bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal next-generation sequencing (NGS) panel for estimating tumor mutation burden (TMB) and its clinical implication for non-small cell lung cancer (NSCLC).
Authors: Ikeda Takaya , Oi Hajime , Yoh Kiyotaka , Matsumoto Shingo , Kato Terufumi , Nishino Kazumi , Nakamura Atsushi , Nakachi Ichiro , Sakakibara-Konishi Jun , Daga Haruko , Furuya Naoki , Taima Kageaki , Iwama Eiji , Ebi Noriyuki , Shibata Yuji , Izumi Hiroki , Nosaki Kaname , Zenke Yoshitaka , Goto Koichi 
Published: June 2021

9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.
Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations.
Authors: Ou Sai-Hong Ignatius , Lin Huamao Mark , Hong Jin-Liern , Yin Yu , Jin Shu , Lin Jianchang , Mehta Minal , Nguyen Danny , Neal Joel W. 
Published: June 2021

9098 Background: There is currently no targeted therapy approved for patients with EGFR exon 20 insertion mutations (exon20ins) in NSCLC. Real world treatment outcome evidence for this rare population is limited. This study describes treatment patterns and outcomes in US patients with advanced NSCLC with EGFR exon20ins. Methods: The nationwide Flatiron Health electronic health record-derived deidentified database (cut-off 29 Feb 2020) was used to select 4 separate cohorts: (1) first-line (1L): patients receiving 1L therapy after documented exon20ins (1L start date as index date); (2) second or later line (≥2L): patients receiving ≥2L therapy after documented exon20ins (start date of ≥2L as index date); (3) ≥2L trial-aligned: ≥2L patients with baseline characteristics aligned with the key eligibility criteria of mobocertinib Trial NCT02716116 Part 3; and (4) ≥2L post platinum: ≥2L trial-aligned patients previously treated with platinum-based chemotherapy. Real-world endpoints were: confirmed overall response rate (cORR), PFS, and OS. Additional analyses were conducted for patients treated with immune-oncology therapy (IO). Results: Of 237 EGFR exon20ins patients, 129 patients were included in 1L cohort and 114 were in ≥2L cohort, including 63 ≥2L trial-aligned and 50 ≥2L post platinum patients. In 1L patients, EGFR TKI (28.7%) and platinum-based chemotherapy ± IO (56.6%) were the most common 1L regimens. In ≥2L patients, 28.1% received IO monotherapy, 17.5% received EGFR TKI, and 23.7% received platinum-based chemotherapy ± IO as index treatment. In the 1L setting, median PFS (mPFS) was 5.7 months for platinum-based chemotherapy and 4.5 months for IO + platinum-based chemotherapy. In the ≥2L setting, mPFS was 3.7 months for any therapy and 2.3 months for IO monotherapy. Full effectiveness data are provided in the accompanying table. Conclusions: This real world study provided a benchmark on the treatment outcome in patients with advanced NSCLC with EGFR exon20ins. Platinum-based chemotherapy was the most common 1L therapy and provided the longest mPFS. Immunotherapy, either as monotherapy or in combination with chemotherapy, appeared less effective for treatment of NSCLC with EGFR exon20ins. There is an unmet medical need for improved therapeutic options.[Table: see text]
Chronic immune checkpoint inhibitor (ICI) pneumonitis in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Stuart Jessica , Ricciuti Biagio , Alessi Joao Victor Machado , Nishino Mizuki , Awad Mark M. 
