bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mefatinib as first-line treatment of patients with advanced non–small cell lung cancer harboring rare EGFR mutations.
Authors: Wang Pingli , Cao Liming , Tian Panwen , Ren Shengxiang , Miao Liyun , Zhou Chengzhi , Fan Yun , Li Yuping , Lv Dongqing , Zhao Xin , Yang Mei , Zhu Chaonan , Xu June , Song Yong , Wang Kai 
Published: June 2022

9102 Background: Mefatinib is a novel, second-generation, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). A Phase Ib/II study has showed promising efficacy in patients with advanced EGFR (19del/L858R) mutant non-small cell lung cancer (NSCLC). This study is aimed to assess the efficacy and safety of mefatinib as first-line therapy for advanced rare EGFR mutations (G719X/S768I/L861Q) NSCLC. Methods: In this phase II study, we enrolled patients with stage IIIB-IV lung adenocarcinoma with at least one mutation in G719X, L861Q, and S768I who hadn¡¯t received front-line anticancer therapy. Other concurrent EGFR mutations were allowed with the exception of Ex19del, L858R, and exon 20 insertions. Eligible patients were treated with mefatinib 80 mg orally once daily. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 criteria. Results: A total of 21 patients (median age 57.6, 47.62% male) have been enrolled, 80.95% with G719X, 33.3% S768I, and 19.05% L861Q. Six (28.57%) patients had concurrent mutations of G719X and S768I, and one (4.76%) patient had co-mutations of G719X and L861Q. As of data cut-off (Jan, 6, 2022), median follow-up was 25.1 months. Among the 21 efficacy evaluable patients, ORR was 85.71% (95% CI, 63.66-96.95) with a duration of response (DOR) of 22.2 months (95% CI, 8.4-NA). Disease control rate (DCR) was 100% (95% CI, 83.89-100.00). Median progression-free survival (mPFS) was 20.6 months (95% CI, 8.3-NA). Median overall survival (OS) was not reached.. The most common treatment-related adverse events (TRAEs) were rash (20, 95.24%), diarrhea (19, 90.48%), stomatitis (15, 71.43%), and pandactilitis (9, 42.86%). Grade 3 TRAEs were reported in 47.63% patients. Common Grade 3 TRAEs (¡Ý5%) included diarrhea (8, 38.10%) and rash (5, 23.81%). No ¡ÝGrade 4 TRAE or treatment-related SAE reported. 33.33% (n=7) of patients experienced dose reduction due to AEs (mainly diarrhea and rash). All TRAEs were reversible and remained stable or recovered without sequelae after dose reduction. None of the patients discontinued treatment or died due to TRAE. Conclusions: Mefatinib has shown promising anti-tumor activity and a favorable safety profile in patients with advanced NSCLC harboring rare EGFR mutations. Clinical trial information: CTR20190110. [Table: see text]
Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.
Authors: Zhang Li , Peng Ping , Gong Juejun , Zhang Yujie , Chu Qian , Xia Shu , Meng Rui , Chen Yongshun , Han Guang , Zhang Peng , Zhang Lu , Chen Yuan 
Published: June 2022

9114 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.
Increased adherence to molecular profiling recommendations in non–small cell lung cancer through use of prior authorization and peer review.
