bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osimertinib as neoadjuvant treatment for resectable stage II-IIIB EGFR mutant lung adenocarcinoma (NEOS).
Authors: Lyu Chao , Fang Wentao , Ma Haitao , Wang Jia , Jiao Wenjie , Wang Rui , Wu Nan , Xu Shi-Dong , Yang Yue 
Published: June 2021

8524 Background: Neoadjuvant treatment has demonstrated efficacy in several types of cancer and is increasingly used for the treatment of early-stage cancers with the potential of cancer downstaging to enhance complete surgical resection and to improve clinical outcomes. Recent evidences have demonstrated that the neoadjuvant use of first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may provide clinically meaningful improvement in EGFRm non-small cell lung cancer (NSCLC) patients, however, limited data were reported on osimertinib, the third-generation EGFR-TKI, in the neoadjuvant setting. Here we present an interim analysis of osimertinib as neoadjuvant treatment for resectable EGFRm NSCLC. Methods: NEOS is a prospective, multi-center, single-arm study to evaluate the efficacy and safety of osimertinib as neoadjuvant treatment in resectable EGFRm (19del/L858R) lung adenocarcinoma. Eligible patients were treated with osimertinib 80 mg orally per day for six weeks followed by surgery. Assessment of response to neoadjuvant therapy was performed according to RECIST 1.1. The primary endpoint was response rate. Secondary endpoints included safety, R0 surgical resection rate, quality of life, major pathologic response (MPR) rate, pathological complete response (pCR) rate, and N2 downstaging rate. Results: As of Dec. 17, 2020, 18 eligible patients (median age 61 [range 46-73], 27.8% male, 22.2% ECOG PS 1) have been enrolled. Patients with clinical stages IIa, IIb, and IIIa (8th AJCC) accounted for 16.7%, 22.2% and 61.1%, respectively. Half (9/18) of the patients had EGFR exon 21 L858R mutations and the other half (9/18) had EGFR exon 19del mutations. Amongst all 15 patients who completed efficacy assessment after neoadjuvant osimertinib, the response rate (RR) was 73.3% (11/15) and the disease control rate (DCR) was 100% (15/15). R0 surgical resection was performed in 93.3% (14/15) patients. Pathological downstaging occurred in 53.3% (8/15) patients. 42.9% (3/7) of the patients with confirmed N2 lymph nodes experienced downstaging to N0 disease after receiving neoadjuvant osimertinib. One patient was identified with a pCR. Adverse events (AEs) were reported in 66.7% (12/18) of patients, with the most common AE being rash (8/18, 44.4%), oral ulceration (8/18, 44.4%), and diarrhea (5/18, 27.8%). No grade 3-5 AEs or serious AEs were reported. Conclusions: Interim analysis from this study indicated neoadjuvant osimertinib as an effective and feasible treatment in patients with resectable stage II-IIIB EGFRm NSCLC. The trial is ongoing and the final results will be provided in the future. Clinical trial information: ChiCTR1800016948.
Cost evaluation of adjunctive osimertinib use in resected epidermal growth factor receptor-positive non-small cell lung cancer.
Authors: Choi Briana , Alrawashdh Neda , McBride Ali , Abraham Ivo 
Published: June 2021

8525 Background: About 30% of patients with epidermal growth factor receptor positive (EGFR+) non small cell lung cancer (NSCLC) are eligible for surgical resection. Osimertinib, a first line therapy for advanced EGFR+ NSCLC (stages 1B, 2, 3A), has shown clinical efficacy compared to placebo as an adjunctive therapy post resection. We evaluated the cost effectiveness/utility of this regimen. Methods: A two health state Markov model was built (disease free vs. disease recurrence or death). Disease free survival (DFS) curves were digitized and fitted to exponential function. 3 year timeline as patients received osimertinib for 3 years in published data. US payer perspective and 3% discount rate were applied. Drug costs were per Redbook whole acquisition cost and monitoring costs were from published data (US$ 2020). No adverse events > 5% were reported hence none were included. Life years (LY) and quality adjusted life years (QALY) were estimated for each stage. Incremental cost-effectiveness and utility ratios (ICER/ICUR) for LY and QALY gained were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Results: Shown in the table are BCA and (PSA) results. Using LY as outcome, for stage 1B, incremental DFSLY of 0.40 (0.39) and incremental cost of $500,782 ($501,034) yielded an ICER/DFSLYG of ̃$1.3 million (M) (̃$1.2 M). For stage 2, incremental DFSLY of 0.79 (0.79) and incremental cost of $503,144 ($503,092) resulted in an ICER/DFSLYG of $636,913 ($638,278). For stage 3A, incremental of DFSLY of 0.18 (0.07) and incremental cost of $322,356 ($293,377) yielded an ICER/DFSLYG of ̃$1.2 M (̃1.2 M). The incremental costs are the same for QALY outcomes. Using QALY as outcome, for stage 1B, incremental of DFSQALY of 0.26 (0.27) yielded an ICUR/DFSQALY of ̃$1.9 M. In stage 2, incremental DFSQALY of 0.53 (0.53) resulted in an ICUR/DFSQALY of $950,616 ($952,654). For stage 1C, incremental DFSQALY of 0.18 (0.07) yielded an ICUR/DFSQALY of ̃$1.8 M (̃$3.7 M). Conclusions: The ICERs and ICURs indicate that cost effectiveness varies markedly across stages of disease. Stage 2 showed the lowest cost to outcome association. In general, the cost burden of adjunctive maintenance therapy with osimertinib in resected EGFR+ NSCLC is substantial relative to the observed clinical benefit. The incremental benefit of osimertinib in stage 2b is more evident than the ones in 1B and 3A.[Table: see text]
Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.
Authors: Sankar Kamya , Bryant Alex K. , Green Michael , Ramnath Nithya 
Published: June 2021