Published: June 2021

9103 Background: ICI pneumonitis is an immune-related adverse event (irAE) of the lung and often requires discontinuation of ICI. While some pneumonitis cases resolve within the recommended 4-6-week period of corticosteroid therapy, others either fail to improve or have multiple flares necessitating longer or repeated courses of steroids. We investigated the clinical features and courses of pts with chronic pneumonitis. Methods: We analyzed 869 pts with NSCLC initiated on ICIs at our institution between 2011 and 2019 for development of ICI pneumonitis. Chronic pneumonitis was defined as any pneumonitis requiring a total of ≥12 weeks of steroids, given either continuously or over multiple courses of treatment. Cases of chronic pneumonitis in which the initial course of steroids lasted ≥12 weeks without interruption were termed “primary refractory pneumonitis”. Subsequent episodes of pneumonitis were categorized as either “recurrent pneumonitis” from ICI rechallenge or “pneumonitis flare” after steroid taper without ICI rechallenge. Chest CT scans were analyzed to classify the imaging patterns. Results: Of the 869 pts analyzed, 44 developed ICI pneumonitis (5.1%) and 22 of the 44 (50%) experienced chronic pneumonitis (Grade 2 in 11, Grade 3 in 9, and Grade 4 in 2). A cryptogenic organizing pneumonia (COP) pattern was the most common CT pattern among all pneumonitis cases (30/44) and in chronic pneumonitis cases (14/22). Among chronic pneumonitis cases, the median number of total weeks on corticosteroid therapy was 25.9 (range: 12.4 – 114.4 weeks). Four pts required additional immunosuppressive agents including mycophenolate or infliximab. Fourteen of 22 pts with chronic pneumonitis had primary refractory pneumonitis, while the remaining 8 pts were weaned off of steroids within 12 weeks but later developed additional episode(s) of pneumonitis, ultimately resulting in a total steroid duration of ≥12 weeks. The 14 pts with primary refractory pneumonitis had significantly shorter time to pneumonitis onset compared to the other 8 pts (median time to onset: 1.8 vs. 5.5 months, Wilcoxon ranksum p = 0.04). Seventeen of 22 patients had their ICI permanently discontinued; of these, 9 pts subsequently experienced pneumonitis flare after steroid taper, necessitating additional course(s) of steroid therapy. 5 of the 22 patients were rechallenged with ICI, and 4 of them had recurrent pneumonitis with ICI rechallenge. Conclusions: Half of the pts diagnosed with pneumonitis developed chronic pneumonitis requiring at least 12 weeks in aggregate of glucocorticoid therapy. Some patients had an initial prolonged steroid course while others initially improved and then flared, even after ICI discontinuation. Recognition of chronic pneumonitis as a distinct and common clinical entity is important in management of pts with ICI pneumonitis.
Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in a phase 3 randomized trial of first-line metastatic uveal melanoma.
Authors: Orloff Marlana , Carvajal Richard D. , Shoushtari Alexander Noor , Sacco Joseph J. , Schlaak Max , Watkins Claire , Abdullah Shaad Essa , Goodall Howard , Butler Marcus O. 
Published: June 2021

9526 Background: Tebentafusp (tebe) is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. Tebe significantly improved OS compared to investigator’s choice (IC) in first line (1L) mUM [NCT03070392]. In a phase (ph) 2 study of tebe in 2L+ mUM (NCT02570308), several checkpoint inhibitor (CPI) refractory pts who were retreated with CPI after tebe achieved durable clinical benefit [1]. We therefore evaluated clinical outcomes of post-tebe CPI in patients treated on the ph3 trial of tebe versus investigator’s choice (IC) [NCT03070392]. Methods: In the ph3 trial, 378 HLA-A*02:01+ 1L mUM pts were randomized 2:1 to tebe (n=252) or IC (n=126) [pembrolizumab (82%), ipilimumab (12%) or dacarbazine (6%)]. No crossover to tebe was permitted, investigators were free to choose subsequent therapy, and there was no re-randomization at time of subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). When pts received more than one subsequent therapy, the first was used in these analyses. Medians and 1-yr OS from the start of post-study therapy are obtained from standard Kaplan-Meier analyses; hazard ratios (HR) are from Cox regression models adjusted for age and gender. Results: 106/252 (42%) tebe pts received ≥ 1 subsequent therapy: 35% CPI, 9% chemo, 6% liver directed therapy (LDT), 6% other. 55/126 (44%) of IC pts received ≥ 1 subsequent therapy: 21% CPI, 10% chemo, 12% LDT, 10% other. Median time to first subsequent therapy was longer for tebe pts at 5.2 mo vs. IC pts at 3.8 mo. The median duration from start of first subsequent CPI to end date was longer in the prior tebe pts at 4 mo vs prior IC pts at 2.8 mo. From the start of any first subsequent therapy, prior tebe pts had longer OS compared to prior IC pts, HR 0.67 (95% CI 0.42, 1.07). Most of the subsequent therapy was CPI, and the OS benefit was also seen in this subset, HR 0.62 (95% CI 0.34, 1.14). For prior tebe pts, the median and 1-yr OS rates from start of any first subsequent therapy were 13 mo and 53% and from start of first subsequent CPI were 16 mo and 63%. Both were higher than the sequence of IC followed by any therapy (11 mo and 44%), IC followed by CPI (9 mo and 47%) and a recent meta-analysis of 2L+ mUM (7 mo and ̃35% 1-yr OS rate). Conclusions: Pts who progressed on tebe and then received CPI had better OS compared to pts who progressed on IC and then received CPI. Further analysis will explore whether confounding factors are influencing this effect. These exploratory data suggest that tebe, relative to IC, may improve outcomes to subsequent CPI. (1)Yang J. et al. ASCO 2019, J . Cli n Oncol 37:15_suppl, 9592. Clinical trial information: NCT03070392.
