bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase Ib/II study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL).
Authors: Li Jianyong , Zhou Keshu , Nian Weiqi , Cui Guohui , Wang Jishi , Zhang Xiaoping , Cen Hong , Li Fei , Yi Shuhua , Feng Ru , Xu Chongyuan , Qian Wenbin , Liu Lihong , Li Caixia , Zhao Xielan , Chen Zi , Qiao Junxiao , Zhang Hongli , Ahmad Mohammad , Zhai Yifan
Published: June 2022

7543

Background: B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins. Approved BCL-2i venetoclax requires a slow dose ramp-up to limit risk of tumor lysis syndrome (TLS) and has been associated with severe neutropenia. Investigational single-agent lisaftoclax is a novel, oral BCL-2i active against hematologic malignancies (HMs), with potentially synergistic antitumor effects when combined with other agents in B-cell malignancies. Methods: The aim of this multicenter open-label study was to evaluate dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), and pharmacodynamics of lisaftoclax in pts with R/R CLL/SLL (per 2008 iwCLL NCI-WG guidelines). Lisaftoclax was administered orally once daily at 3 dose cohorts (400, 600, or 800 mg) every 28 days, with 15 pts in each cohort. Results: As of the data cutoff date of January 25, 2022, 45 pts had been enrolled, with a median (range) age of 58 (38-80) years. DLT and MTD were not observed. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 400 to 800 mg (average half-life: 4.2-6.6 hours). A total of 42 pts experienced any-grade treatment-related adverse events (AEs), including neutropenia (55.6%); anemia (42.2%); decreased leukocyte count (40%); thrombocytopenia (37.8%); lowered lymphocyte count (17.8%); hyperuricemia (31.1%); hypokalemia (24.4%); increased blood bilirubin (22.2%); hypertriglyceridemia (20%); diarrhea (20%); hyperphosphatemia, hypocalcemia, and decreased weight (15.6% each); increased AST (15.6%) and blood LDH (13.3%); pyrexia; and increased ALT and blood creatinine (11.1% each). A total of 28 (62.2%) pts experienced grade ≥ 3 AEs and 13 (28.9%) serious AEs. Of these, 25 (55.6% of total) and 9 (20%) were related to lisaftoclax, and 14 (31.1%) led to treatment discontinuation. One clinical TLS was reported. With a median (range) treatment of 7 (1-17) cycles and median (range) time to response of 1 (1-13) cycles, 1 of 41 evaluable pts with CLL experienced complete response (CR) and 27 with CLL/SLL achieved partial response (PR), for an objective response rate (ORR) of 68.29%. The RP2D of lisaftoclax as monotherapy was determined as 600 mg. Conclusions: BCL-2i lisaftoclax was well tolerated up to 800 mg/day. There were no significant new or unmanageable safety findings, and the ORR was 68.29%. Lisaftoclax may offer a treatment alternative for pts with R/R HMs, with a daily ramp-up schedule that may be more convenient and “user friendly.” Clinical trial information: NCT04494503.
A novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma (RRMM): Updated phase 1b results for daratumumab in combination with teclistamab (a BCMA x CD3 bispecific antibody).
Authors: Rodríguez-Otero Paula , D'Souza Anita , Reece Donna Ellen , van de Donk Niels W.C.J. , Chari Ajai , Krishnan Amrita Y. , Martin Thomas G. , Mateos Maria-Victoria , Morillo Daniel , Hurd David Duane , Rosiñol Laura , Sureda Balari Anna , Wäsch Ralph , Vishwamitra Deeksha , Wang Lin Shun Xin , Prior Thomas , Vandenberk Lien , Smit Marie-Anne Damiette , Oriol Rocafiguera Albert , Dholaria Bhagirathbhai R.
Published: June 2022

8032

Background: Teclistamab (tec; JNJ-64007957) is a BCMA × CD3 T-cell redirecting bispecific antibody under investigation in patients (pts) with RRMM. Daratumumab (dara) is a CD38 mAb with direct on-tumor and immunomodulatory actions. Initial clinical data from the phase 1b multicohort TRIMM-2 study support the combination of tec + dara for the treatment of RRMM, with tolerable safety, no overlapping toxicities, and promising efficacy. We present updated results with additional pts and longer follow-up. Methods: Eligible MM pts aged ≥18 y had received ≥3 prior lines of therapy (LOT; including a proteosome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double-refractory to a PI and IMiD. Pts treated with anti-CD38 therapy ≤90 d prior were excluded. Pts received dara SC 1800 mg per approved schedule and tec SC 1.5–3 mg/kg QW or Q2W. Primary objectives were to identify the recommended phase 2 dose of tec for combination therapy and evaluate safety of the combination. Responses were assessed by IMWG criteria. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Results: At data cutoff (Jan 13, 2022; safety population: N=46), median follow-up was 7.2 mo (range 0.1–16.6; median age 67 y [range 50–79]; 52% female). Pts received a median of 6 prior LOT (range 2–17; 74% triple-class exposed; 63% penta-drug exposed; 15% anti-BCMA exposed). 91% of pts had ≥1 AE (grade 3/4 78%), most commonly CRS (61%; all grade 1/2; median time to onset 2 d; median duration 2 d), neutropenia (54%; grade 3/4 50%), anemia (46%; grade 3/4 28%), thrombocytopenia (33%; grade 3/4 28%), and diarrhea (33%; grade 3/4 2%). Infections occurred in 29 pts (63%; grade 3/4 28%). One pt had grade 1 ICANS that fully resolved. Among 37 response-evaluable pts, ORR was 78% (29/37); 27 pts (73%) had very good partial response (VGPR) or better (Table). Median time to first response across dosing cohorts was 1.0 mo (range 0.9–2.8); median duration of response was not reached. Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed with tec + dara, supporting potential synergy of the combination in pts with prior anti-CD38 exposure. Updated results will be presented. Conclusions: Tec + dara provides a novel immunotherapy approach for the treatment of RRMM that may yield improved clinical efficacy in heavily pretreated pts. Clinical trial information: NCT04108195. [Table: see text]
Early intervention for high-risk and low-risk of progression for patients with smoldering multiple myeloma.
Authors: Sweeney Nathan W. , Cheung Christian S. , Molina Thomas H. , Ahlstrom Jennifer M.
Published: June 2022