8546 Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p < 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.
Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).
Authors: Lu Shun , Dong Xiaorong , Jian Hong , Chen Jianhua , Chen Gongyan , Sun Yuping , Ji Yinghua , Wang Ziping , Shi Jianhua , Lu Junguo , Chen Shaoshui , Zhang Guojun , Lv Dongqing , Liu Chunling , Li Juan , Yu Xinmin , Lin Zhong , Yu Zhuang , Wang Zhehai , Cui Jiuwei ,   Hansoh Pharma Clinical Development Group
Published: June 2021

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value <0.0001). DoR was also significantly prolonged with Au. Median OS has not been reached. Efficacy and relevant safety results are summarized in Table. Despite a significantly longer duration of treatment (median 463 vs 254 days), Au was associated with a lower incidence of rash, diarrhea, AST/ALT increase, and treatment related serious adverse events (SAEs) (4.2% vs 11.2%). Au was associated with more frequent events of CPK increased, platelet count decreased, and neutrophil count decreased, which were predominantly low grade. Conclusions: Au significantly prolonged PFS and DoR compared to G as first-line therapy in pts with advanced NSCLC with EGFRm. Au demonstrated a favorable safety profile, especially regarding toxicities mediated by wild-type EGFR. These results establish Au as a promising option for advanced NSCLC with EGFRm. Clinical trial information: NCT03849768. [Table: see text]
Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): Additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study.
Authors: Ramalingam Suresh S. , Zhou Caicun , Kim Tae Min , Kim Sang-We , Yang James Chih-Hsin , Riely Gregory J. , Mekhail Tarek , Nguyen Danny , García Campelo Maria Rosario , Felip Enriqueta , Vincent Sylvie , Jin Shu , Bunn Veronica , Lin Jianchang , Lin Huamao Mark , Mehta Minal , Janne Pasi A. 
Published: June 2021