The use of cryoablation to overcome resistance to PD-1 blockade in unresectable melanoma.
Authors: Mooradian Meghan , Fintelmann Florian J. , Kaufman Howard E. , Mino-Kenudson Mari , Barth Jaimie Lynn , Lawless Aleigha , Sharova Tatyana , Fadden Riley , Rubin Krista M. , Lawrence Donald P. , Frederick Dennie T. , Sade-Feldman Moshe , Sullivan Ryan J. 
Published: June 2021

9538 Background: Percutaneous image-guided cryoablation (cryo) is an established minimally invasive oncologic treatment that modulates the immune microenvironment. We hypothesized that cryo can augment anti-tumor responses in melanoma patients progressing on immune checkpoint inhibitors (ICI). Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryo of an enlarging lesion and ICI continuation for a minimum of 2 additional cycles. Computed tomography was performed at 6-8 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-12 weeks. The primary endpoint was safety and feasibility. Secondary endpoints were overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analyses on pre- and post-cryo tumor biopsy and blood samples were performed. Results: From May 2018 through July 2020, 20 pts were screened, 18 enrolled and 17 treated per protocol. All pts received prior PD-1/PD-L1 monotherapy and 12 (67%) experienced primary resistance to ICI. Median follow-up was 8.5 months. Ablated lesions included lymph nodes (n = 4), lung/pleura (n = 4), soft tissue/bone (n = 3), adrenal (n = 3), chest wall (n = 1), and kidney (n = 1). Peri-procedural events occurred in 3 cases (pneumothorax, diaphragm puncture, osteomyelitis). One pt. with underlying ICI-induced hypophysitis experienced an adrenal crisis post-procedure, which rapidly corrected with stress-dose steroid administration; there were no de novo immune-related adverse events post-ablation and there were no grade 4/5 events. In evaluable pts (n = 17), ORR was 18% and DCR was 47% (3 PR, 5 SD). To investigate the inflammatory state of the tumor microenvironment prior to cryo, PD-1, CD8+ TIL IHC, was performed and will be presented at the meeting. Additional exploratory analyses (serial ctDNA analysis, single cell RNA sequencing, HLA-subtyping) are ongoing. Conclusions: Cryoablation in patients with unresectable melanoma following progression on ICI is feasible with an acceptable side effect profile. Efficacy data of this potentially synergistic approach in metastatic melanoma is encouraging. Correlative analyses are underway to identify biomarkers of response to this novel strategy. Clinical trial information: NCT03290677. [Table: see text]
KEYNOTE-555 Cohort B: Efficacy, safety, and PK of pembrolizumab (pembro) 400 mg every 6 weeks (Q6W) as 1L therapy for advanced melanoma.
