bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinico-pathological and genomic features of NRAS- or HRAS-mutated non-small cell lung cancer (NSCLC) identified in large-scale genomic screening project (LC-SCRUM-Asia).
Authors: Tamiya Yutaro , Matsumoto Shingo , Ikeda Takaya , Yoh Kiyotaka , Kato Terufumi , Nishino Kazumi , Kodani Masahiro , Nakamura Atsushi , Furuya Naoki , Kuyama Shoichi , Miyamoto Shingo , Toyozawa Ryo , Shingyoji Masato , Naito Tomoyuki , Oizumi Satoshi , Tanaka Hiroshi , Udagawa Hibiki , Nosaki Kaname , Zenke Yoshitaka , Goto Koichi 
Published: June 2021

9054 Background: RAS ( KRAS, NRAS and HRAS) is a targetable oncogene family in several cancers, including NSCLC, and the clinical development of various RAS-targeted therapies are ongoing. However, the clinical relevance of uncommon RAS mutations, such as NRAS and HRAS mutations, in NSCLC patients (pts) remains unclear. Methods: In a large-scale genomic screening project (LC-SCRUM-Asia), we have prospectively analyzed lung cancer pts for genomic alterations by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay. We evaluated clinico-pathological and genomic characteristics in NRAS- or HRAS-mutated NSCLC pts comparing with those in KRAS-mutated pts based on the LC-SCRUM-Asia database. Results: Since March 2015 to December 2020, 9131 NSCLC pts were enrolled in the LC-SCRUM-Asia, and 8374 of them (92%) were successfully analyzed by NGS. The RAS mutation frequencies were 1134 KRAS (14%), 50 NRAS (0.6%), and 15 HRAS (0.2%). The most frequent variant of NRAS and HRAS mutations was Q61X (78%) and G13X (80%), respectively, whereas that of KRAS was G12X (84%). Patient characteristics were summarized in Table. Male was significantly frequent in NRAS- than in KRAS-group (p=0.03), and smokers were frequent in all the three groups (overall, 79%). The majority of NRAS (70%) and KRAS mutations (89%) were detected in adenocarcinoma (Ad), whereas 60% of HRAS mutations were in squamous cell carcinoma (Sq). Tumor mutation burden (TMB) was significantly higher in NRAS-mutated tumors than in KRAS-mutated tumors (p=0.03). Concomitant TP53 mutations were significantly frequent in HRAS-mutated pts than in KRAS-mutated pts (53% vs. 30%, p=0.05), and STK11 mutations were also tended to be frequent in HRAS-mutated pts than in KRAS-mutated pts (20 vs. 7%, p=0.10). Therapeutic efficacy of PD-1/PD-L1 inhibitors was not different among the three groups in the current follow-up data, but HRAS-mutated tumors did not respond to PD-1/PD-L1 inhibitors (response rate, 0%; median PFS, 1.6 months). Conclusions: NRAS- or HRAS-mutated NSCLCs were different from KRAS-mutated NSCLCs in clinico-pathological and genomic profiles. In particular, the immunotherapies were not effective for HRAS-mutated NSCLCs.[Table: see text]
Comparison of time to failure of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy: A consecutive analysis of NSCLC patients with high PD-L1 expression.
Authors: Takumida Hiroshi , Horinouchi Hidehito , Masuda Ken , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Yamamoto Noboru , Ohe Yuichiro 
Published: June 2021

9061 Background: There are two types of pembrolizumab-containing strategies for patients with non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥50%): the early combination of pembrolizumab plus chemotherapy, and chemotherapy after pembrolizumab failure. Which strategy is superior, however, remains unclear. Comparing progression-free survival (PFS) or progression after the next therapy line (PFS2) in previous clinical trials has not allowed any conclusions regarding superiority to be made. Instead, the time to failure of strategy (TFS), which represents the time until disease exacerbation when the same number of drugs has been used, should be used to compare the two strategies. Methods: We consecutively reviewed the efficacy and safety of first-line, pembrolizumab-containing regimens administered between December 2017 and November 2020. We divided the patients who received pembrolizumab as a first-line treatment into two groups according to whether they received chemotherapy: a pembrolizumab plus chemotherapy group (combo group), and a pembrolizumab monotherapy group (mono group). TFS was defined as the PFS in the combo group and the PFS2 in the mono group. We used the propensity score matching (PSM) method to reduce the bias. Results: Of the 964 patients with advanced NSCLC who underwent first-line treatment, 126 with a PD-L1 TPS ≥50% were eligible for inclusion in this analysis (89 in mono group, 37 in combo group). PSM matched 36 people from each of the two groups. The median follow-up period was 16.2 months (range, 0.1-34.3 months). The patient backgrounds were similar. The overall response rate (ORR) of the combo group was higher than that of the mono group (69.4% vs. 50.0%). The median PFS (mPFS) in the combo group was longer (11.4 months vs. 6.0 months). However, the median TFS (mTFS) of the two groups was almost the same (11.4 months vs. 11.7 months). At the time of the analysis, the median overall survival had not been reached. The frequency of all immune-related serious adverse events (irSAE) was similar, however, that of all SAE and AE leading to treatment discontinuation were larger in the combo group. Conclusions: The ORR of the combo group was higher than that of the mono group; however, the TFS was similar. We suggest that pembrolizumab plus chemotherapy, which can increase toxicity, might be of value in patients, producing a clinically meaningful increase in the ORR.[Table: see text]
Cemiplimab monotherapy as first-line (1L) treatment of patients with brain metastases from advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥ 50%: EMPOWER-Lung 1 subgroup analysis.