Authors: Hamilton Stephen A. , Sagar Bhuvana , Christensen Kathryn , Bowers Anne , Dollear Tim 
Published: June 2022

9129 Background: National oncology guidelines advocate for broad molecular profiling to detect potentially actionable driver mutations prior to initiation of first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). Results of genomic tests can confirm the presence of specific cancer tumor mutations that are best treated with more targeted therapies. Recent studies have shown that up to 30% of lung cancer patients may not receive the most effective treatment due to a lack of guideline-concordant genomic testing. We analyzed data from our prior authorization medical oncology program to determine adherence to national guidelines recommendations, and then developed a program to improve adherence to broad molecular profiling utilizing our proprietary prior authorization algorithms and our proactive peer consultation model. Methods: eviCore healthcare uses the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to support its proprietary program for medical oncology drug management, and requires attestation on the results of NCCN recommended genomic/molecular test results in advanced NSCLC during prior authorization of systemic therapy. In November 2019, we implemented a next-generation sequencing (NGS) testing results requirement for metastatic non-squamous NSCLC patients prior to first-line therapy approval. If testing had not been completed, a peer to peer consultation was performed to advocate for testing prior to initiation of chemoimmunotherapy regimens. The rate of appropriate tumor testing is defined by provider attestation of test results prior to initiation of therapy. We define the control period (pre- implementation) as October 2018 through September 2019 ( n = 667). The measurement period (post-implementation) is January 2020 through December 2020 ( n = 390). Results: From pre to post there was a 35% increase in testing adherence (p < 0.001). After the testing requirement was implemented, the appropriate tumor testing rate increased to 99% by the second half of 2020, compared to the control period (62%). Additionally, after the testing requirement began, pembrolizumab utilization for advanced stage NSCLC decreased by a net 4.2% per month. This decrease in pembrolizumab utilization likely reflected patients being matched to more appropriate targeted therapy based on genomic testing results. Conclusions: We demonstrate that by combining medical oncology prior authorization with focused peer consultation, adherence to national society recommendations for broad molecular profiling prior to initiating first line therapy in advanced NSCLC can be significantly improved. By improving testing adherence, the most effective and appropriate therapy can be matched to the patient.
Predictors of biomarker testing among patients (pts) with metastatic non–small cell lung cancer (mNSCLC).
Authors: Robert Nicholas J. , Chen Liwei , Espirito Janet L. , Karhade Mandar , Evangelist Makenzi Colleen , Neubauer Marcus A. , Bullock Susie A. , Walberg Jennifer M. , Coleman Robert L. 
Published: June 2022

9130 Background: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) Consortium pragmatic study assessed real-world biomarker testing rates for mNSCLC within The US Oncology Network of over 1,000 providers. We previously reported that 90% of pts had at least one test performed for ALK, BRAF, EGFR, ROS1, or PD-L1, but only 46% had testing for all 5. We examined patient factors associated with rates of biomarker testing. Methods: Retrospective observational chart review study of pts with mNSCLC initiating first-line systemic therapy between 04/01/2018 and 03/31/2020. Patient characteristics including age, sex, race, geographic location, BMI, laboratory values, histology, performance status, stage at diagnosis, and comorbidities were obtained from iKnowMed electronic health records. Predictors of biomarker testing were identified using multivariable logistic regression. Results: Of the 3474 adults included in the study, median age was 69 years (range 23-90), 51% female, 65% White, 8% Black or African American, and 46% treated in the South US census region. Histology was adenocarcinoma in 74% and squamous cell carcinoma in 19%. Modeling for any biomarker testing resulted in histology and geographic region as significantly associated with increased likelihood of testing: adenocarcinoma vs squamous cell, odds ratio (OR) 1.76 (CI 1.33-3.23, p<0.0001) and Midwest vs South, OR 2.04 (CI 1.24-3.34, p=0.005). For comprehensive testing of all 5 biomarkers, increased albumin, adenocarcinoma or not otherwise specified histology, Midwest, Northeast or West geographic regions, and larger practice size were all significantly associated with increased likelihood of testing, while Black or African American race was associated with significantly decreased likelihood of testing (Table). Conclusions: Black or African American race, smaller practice size, Southern practice, and squamous cell histology were significantly associated with lower comprehensive biomarker testing rates. Understanding clinical and social determinants of health will be important when evaluating interventions to improve testing rates in the prospective phases of the MYLUNG study. [Table: see text]
The 10-year journey of non–small cell lung cancer: A real-world experience.