Authors: Jacobs Conrad R. , Rapoport Bernardo Leon , Chan Sze Wai , Ruff Paul , Arance Ana Maria , Mujika Karmele , Anderson James Robert , Lala Mallika , Jain Lokesh , Akala Omobolaji Oyekunle , Chartash Elliot , Cohen Graham Lawrence 
Published: June 2021

9541 Background: In KEYNOTE-555, a model-based approach suggested expected drug exposure with pembro 400 mg Q6W is similar to that observed with approved doses of pembro 200 mg or 2 mg/kg Q3W. The pembro Q6W dose is now approved. We present interim efficacy, safety and PK of 1L pembro 400 mg Q6W for patients (pts) with advanced melanoma in KEYNOTE-555 Cohort B (NCT03665597). Methods: Eligible pts had unresectable stage III or IV melanoma, ECOG PS ≤1, and no prior systemic therapy for advanced disease.Pts received pembro 400 mg Q6W for up to 18 cycles (≈2 years).The primary efficacy endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included PFS by BICR per RECIST v1.1 and safety. PK profile and exposure were evaluated for cycle 1 and steady state (cycle 4). Results: Between May 2019 and Jan 2020, 101 pts were enrolled and received ≥1 dose of pembro. Baseline characteristics were generally similar to pt cohorts of historical pembro studies in advanced melanoma. As of the data cutoff date of August 6, 2020, all pts had ≥6 mo of follow-up and 40.6% of pts had discontinued study treatment. Median (range) duration of treatment and doses administered were 8.2 mo (1 day–13.9 mo) and 6 (1–11) doses, respectively. Observed exposure with pembro 400 mg Q6W had lower variability than model predictions and was within PK parameters from clinical experience with other pembro regimens (Table). ORR was 50.5% (95% CI 40.4–60.6). 12.9% of pts had CR and 37.6% had PR. Median PFS was 13.8 mo (95% CI 3.0–not reached). Estimated PFS rates were 56.5% at 6 mo and 54.3% at 12 mo. Treatment-related AEs of any grade occurred in 79.2% of pts (grade 3–4: 6.9% of pts; no deaths due to a treatment-related AE). The most common immune-mediated AEs were hyperthyroidism (6.9%) and hypothyroidism (6.9%). Conclusions: 1L treatment with pembro 400 mg Q6W yielded a clinically meaningful ORR in pts with advanced melanoma. PK, efficacy and safety results from KEYNOTE-555 Cohort B support prior findings from the model-based assessment and indicate that the benefit-risk profile for the more practical pembro 400 mg Q6W regimen is consistent with that of 200 mg or 2 mg/kg Q3W regimens. Clinical trial information: NCT03665597. [Table: see text]
Multicentre retrospective assessment of toxicity and response to immunotherapy in elderly patients with metastatic melanoma.
Authors: Pathmanathan Shivanshan , Babu Hari S , Mason Robert , Htut Saw , Otty Zulfiquer Ali , Lyle Megan , Dzienis Marcin Radoslaw 
Published: June 2021

9565 Background: The incidence of melanoma increases with age, however, elderly patients remain under-represented in landmark immunotherapy trials for metastatic melanoma. This study aims to investigate the impact of age on efficacy and toxicity of immunotherapy, and complications of immunosuppression to treat toxicity. Methods: A multicentre retrospective study involving centres in Australia [Gold Coast University Hospital, Cairns Base Hospital, Townsville University Hospital] was performed to compare the efficacy and toxicity of immunotherapy in metastatic melanoma in patients ≥70 years versus patients < 70 years treated between 2015 and 2019. Data collected included: baseline demographics, PFS, OS, Grade 3 or higher (Gr3+) adverse events as per CTCAEv5, adverse events leading to discontinuation, duration of steroids used to treat toxicity and complications secondary to steroids. Comparison of survival outcomes between the groups was calculated using Kaplan Meier, Log rank test and multivariate Cox regression analysis. Fisher exact test was used to determine differences in toxicity between the two groups. Results: A total of 229 patients were included with 106 patients ≥70years and 123 patients < 70 years. Baseline demographics were similar. Dual immunotherapy (ipilimumab + nivolumab) was less commonly used in patients ≥70years [13 v 38% p < 0.001]. Although the median PFS was numerically higher amongst ≥70years [10.8 v 6.9months p = 0.99], the landmark PFS was not [3yr PFS: 31 v 39%; 4yr PFS: 22 v 39%]. The median OS was similar in patients ≥70 years v < 70years [27.5 v 28.7 months p = 0.91], with similar landmark survival [3yr OS: 46 v 49%; 4yr OS: 42 v 49%]. Age was not associated with a difference in overall survival on multivariate analysis. There was no increase in Gr3+ adverse events in patients ≥70 years [22 v 21% p = 1.00] or discontinuation rates [26 v 20% p = 0.35]. There was one death in a patient < 70years secondary to colitis. There was a significantly higher rate Gr3+ adverse events in ≥70years patients receiving dual immunotherapy [71 v 35% p = 0.029] and a similar rate of Gr3+ adverse events with PDL1 inhibitors [13 v 11% p = 0.7]. Median duration of steroids was similar in both group [15 v 17wks], as was the median duration of high dose steroids defined as greater than 10mg of prednisone [5 v 6wks]. Complications of steroids was numerically higher in the elderly population [42 v 25% p = 0.15]. The most common adverse event to immunosuppression was infection. Conclusions: Patients ≥70years received similar benefit from immunotherapy in comparison to their younger counterparts. Toxicity related to PDL1 inhibitors was similar in both groups and was higher in patients ≥70years receiving dual immunotherapy. Patients ≥70 years had a clinically significant higher rate of complications secondary to steroids.