Authors: Ozguroglu Mustafa , Sezer Ahmet , Kilickap Saadettin , Gumus Mahmut , Bondarenko Igor , Gogishvili Miranda , Turk Haci M. , Cicin Irfan , Bentsion Dmitry , Gladkov Oleg , Clingan Philip R. , Sriuranpong Virote , Rizvi Naiyer A. , McGinniss Jennifer , Pouliot Jean-Francois , Lee Sue , Seebach Frank A. , Lowy Israel , Gullo Giuseppe , Rietschel Petra 
Published: June 2021

9085 Background: In the Phase 3, EMPOWER-Lung 1 study, cemiplimab monotherapy provided significant survival benefit and an acceptable safety profile vs chemotherapy in patients with advanced NSCLC and PD-L1 ≥50%. EMPOWER-Lung 1 included patients with brain metastases at baseline who are typically underrepresented in clinical trials. Other published exploratory analyses in single-cohort studies suggest benefit from immunotherapy in this patient population. Here, we present subgroup analysis of patients with brain metastasis from EMPOWER-Lung 1. Methods: Patients were randomized 1:1 to cemiplimab 350 mg IV every 3 weeks or investigator’s choice of chemotherapy (NCT03088540). Patients with treated, clinically stable brain metastases (radiological stability not required) were eligible to enroll and are the focus of this subgroup analysis from the PD-L1 ≥50% population (n=563) of the EMPOWER-Lung 1 study. Results: A total of 68 of 563 (12.1%) cases had treated stable brain metastases at time of randomization. Patients were evenly distributed between cemiplimab (n=34) and chemotherapy (n=34), with similar median duration of follow-up (Table). Baseline characteristics were generally similar; median (range) age: 60.0 (45–76 ) vs 62.0 (48–77); male: 97.1% vs 85.3%; and non-squamous histology: 85.3% vs 76.5%; between cemiplimab vs chemotherapy, respectively. Per independent review committee, median overall survival (OS, 18.7 vs 11.7 months), median progression-free survival (PFS, 10.4 vs 5.3 months), and objective response rate (ORR, 41.2% vs 8.8%) were superior with cemiplimab vs chemotherapy (Table). After baseline, central nervous system (CNS) disease progression occurred in 2 (5.9%) patients with cemiplimab vs 4 (11.8%) patients with chemotherapy; extra-CNS disease progression occurred in 9 (26.5%) patients with cemiplimab vs 15 (44.1%) patients with chemotherapy. Conclusions: 1L cemiplimab monotherapy improved OS, PFS, and ORR vs chemotherapy, in patients with advanced NSCLC with PD-L1 ≥50%, and clinically stable brain metastases at baseline. Cemiplimab monotherapy represents a suitable option for this subgroup of patients. Clinical trial information: NCT03088540. [Table: see text]
First-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥ 50%) advanced non-small cell lung cancer (aNSCLC) in the real world: A national French bispective multicentric cohort—ESCKEYP trial (GFPC 05-2018).
