate (DCR), and safety. Data cut-off: 24 Jun 2016. Results: Overall, 485 pts were randomized (n = 475 treated). Pt characteristics were well balanced between the two arms. Bev plus chemo resulted in a median OS of 11.9 mos versus 10.2 mos for SOC alone (HR 0.84, 90% CI 0.71–1.00; p = 0.1016; 387 OS events). The primary endpoint was not met (416 OS events were required, at 10% two-sided significance level). OS rates were 10% higher in the Bev arm vs SOC alone at 6-, 12- and 18-mos. Median PFS2 was 4.9 mos with Bev vs 3.8 mos with SOC (HR 0.85, 90% CI 0.72–1.00; p = 0.0907). PFS3 was significantly improved (3.5 mos for Bev, 2.4 mos for SOC; HR 0.65, 90% CI 0.51–0.84; p = 0.0047). ORR and DCR were slightly higher in the Bev arm versus the SOC arm (ORR 9.7% vs 6.7%; DCR 86.2% vs 79.3%, respectively). No new safety signals were identified. Grade ≥3 adverse events were reported in 78.2% of Bev pts and 61.6% of SOC pts. Conclusions: Although the primary endpoint was not met, efficacy data suggest a positive trend for continued Bev plus SOC after PD1 compared with SOC alone. No cumulative safety signals were identified. Clinical trial information: NCT01351415.
Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD(L)-1 therapy.
Authors: Santini Fernando Costa , Rizvi Hira , Wilkins Olivia , van Voorthuysen Martine , Panora Elizabeth , Halpenny Darragh , Kris Mark G. , Rudin Charles M. , Chaft Jamie E. , Hellmann Matthew David 
Published: September 2018

9012 Background: Anti-PD(L)-1 therapy is generally well tolerated, but immune-related adverse events (irAEs) can occur. No data currently exists to guide decisions related to considering re-treatment following an irAE. Methods: Patients (pts) with lung cancer treated with anti-PD(L)-1 (+/- anti-CTLA-4) between 4/2011 to 5/2016 who had a treatment delay of at least one week were identified. Those in whom delay was a result of a definite irAE were included, and subsequent treatment details and outcomes were captured. Pts with an irAE concurrent with disease progression were excluded. Results: Among 482 pts treated, 71 (14.7%) had treatment delay related to an irAE. Most events were Grade 2 (38/71, 54%) or Grade 3 (30/71, 42%), and predominantly included pneumonitis (21%), colitis (17%), rash (14%), or hepatitis (13%). 32 pts (45%) were permanently discontinued after the irAE and 39 (55%) were later retreated with anti-PD(L)-1 therapy. In retreated pts, the same irAE recurred in 10/39 (26%), a new irAE occurred in 9/39 (23%), and 20/39 (51%) had no subsequent irAE. The rate of recurrent/new irAEs was similar in those with Grade 3 compared to Grade 2 irAEs (p = 1.0), but were more common following initial irAE that occurred early ( < 3 months) compared to later (≥3 months) in treatment course (16/24 [67%] vs 3/15 [20%], p = 0.0079). The rate of recurrent/new irAE was 33% (2/6) in those with pneumonitis, 40% (2/5) with rash, 57% (4/7) with colitis, and 80% (4/5) with arthralgia. Recurrent/new irAEs were successfully managed with immunosuppression in 17/19 (90%) pts. However, 2 pts died, both related to a new irAE different from the one initially experienced. Of the pts retreated, 3 (8%) had onset of objective response to anti-PD(L)-1 therapy following resumption of treatment. Conclusions: In pts who develop irAEs and improve, re-treatment with anti-PD(L)-1 therapy was associated with recurrent or new irAEs in half of pts, and was more common in early-onset irAEs. The majority of the pts with recurrent/new irAEs were managed successfully, but two deaths occured. Few objective responses occurred following retreatment.
A phamacoeconomic analysis of personalized dosing versus fixed dosing of pembrolizumab in first-line PD-L1 positive non-small cell lung cancer.
Authors: Goldstein Daniel A. , Gordon Noa , Davidescu Michal , Leshno Moshe , Steuer Conor Ernst , Patel Nikita , Stemmer Salomon M. , Zer Alona 
Published: September 2018

9013 Background: In October 2016 pembrolizumab became the new standard of care for first-line treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death ligand 1 in at least 50% of cells. The FDA recommended dose is 200mg every three weeks. Multiple studies have demonstrated equivalent efficacy with weight-based doses between 2mg/kg to 10 mg/kg. The objective of this study was to compare the economic impact of using personalized dosing (2mg/kg) versus fixed dosing (200mg) in the first line setting of mNSCLC. Methods: We performed a budget impact analysis from the US societal perspective to compare fixed dosing with personalized dosing. We calculated the target population and weight of patients that would be treated with pembrolizumab annually in the first-line setting. Using survival curves from the KEYNOTE 024 trial with Weibull extrapolation we estimated the mean number of cycles that patients would receive. Using the Medicare average sales price we calculated the difference in cost between personalized and fixed dosing. Results: Our base case model demonstrates that the total annual cost of pembrolizumab with fixed dosing is US$ 3,440,127,429, and with personalized dosing it is US$ 2,614,496,846. The use of personalized dosing would lead to a 24% annual saving of US$ 825,630,583 in the United States. Conclusions: Personalized dosing of pembrolizumab may have the potential to save approximately 0.825 billion dollars annually in the United States, likely without impacting outcomes. This option should be considered for the first-line management of PD-L1 positive advanced lung cancer.