Adjuvant anti-PD-1 ab (Toripalimab) versus high-dose IFN-a2b in resected mucosal melanoma: A phase randomized trial.
Authors: Cui Chuanliang , Lian Bin , Si Lu , Chi Zhihong , Sheng Xinan , Kong Yan , Wang Xuan , Tian Hui , Mao Lili , Bai Xue , Tang Bixia , Yan Xieqiao , Li Siming , Zhou Li , Guo Jun 
Published: June 2021

9573 Background: Immunotherapies including anti PD-1 ab and high-dose IFN-a2b (HDI) have been approved for adjuvant therapies in resected cutaneous melanoma, but their roles in mucosal melanoma are still unknown. To determine the efficacies of toripalimab versus HDI as adjuvant therapy in patients (pts) with resected mucosal melanoma, this open-label, phase randomized trial was conducted. Methods: Mucosal melanoma pts who have undergone complete resections of localized with or without regional lymphatic disease were randomly (1:1) assigned to receive HDI (15x106 IU/m2/d1-5/w/ 4weeks IH, followed by 9x106 IU tiw IH) or toripalimab (3mg/kg intravenously q2w) for 52 weeks unless disease recurrence, unacceptable toxicity or consent withdrawal. Head and neck primary would receive adjuvant radiotherapy within 6-8weeks after enrollment. The primary end point was RFS in the intention-to-treat population. Data cutoff was December 10, 2020. Clinical trial information: NCT03178123. Results: From Jul 2017 to May 2019, 187 pts were screened, and 145 were randomized into HDI group (n = 72) and toripalimab group (n = 73). The median age was 58years; M:F 37.2%: 62.8%; localized disease 80.7%, regional lymphatic disease 19.3%; local excision ± CLND 37.2%, wide excision ± CLND 62.8%; head and neck primary 39.3%( 87.5% received adjuvant radiotherapy); PDL-1positive 51.0%(CPS≥1%, 22C3), PDL-1 negative 49.0%. There was no difference in baseline characteristics between two groups. At a median follow-up of 31.5 months, there were 93 RFS events (43 in HDI group vs. 50 in toripalimab group), 76 DMFS events (35 vs. 41respectively) and 65 OS events (30 vs. 35 respectively). The median RFS, DMFS and OS were shown in the table. In the HDI group, 32.6% of pts received anti PD-1 ab in the following treatment. Grade 3/4 AEs were reported in 83.3% of pts in HDI group (most decrease of leukocytes or neutrophils) and 15.1% of pts in toripalimab group (mainly increase of amylase or liver enzymes). Discontinuations of treatment due to any AE occurred in 20.8% of HDI group and 15.1% of toripalimab group. Conclusions: Both adjuvant toripalimab and HDI therapy improve RFS of mucosal melanoma. Toripalimab shows longer RFS in PDL1 (+) subgroup and better tolerance than HDI. Clinical trial information: NCT03178123. [Table: see text]