Authors: Descourt Renaud , Greillier Laurent , Perol Maurice , Ricordel Charles , Auliac Jean-Bernard , Falchero Lionel , Demontrond Pierre , Veillon Remi , Vieillot Sabine , Guisier Florian , Marcq Marie , Justeau Gregoire , Bigay Game Laurence , Bernardi Marie , Fournel Pierre , Doubre Helene , Pinsolle Julian , Amrane Karim , Chouaid Christos , Decroisette Chantal 
Published: June 2021

9091 Background: To determine real-world outcomes with first line pembrolizumab monotherapy, for aNSCLC with PD-L1 TPS ≥50%. Methods: Bispective, national and multicentric study including consecutively aNSCLC patients who initiated first-line pembrolizumab monotherapy from May 5, 2017 (marketing authorization of pembrolizumab monotherapy in France) to Nov 22, 2019 (marketing authorization of pembrolizumab-chemotherapy for non-squamous aNSCLC). Data were collected on medical charts. Responses were locally assessed according to RECIST v1.1; overall survival (OS) and real-world progression-free survival (rwPFS) were assessed by Kaplan-Meier method. Results: 845 patients (pts) were included by 33 centres: 67.8% were men, PS 0/1/≥2: 25.5%/46.9%/27.6%, active/former/nonsmokers: 39.1%/51.7%/6.4%, adenocarcinoma: 70.8%; stage IV at diagnosis: 91.6%; median number of metastatic sites at baseline: 2±1 (brain (20.8%), liver (13.9%) and bone (35%)); KRAS mutated: 27.7%, PDL1 TPS > 75%: 53.7% At the cut off date (31 December 2020), on the 783/845 (92.7%) evaluable pts, CR, PR, disease stabilization and progression were reported on 4.7%, 42.6%, 24.1% and 28.6% of cases, respectively; 588 (69.6%) pts had discontinued pembrolizumab, 390 (66.4%) had a first disease progression; 320/390 (82.1%) received a second line treatment, mainly platinum-based chemotherapy (90.6%). With a median follow up of 25,8 [95%CI: 24,8-26,7] months, median rwPFS and median OS were 8,2 [95%CI: 6,9-9,5] and 22,6 [95%CI: 18,5-27,4] months, respectively; 6, 12, 18-months survival rates were 76,8%, 64,8% and 54,3%. 835 adverse events were reported in 48% of the patients, grade ≥3 in 13.8% of cases, mainly asthenia, colitis, pneumonitis. For evaluable patients receiving a platinum-based doublet in second line (266/290, 89%), CR, PR, disease stabilization and progression were reported on 1.9%, 41%, 35.3% and 21.8% of cases, respectively. Uni and multivariate analysis of factors related to OS will be presented at the congress. Conclusions: Despite a less stringent selection of patients, pembrolizumab as a single agent achieves similar tumor shrinkage, rwPFS and OS than those of pivotal clinical trials.
Interim results of viagenpumatucel-L (HS-110) plus nivolumab in previously treated patients (pts) with advanced non-small cell lung cancer (NSCLC) in two treatment settings.
Authors: Cohen Roger B. , Peoples George Earl , Kawashima Toana , Arana Bill , Cui Xiaoxing , Bazhenova Lyudmila , Sanborn Rachel E. , Harb Wael A. , Pennell Nathan A. , Morgensztern Daniel 
Published: June 2021

9100 Background: Viagenpumatucel-L (HS-110) is an allogeneic cell therapy derived from a human lung adenocarcinoma cell line incorporating multiple cancer testis antigens and transfected with a gp96-Ig fusion protein. Methods: We report interim results of cohort A (previously treated pts who had not received a checkpoint inhibitor [CPI]) and cohort B (pts who progressed after CPI treatment) in an ongoing phase 2 trial evaluating HS-110 plus nivolumab (NIVO) in advanced NSCLC pts (NCT02439450). Pts received HS-110 (1×107 cells) intradermally QW for 18 wk and NIVO Q2W until tumor progression. Stratified analyses were performed by injection site reaction (ISR), yes (+) or no (–); baseline blood tumor mutational burden (bTMB), bTMB-L (<10 mutations/ megabase [mut/Mb]) or bTMB-H (≥10 mut/Mb) by FoundationACT test; and baseline PD-L1 expression, – (<1%) or + (≥1%). Results: As shown in the Table, median progression-free survival (PFS) in cohort A (n=47) was 1.8 mo (95% CI 1.8-7.8) and median overall survival (OS) was 24.6 mo (95% CI 11.7-36.0) after a median follow-up (MFU) of 19.5 mo. We observed significantly longer PFS and OS in ISR+ pts (hazard ratio [HR] 0.43, p=0.01; HR 0.23, p<0.001) and longer OS in PD-L1+ pts (HR 0.25, p=0.02). In cohort B (n=68), median PFS was 2.8 mo (1.8-3.9) and median OS was 11.9 mo (9.7-16.3) after a MFU of 11.9 mo. We observed significantly longer OS in ISR+ pts (HR 0.48, p=0.03) and a trend toward extended OS in bTMB-L pts (HR 0.58, p=0.20). HS-110 TEAEs were reported in 21 (44.7%) pts in cohort A and 18 (26.5%) pts in cohort B. TEAEs in >5% of pts included fatigue, maculopapular rash, nausea, diarrhea, and pruritus. Few HS-110–related TEAEs led to discontinuation of treatment [cohort A, 5 (10.6%); cohort B, 3 (4.4%)], and no serious AEs were considered related to HS-110. Conclusions: HS-110 was well tolerated when administered in combination with NIVO. In previously treated pts with advanced NSCLC, we observed (1) significantly longer PFS and OS in ISR+ pts in both CPI naïve and CPI progressor cohorts; (2) significantly longer OS in PD-L1+ patients in the CPI naïve cohort; and (3) a trend of improved OS in bTMB-L pts in the CPI progressor cohort. Further clinical evaluation of HS-110 is warranted in both CPI naïve and CPI progressor NSCLC patients. Clinical trial information: NCT02439450. [Table: see text]
Stereotactic body radiation therapy and in situ oncolytic virus therapy followed by immunotherapy in metastatic non-small cell lung cancer.