Authors: Jung Hyun Ae , Kim Kyunga , Chi Sang Ah , Yu Hyeyeon , Park Sehhoon , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju 
Published: June 2022

9133 Background: Over the past 10 years, the treatment of non-small cell lung cancer (NSCLC) has been continuously revolutionized. This study evaluated how this revolution improved outcomes in the real-world. Methods: We collected clinical, pathological, and molecular data of patient with NSCLC using an in house real-time updated cohort (ROOT-HEALTH). The primary objective was the 3-year survival (OS3) rate by clinical stage, histology, and driver mutations including EGFR, ALK, ROS1, RET, MET exon 14 skipping, BRAF V600E, KRAS G12C, and NTRK between two time periods (Period I: 2010-2015 vs. Period II: 2016-2021). Results: We included data on 22,060 patients who received any anti-cancer treatment between January 2010 and December 2020. Adenocarcinoma (AD) was the predominant histology (70.2% in Period I vs. 74.2% in Period II) (Standardized mean difference [SMD] = 0.09, P < 0.001). In Period I, 36.8%, 10.4%, 15.9%, and 34.6% patients were in stage I, II, III, and IV respectively. In Period II, 44.8%, 9.6%, 15.1%, 29.9% were in each stage, respectively (SMD = 0.15, P < 0.001). Patients during Period II were more likely to perform molecular tests for EGFR, ALK, and/or others than those during Period I in both of AD (79.1% in Period I vs. 95.1% in Period II) and non-AD (53.5% in Period I and 85.0% in Period II). In patients with AD, 49.4% in Period I and 56.4% in Period II had any druggable mutations. Among non-AD patients, 4.9% and 6.2% of patients had any druggable mutations in Period I and II, respectively. In patients with AD, in Period I, the OS3 rates were 92.9 %, 72.6%, 56.6%, and 29.0% for each stage (I, II, III, and IV), respectively. In Period II, the OS3 rates of AD were 96.4 %, 86.8%, 70.2%, and 52.1% for each stage, respectively (P < 0.001). In stage IV AD with EGFR mutation, the OS3 rates were 42.5% and 65.4% in Period I and II, respectively (P < 0.001). In stage IV AD with ALK rearrangement, the OS3 rates were 53.2% and 73.6% in Period I and II, respectively (P < 0.001). In patients with non-AD, the OS3 rates were 71.6%, 60.2%, 38.8%, and 10.2% for each stage in Period I. In Period II, the OS3 rates of non-AD were 83.1%, 73.7%, 58.2%, and 29.6% for each stage (P < 0.001). In stage IV non-AD with any druggable mutations, the OS3 rates were 27.1% and 46.0% in Period I and II, respectively (P = 0.05). Conclusions: Our study is meaningful as a large-scale study that reflects changes of survival outcome in a timely manner.Through our real-world experience of over 10 years, the proportions of early stage and were found to be increased. The implementation of molecular testing has also been expanded. Of note, the survival outcomes were remarkably improved across all stages, especially in patients with stage III-IV. Further improvement of outcomes through effect of emerging driver mutations in the next five years is expected.
Nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) +/- ipilimumab (IPI) for kidney transplant recipients (KTR) with advanced cutaneous cancers.
Authors: Schenk Kara M. , Stein Julie E. , Chandra Sunandana , Davar Diwakar , Eroglu Zeynep , Khushalani Nikhil I. , Luke Jason J. , Ott Patrick Alexander , Sosman Jeffrey A. , Aggarwal Vikram , Schollenberger Megan Davis , Sharfman William Howard , Sharon Elad , Bagnasco Serena M. , Taube Janis M. , Topalian Suzanne Louise , Brennan Daniel C. , Lipson Evan J. 