9014 Background: No approved targeted therapies are available for EGFR ex20ins+ mNSCLC. Mobocertinib, a first-in-class, potent, oral TKI targeting EGFR ex20ins mutations, has Breakthrough Therapy Designation in the US and China for post-platinum-based chemotherapy pts with EGFR ex20ins+ mNSCLC. Methods: This 3-part, open-label, multicenter study (NCT02716116) has dose-escalation/expansion and extension (EXCLAIM) cohorts. Pts with EGFR ex20ins+ mNSCLC, ECOG status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease received mobocertinib 160 mg QD. Primary endpoint was confirmed objective response rate (ORR; RECIST v1.1) assessed by independent review committee (IRC). We present additional efficacy and safety data for 114 platinum-pretreated pts (PPP) and 96 pts from EXCLAIM safety cohort. Results: Results are from Nov 1, 2020, data cutoff. Among PPP pts (n=114; median age 60 y [27–84 y]), 66% were female, 60% were Asian, and 59% had ≥2 prior systemic anticancer lines. Confirmed ORR per IRC was 28%, including 1 complete response (CR); disease control rate (DCR) was 78% [95% CI: 69–85]; median duration of response (DOR) was 17.5 mo (Table). In EXCLAIM (n=96; median age 59 y [27–80 y]), 65% were female, 69% were Asian, and 49% had ≥2 prior lines. Confirmed ORR per IRC was 25%, with 1 CR; DCR was 76% [95% CI: 66–84]; median DOR was not reached (Table). In EXCLAIM, baseline brain metastases were present in 33/96 pts (34%); the first site of disease progression by IRC was the brain in 40% of all pts and 73% of pts with baseline brain metastases. Confirmed responses were seen in all prespecified subgroups in PPP and EXCLAIM. Efficacy by EGFR ex20ins mutation variant will be presented. Treatment-related adverse events (TRAEs; >20%) in PPP were diarrhea (91%), rash (45%), paronychia (38%), decreased appetite (35%), nausea (34%), dry skin (31%), vomiting (30%), increased blood creatinine (25%), stomatitis (24%), and pruritus (21%); the only grade ≥3 TRAE in ≥5% was diarrhea (22%). AEs leading to discontinuation in >2% were diarrhea (4%) and nausea (4%). A similar safety profile was observed in EXCLAIM. Conclusions: Mobocertinib demonstrated clinically meaningful benefit for pts with EGFR ex20ins+ mNSCLC in PPP and EXCLAIM cohorts, with a manageable safety profile. Clinical trial information: NCT02716116. [Table: see text]
Association of a very high tumor mutational load with increased CD8+ and PD-1+ T-cell infiltration and improved clinical outcomes to PD-(L)1 blockade across different PD-L1 expression levels in non-small cell lung cancer.
Authors: Ricciuti Biagio , Arbour Kathryn Cecilia , Alessi Joao Victor Machado , Mahadevan Navin , Lindsay James , Sinha Rileen , Vokes Natalie I. , Recondo Gonzalo , Lamberti Giuseppe , Rizvi Hira , Leonardi Giulia Costanza , Plodkowski Andrew J. , Felt Kristen , Tolstorukov Michael , Janne Pasi A. , Van Allen Eliezer Mendel , Sholl Lynette M. , Rodig Scott J. , Hellmann Matthew D. , Awad Mark M. 
Published: June 2021

9018 Background: Although high TMB correlates with improved outcomes to immune checkpoint inhibitors (ICI) in patients (pts) with non-small cell lung cancer (NSCLC), an optimal TMB cutoff to discriminate cancers most likely to respond to ICI has not been identified. Whether TMB impacts outcomes to ICI in different PD-L1 levels subgroups is also unclear. Methods: Unbiased recursive partitioning (URP) was used to identify an optimal TMB cutoff for objective response rate (ORR) in two independent cohorts of pts with NSCLC treated with ICI at DFCI and MSKCC. TCGA was interrogated to find differences in tumor immune cell subsets according to the TMB cutoff identified. Multiplexed immunofluorescence (IF) for CD8, PD-1, PD-L1, Foxp3, and CK7 was also performed on NSCLC samples at the DFCI. Results: In the DFCI (N=686) and MSKCC (N=672) cohorts, URP found an optimal TMB cutoff for ORR at 19 mutations/megabase (mut/Mb), corresponding to the ̃90th percentile in each cohort. Median progression-free (PFS) and overall survival (OS) were significantly longer in NSCLCs with TMB ≥19 mut/Mb vs <19 mut/Mb, in both cohorts (Table). After harmonizing TMB between DFCI OncoPanel and MSK-IMPACT NGS platforms, URP confirmed an optimal TMB cutoff for ORR at the 90th percentile in the combined cohort, which also associated with longer PFS/OS to ICI (Table). A TMB ≥90th percentile correlated with longer PFS/OS to ICI among NSCLCs with PD-L1 levels ≥50% and 1-49%, and longer PFS among those with PD-L1 <1% (Table). Cell subset transcriptome analysis from the TCGA showed higher proportions of CD8+ T cells (P=0.02) and M1 macrophages (P<0.01) among NSCLCs with a TMB ≥ vs <90th percentile. IF confirmed increased CD8+, CD8+ PD1+ T-cell infiltration (P<0.01), and increased CD8+/Foxp3+ ratio in NSCLC with very high TMB Conclusions: A very high TMB is associated with better outcomes to ICI and a distinct immunophenotype in NSCLC. Rational integration of TMB and PD-L1 expression may identify NSCLCs most likely to respond to ICI.[Table: see text]
Phase II trial of atezolizumab (A) + carboplatin (C) + pemetrexed (P) + bevacizumab (B) in pts with stage IV non-squamous non-small cell lung cancer (NSq-NSCLC): Big Ten Cancer Research Consortium Study LUN 17-139.
Authors: Ardeshir-Larijani Fatemeh , Althouse Sandra K. , Leal Ticiana , Feldman Lawrence Eric , Abu Hejleh Taher , Patel Malini , Gentzler Ryan D. , Miller Adam Ryan , Hanna Nasser H. 
Published: June 2021