Authors: Guerrero Carlo , Ensor Joe E. , Sun Kai , Farach Andrew M. , Nair Sindhu , Zhang Jun , Singh Monisha , Darcourt Jorge German , Ramshesh Priya V. , Butler Edward Brian , Teh Bin S. , Sultenfuss Mark , Gupta Nakul , Heslop Helen E. , Mejia Jaime A. , Chang Jenny Chee Ning , Bernicker Eric 
Published: June 2021

9115 Background: The introduction of immunotherapy has altered the treatment paradigm for metastatic non-small cell cancer (mNSCLC). Unfortunately, many patients with mNSCLC have limited or no benefit from immune checkpoint inhibitors (ICIs). A variety of approaches have been explored to augment the efficacy of ICIs. Our study’s aim was to determine whether the addition of stereotactic body radiation therapy (SBRT) and intratumoral injection of the oncolytic virus ADV/HSV-tk (adenovirus-mediated expression of herpes simplex virus thymidine kinase) to a monoclonal antibody targeting programmed cell death-1 (PD-1) would improve the ICI’s efficacy in the treatment of mNSCLC. Methods: In this single-arm, open-label phase II study, patients with mNSCLC (squamous or non-squamous) who were ICI-naive or who were previously treated with a maximum of one line of therapy that included an ICI received an intratumoral injection of ADV/HSV-tk (5 x 1011 vp) followed by SBRT (30 Gy in 5 fractions) to the same tumor. An anti-PD-1 agent (pembrolizumab 200 mg IV every 3 weeks or nivolumab 240 mg IV every 2 weeks) was then given for up to 24 months (pembrolizumab) or 12 months (nivolumab), or until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A secondary endpoint was clinical benefit rate (CBR). Results: A total of 35 patients were enrolled, with 28 (80%) receiving pembrolizumab and 7 (20%) receiving nivolumab; 14 (40%) had previous ICI therapy while 21 (60%) were ICI-naive. The ORR and CBR were 28.5% and 61.9% in the ICI-naive group, and 14.2% and 64.2% in the group that previously received an ICI, respectively. Grade 3 or higher toxicity was seen in five patients (26.3%) in the ICI-naive group and in one patient (7.1%) in the previously ICI-treated group. No treatment-related deaths were observed. Conclusions: The addition of SBRT and intratumor injection of ADV/HSV-tk to anti-PD-1 therapy in mNSCLC resulted in a CBR of over 60% for both ICI-naive and previously ICI-treated patients without the use of chemotherapy. The combination was able to reinstitute sensitivity to ICIs in patients previously treated with an ICI, and also benefited some patients whose tumors did not express PD-L1. These findings should be further explored in a larger study population. Clinical trial information: NCT03004183. [Table: see text]
Phase II study of ceralasertib (AZD6738), in combination with durvalumab in patients with metastatic melanoma who have failed prior anti-PD-1 therapy.