Published: June 2022

9507 Background: Cancer is a leading cause of death among KTR, but these patients (pts) have been excluded from trials of immune checkpoint inhibitors due to immunosuppression and risk of allograft loss. We report findings from the first prospective clinical trial of NIVO + TACRO + PRED +/- IPI in KTR with selected advanced cutaneous cancers. Methods: The primary composite endpoint was lack of tumor progression per RECIST v1.1 without allograft loss at 16 weeks (W) on NIVO. Adult KTR with advanced melanoma, basal, cutaneous squamous, or Merkel cell carcinoma (MEL, BCC, CSCC, MCC), for whom non-immune therapies were insufficient were eligible. Immunosuppression was standardized to low-dose TACRO (goal trough 2-5 ng/mL) + PRED 5mg daily; pts then received NIVO 480mg IV q4W. Pts with progressive disease (PD) could receive NIVO 3mg/kg + IPI 1mg/kg IV q3W x 4 followed by NIVO 480mg IV q4W. Donor-derived cell-free DNA (dd-cfDNA) levels were measured q2W as a potential predictor of allograft rejection. Results: From 11/2019 - 4/2021, of 12 pts enrolled, 8 pts with CSCC, MCC or MEL were evaluable for response (Table). All pts experienced PD on NIVO; treatment-related allograft loss (TRAL) occurred in 1 pt. 6 pts then received IPI + NIVO. Responses: 2 (33%) with marked tumor regression at 6W and eventual complete response (CR; 1 with TRAL), and 4 (67%) with PD (1 with TRAL). 7/8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. Only 2/5 on-NIVO biopsies demonstrated moderate immune infiltrates; both of these pts later developed a CR to IPI + NIVO. Rejecting allografts contained dense immune responses (plasma cells, CD4+ & CD8+ lymphocytes, PD-1+ lymphocytes, macrophages, PD-L1+ glomerular endothelium, and focal PD-1 & PD-L1 positivity in renal tubules). In 2/3 pts with TRAL, elevations in dd-cfDNA levels occurred 10 and 15 days earlier than increases in weekly serum creatinine levels. TRAL #3 occurred after discontinuation of study therapy (including TACRO) and dd-cfDNA monitoring. Conclusions: In KTR receiving low-dose TACRO + PRED, NIVO augments tumor immune cell infiltration in some pts but is insufficient to mediate tumor regression. Adding IPI can enhance anti-tumor immunity and mediate tumor regression. TACRO + PRED was insufficient to prevent allograft rejection after PD-1 +/- CTLA-4 blockade in 2/8 pts. In pts with TRAL, increased dd-cfDNA levels preceded increased serum creatinine. Based on these findings, we are modifying the trial therapy regimen to augment anti-tumor immunity and preserve allograft function. Clinical trial information: NCT03816332. [Table: see text]
AMBER parts 1c and 1e: A phase 1 study of cobolimab plus dostarlimab in patients (pts) with advanced/metastatic melanoma.
Authors: Ribas Antoni , Eroglu Zeynep , Trigo Perez Jose Manuel Manuel , Di Pace Brian , Wang Tianli , Ghosh Srimoyee , Dhar Arindam , Borgovan Theo , Waszak Angela , Davar Diwakar 
Published: June 2022

9513 Background: TIM-3 and PD-1 are markers of T-cell suppression that are upregulated in melanoma. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889), an anti-TIM-3 therapy, monotherapy or with PD-1 inhibitors, including dostarlimab, in pts with solid tumors. Methods: This multicenter, open-label study was conducted in 2 parts: dose escalation (Parts 1 A–D and F–H) and cohort expansion (Parts 2 A–D). Part 1C and exploratory cohort 1E (reported here) included pts with advanced/metastatic melanoma; prior therapies, except for immunotherapies, were permitted. Pts received cobolimab (100 [1C only], 300, or 900 mg IV) with dostarlimab (500 mg IV) Q3W. Part 1C primary endpoints were safety, tolerability, and recommended Phase 2 dose. Objective response rate (ORR; complete [CR] or partial [PR] response per RECIST v1.1) was a secondary endpoint in 1C and the primary endpoint in 1E (ad hoc efficacy analysis reported). An integrated safety analysis for all pts (Parts 1 and 2) receiving cobolimab with dostarlimab, regardless of tumor type or cobolimab dose, is reported here. Results: 28 pts were enrolled in 1C (n=10) and 1E (n=18). Most pts (n=23; 82.1%) had cutaneous disease of the skin. One pt had anorectal mucosal disease and 3 pts in the 