9034 Background: The addition of A to C+ Paclitaxel (Pac) + plus B improved progression free survival (PFS) and overall survival (OS) compared with C + Pac + B alone in pts with metastatic NS-NSCLC. However, C + Pem is more commonly used for this patient population with a shorter infusion time and favorable toxicity profile compared with Pac. Methods: Multicenter single arm phase II clinical trial of chemo and immunotherapy-naïve pts with stage IV NSq-NSCLC. All pts received A (1200 mg, D1) + C (AUC 5, D1) + P (500 mg/m2, D1) + B (15mg/kg D1) q3 week x4. If non-PD, pts could receive maintenance APB until PD or intolerable side effects. The primary endpoint was 1 yr. PFS. Sample size of 42 planned with 87% power and two-sided type I error of 0.05 for 1 yr PFS. Secondary endpoints included ORR, disease control rate (DCR) [defined by CR + PR + SD], and toxicity. Results: 30 pts were enrolled from 11/15/2018 to 10/5/2020. The study was closed early due to 3 patient deaths, possibly related to treatment (VTE, Febrile neutropenia, colonic perforation). Median age 64 (range 38-83); M/F 20/10; mutations in EGFR/ALK/KRAS/BRAF (5/1/4/2); PD-L1 TPS < 1%/1-49%/ > 50% (9/14/6) and one pt did not have PDL-1 status. Median f/u was11.6 mos (range 1-20). ORR 35.71% (95% CI: 18.64%-55.95%), DCR 92.85% (95% CI: 83%-100%). 1yr PFS and OS were 55.27% and 82.90% respectively. The most common G III and G II toxicity were HTN (20%) and fatigue (33.3%).3 pts had G IV toxicity (Anemia, Febrile neutropenia and colonic perforation) and 2 pts had Grade (G) V toxicity (VTE, Hypoxia/Sepsis). Conclusions: Atezolizumab + Carboplatin + Pemetrexed + Bevacizumab was associated with longer DCR, PFS, and OS than historical controls. 3 on-treatment deaths, possibly related to therapy (more likely bevacizumab), prompted early closure. A phase 3 study evaluating this regimen is ongoing by another group NCT03786692. Clinical trial information: NCT03713944.
Phase II study of brigatinib in ROS1 positive non-small cell lung cancer (NSCLC) patients previously treated with crizotinib: Barossa cohort 2.
Authors: Daga Haruko , Niho Seiji , Sakakibara-Konishi Jun , Tanaka Hiroshi , Goto Yasushi , Ohashi Kadoaki , Toyozawa Ryo , Kodani Masahiro , Takahashi Toshiaki , Hattori Yoshihiro , Morise Masahiro , Ikeda Takaya , Matsumoto Shingo , Yoh Kiyotaka , Nomura Shogo , Goto Koichi 
Published: June 2021

9040 Background: Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket, study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2. Patients with ROS 1 positive solid tumors other than NSCLC were enrolled in the cohort 3. This time we report the cohort 2 results. Methods: Patients with advanced, previously treated with crizotinib, ROS1 positive NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoint was PFS, OS, and safety. The sample size was set at 19 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 20% and 50%, respectively. Results: From July 2019 and Jan 2020, 19 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 60 (31-75) years; women, n = 10 (53%); ECOG PS of 0 to 1, n = 18 (95%); never smoker, n = 11 (58%); tumor histopathological type: adenocarcinoma, n = 18 (95%). Five and 6 patients achieved PR and SD, respectively at data cutoff date of 30 Oct 2020. The ORR was 26.3% (90%CI, 11.0-47.6), and the disease control rate was 57.9% (95%CI, 33.5-79.7). The median duration of follow-up for PFS was 12.0 months. The median PFS was 7.3 months (95% CI, 1.3-9.3), and the 1-year PFS rate was 26.9% (95%CI, 9.2-48.6). Grade ≥3 TRAEs were CPK increased (21.1%), infection (5.3%), AST and/or ALT increased (5.3%), hypercalcemia (5.3%), anorexia (5.3%), hypoxia (5.3%), erythema (5.3%), hypertension (5.3%). Pneumonitis was observed in one patient (5.3%, Grade 2). No treatment-related death was observed. Conclusions: Brigatinib has modest activity for ROS1 positive NSCLC patients previously treated with crizotinib. The safety profile of brigatinib was consistent with previous studies. Enrollment of the cohort 1 for ROS1 inhibitor-naïve NSCLC patients is ongoing, and the data will be presented at a future congress. Clinical trial information: JapicCTI-194851.