Authors: Kwon Minsuk , Kim Seung Tae , Smith Simon , Smith Claire , Mortimer Peter G. , LoembE Bienvenu , Kozarewa Iwanka , Dean Emma , Lee Jeeyun 
Published: June 2021

9514 Background: Alterations in DNA damage response (DDR) and repair are associated with genomic instability and increased somatic tumor mutational burden, and modulating DNA repair is a promising strategy to boost the efficacy of cancer immunotherapy. Ceralasertib is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related (ATR), which is crucial to the cell’s response to replication stress. Methods: This phase 2 trial was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with metastatic melanoma (MM) who had failed to anti-PD-1 therapy. The study drug schedule was: ceralasertib at 240 mg BD on days 15 to 28 in combination with durvalumab at 1500 mg on day 1 in a 28-day cycle. The primary end point was overall response rate (ORR) by RECIST (v1.1). To investigate markers predictive of clinical outcome, fresh tumor biopsies were obtained from all enrolled patients before treatment. Results: From August 2019 to May 2020, 30 MM patients (median # of lines, 2; range, 2 - 5) were enrolled. All enrolled patients were exposed to prior anti-PD-1 treatment (immediate failure, n = 23). The ORR was 30.0% (9 PRs, 10 SDs, 10 PDs), DCR 63.3%, median PFS 7.1 months (95% confidence interval (CI), 3.6-10.6), and median OS was 14.2 months (95% CI, 9.3-19.1). Common adverse events of any grade were anemia (n = 23, 76.7%), anorexia (n = 20, 66.7%) and thrombocytopenia (n = 19, 63.3%). Common adverse events of grade 3 or more included anemia (n = 10, 33.3%). One death occurred due to febrile neutropenia in a patient with a pre-existing wound infection. Conclusions: Ceralasertib in combination with durvalumab demonstrated a promising anti-tumor activity, particularly in melanoma patients who failed to standard of care including anti-PD1 treatment. Clinical trial information: NCT03780608.
Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: Three-year results of CheckMate 511.
Authors: Lebbe Celeste , Meyer Nicolas , Mortier Laurent , Marquez-Rodas Ivan , Robert Caroline , Rutkowski Piotr , Butler Marcus O. , Eigentler Thomas , Menzies Alexander M. , Smylie Michael , Arance Ana Maria , Ascierto Paolo Antonio , Svane Inge Marie , Ajaz Mazhar , Khushalani Nikhil I. , Lobo Maurice , Zoco Jesus , Pigozzo Jacopo 
Published: June 2021

9516 Background: NIVO 1 mg/kg plus IPI 3 mg/kg (NIVO1 + IPI3) is approved for treatment (tx) of unresectable/adv melanoma, with demonstrated durable clinical benefit on long-term follow-up. Analysis of the phase 3b/4 CheckMate 511 study (NCT02714218) at 1 y showed that NIVO 3 mg/kg plus IPI 1 mg/kg (NIVO3 + IPI1) improves the safety profile of the combination; efficacy with the 2 regimens was similar in descriptive analyses. Here we present 3-y safety/efficacy results. Methods: Patients (pts) ≥ 18 y of age with previously untreated unresectable stage III/IV melanoma were randomized 1:1 to receive NIVO3 + IPI1 Q3W × 4 (N = 180) or NIVO1 + IPI3 Q3W × 4 (N = 178), both followed by NIVO 480 mg Q4W until progression/unacceptable toxicity. The primary endpoint was the incidence of grade (gr) 3–5 tx-related adverse events (TRAEs); secondary endpoints (descriptive analyses) included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The study was not powered to formally demonstrate noninferiority for efficacy endpoints. Results: At a median follow-up of 44.4 and 43.9 mo in the NIVO3 + IPI1 and NIVO1 + IPI3 groups, respectively, TRAEs led to tx discontinuation in 26% and 39% of pts; 57% and 42% of pts had received maintenance therapy. Gr 3–5 TRAE incidence remained significantly lower with NIVO3 + IPI1 than NIVO1 + IPI3 (33.9% vs 48.3%; odds ratio 0.55 [95% CI 0.36–0.84]). The most frequent TRAEs (any gr) were diarrhea (27%), fatigue (26%), and pruritus (26%) with NIVO3 + IPI1 and diarrhea (31%), pruritus (29%), and rash (27%) with NIVO1 + IPI3. In descriptive analyses, efficacy results were similar to those observed at 1 y. OS and tx-free–analysis outcomes were numerically similar in the 2 groups (table). Conclusions: At 3-y follow-up, NIVO3 + IPI1 continued to demonstrate an improved safety profile compared with NIVO1 + IPI3. In descriptive analyses, both groups demonstrated high 3-y OS rates that were numerically similar. This study provides important information regarding the benefit–risk profile of both dosing regimens of NIVO + IPI in pts with adv melanoma. Clinical trial information: NCT02714218. [Table: see text]