900-mg cohort had uveal melanoma. Most pts (67.9%) had an ECOG PS=0. At data cut-off (May 19, 2021), treatment was ongoing in 5 pts. In the integrated safety analysis of pts who received cobolimab 100 mg (n=41), 300 mg (n=167), or 900 mg (n=69) with dostarlimab, treatment-related treatment-emergent AEs (TR-TEAEs) occurred in 53.7%, 57.5%, and 59.4%, respectively. The most common TR-TEAEs (any grade, ≥10% in 100 mg, 300 mg, or 900 mg groups, respectively) were fatigue (22.0%, 13.2%, 24.6%), rash (9.8%, 5.4%, 11.6%), diarrhea (4.9%, 6.0%, 10.1%), and dyspnea (2.4%, 0%, 10.1%). Grade ≥3 TR-TEAEs occurred in 12.2% (100 mg), 10.8% (300 mg), and 20.3% (900 mg); serious TR-TEAEs occurred in 7.3%, 7.8%, and 11.6%, respectively. No pts died due to TR-TEAEs; 2.4% (100 mg), 4.2% (300 mg), and 7.2% (900 mg) discontinued due to TR-TEAEs. ORR and disease control rate (DCR: stable disease [SD] ≥16 weeks, PR, or CR) are shown in the Table. Twelve pts achieved a PR and an immune-related (ir)PR (1 in 100 mg; 8 in 300 mg; 3 in 900 mg groups). Three pts achieved SD (2 in 300 mg; 1 in 900 mg groups); 8 pts had irSD (1 in 100 mg; 4 in 300 mg; 3 in 900 mg groups). Conclusions: Cobolimab with dostarlimab showed preliminary clinical responses in pts with advanced/metastatic melanoma and an acceptable safety profile across advanced cancers. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]
Primary analysis of a phase 2, open-label, multicenter trial of talimogene laherparepvec (T-VEC) plus pembrolizumab (pembro) for the treatment (Tx) of patients (pts) with advanced melanoma (MEL) who progressed on prior anti–PD-1 therapy: MASTERKEY-115.
Authors: Gastman Brian , Robert Caroline , Gogas Helen , Rutkowski Piotr , Long Georgina V. , Chaney Marya F. , Joshi Harshada , Lin Yu-Lin , Snyder Wendy , Chesney Jason Alan 
Published: June 2022

9518 Background: Despite advances in anti–PD-1–based Tx for MEL, an unmet need remains for immunotherapy failure in advanced metastatic or unresectable MEL. Also, there is a growing population of pts who received adjuvant anti–PD-1 and recurred; yet trials to address this population are lacking. Combination Tx with T-VEC, an oncolytic viral intratumoral Tx designed to produce GM-CSF, and pembro, an anti–PD-1 agent, may overcome immunotherapy failure. We report the MASTERKEY-115 primary analysis on the efficacy and safety of T-VEC + pembro in pts with advanced MEL who had progressive disease (PD) on prior anti–PD-1. Methods: This open-label, single-arm, multicenter, phase 2 study (NCT04068181) enrolled pts at 26 international sites (Jan 2020‒Feb 2021). Cohorts 1 and 2, primary and acquired resistance, respectively, received anti–PD-1 in a locally recurrent or metastatic setting and had PD within 12 wks of the last anti–PD-1 dose. Cohorts 3 and 4 included only pts who received adjuvant anti–PD-1 and were disease-free for < 6 mos (Cohort 3) or ≥ 6 mos (Cohort 4) before confirmed PD. Eligible pts had histologically confirmed unresectable or metastatic stage IIIB–IVM1d MEL, measurable and injectable disease, ECOG PS 0/1, and progressed on anti–PD-1 directly before enrollment. T-VEC at standard dosage and pembro 200 mg were given Q3W. The primary endpoint was objective response rate (ORR). Key secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Tx decisions were per modified immune-related response criteria (irRECIST). Results: 72 pts (median age, 65 y) were enrolled. Of the 71 evaluable pts, 37 (52.1%) had stage IVM1b‒d disease, 30 (42.3%) had confirmed PD-L1–positive tumor (CPS ≥ 1%), 20 (28.2%) had a BRAFV600 mutation, and 21 (29.6%) had LDH > 1ULN. At data cutoff (Aug 2021), 47 (65.3%) pts remained on study. ORR was 0%, 6.7%, 40%, and 46.7% in cohorts 1–4, respectively (table). Any-grade Tx-related adverse events (TRAEs) were reported in 54 (76.1%) pts; the most common were pyrexia (29.6%), fatigue, and influenza-like illness (15.5% each). Grade ≥ 3 TRAEs occurred in 9 (12.7%) pts. Conclusions: T-VEC + pembro showed manageable safety in pts with advanced MEL after anti–PD-1 failure; the promising ORR observed in pts who progressed on prior adjuvant anti–PD-1 warrants further analysis. Clinical trial information: NCT04068181. [Table: see text]