8058

Background: Previous studies have observed smoldering multiple myeloma (SMM) patients with a biomarker criteria of > 20% bone marrow plasma cells, > 2 g/dL M protein spike, and > 20 free light chain ratio, also known as 20/2/20, are at a higher risk of progressing to multiple myeloma (MM) than others. These findings have ignited interest in pursuing early intervention for these high-risk patients. However, we asked if early intervention would be beneficial for all SMM patients regardless of the progression risk level. Methods: We utilized real-world data from HealthTree Cure Hub for Multiple Myeloma to first, determine whether 20/2/20 resulted in a higher risk of progression and second, analyze whether early intervention delayed progression from SMM to MM. A 2-sample t-test was used to compare 20/2/20 to non-20/2/20 patients, as well as in the comparison between SMM patients who received early intervention with treatment to without early intervention. Results: We found that patients who met at least two of the criteria of 20/2/20 had a tendency to progress to MM 35% faster than patients who did not meet the criteria (n = 36, p-value < 0.10). While not significant, it’s still worth noting that there is a difference in the mean time to progression for these patients. Next, we found SMM patients who do not receive early intervention with treatment develop MM two times faster than those who do receive early intervention with treatment, regardless of progression risk level (n = 129, p-value < 0.001). Conclusions: Our results revealed that at least two of the biomarker criteria could aid in the identification of patients with a higher risk of progression. However, a casual approach of “sit and wait” for patients to develop 20/2/20 is not warranted since our findings revealed that all SMM patients benefited from treatment intervention regardless of the progression risk level.
Predictors of adjuvant chemotherapy refusal in lung cancer: A National Cancer Database Study.
Authors: Katel Anjan , Nelson Rebecca A. , Pathak Ranjan
Published: June 2022

8521

Background: Adjuvant chemotherapy (AC) have been shown to improve overall survival in non-small cell lung cancer (NSCLC). Despite showing significant survival benefit across various age groups, patients are known to refuse AC. However, the factors associated with such a decision remain poorly understood in lung cancer. We therefore sought to investigate the factors associated with AC refusal in a nationally representative database in the United States (US). Methods: From 2004 to 2017, adults (≥20 years) with histologically confirmed non-small cell lung cancer (NSCLC) who underwent complete resection and were deemed to be chemotherapy eligible (node-positive or size ≥5 cm) were identified in the National Cancer Database (NCDB). Annual trends and factors associated with refusal of AC in chemotherapy-eligible NSCLC patients were evaluated using Joinpoint regression and multivariable logistic regression. Results: Among the 44,957 patients who met the inclusion criteria, 18,468 (3,678 (8.2%)) were noted to refuse chemotherapy in the NCDB. Patients refusing adjuvant chemotherapy were more likely to be elderly (OR 1.08, 95% CI, 1.07-1.08; P<.001), uninsured when compared with government insurance (OR 1.79, 95% CI, 1.38-2.33; P<.001), treated in the Western region of the when compared with patients in the Northeast (OR 1.47, 95% CI, 1.28-1.68; P<.001). They were also more likely to have a higher Charlson score versus patients with Charlson score of zero (OR 1.31, 95% CI, 1.18-1.46; P<.001), have squamous cell carcinoma versus adenocarcinoma (OR 1.20, 95% CI, 1.11-1.31; P<.001), undergo pneumonectomy versus lobectomy (OR 1.31, 95% CI, 1.16-1.47, P<.001), and have ≥2 weeks hospital length of stay versus < 2 weeks (OR 2.25, 95% CI, 1.93-2.63; P<.001). Conclusions: In our analysis, we identified several sociodemographic and clinicopathologic variables that were independently associated with chemotherapy refusal. We saw the number of patients refusing AC increased sharply during the study period. Our study shows that in addition to poor post-operative recovery, underlying sociodemographic factors might predict patients at risk for refusing adjuvant chemotherapy in lung cancer. Further understanding of these factors might help devise effective interventions to motivate patients to undergo potentially life-extending chemotherapy in lung cancer.
A phase I study of anlotinib with concurrent chemoradiotherapy for limited-stage small cell lung cancer.
Authors: Huang Dingzhi , Ren Kai , Wang Xinyue , Lin Li , Chen Jinliang , Wang Liuchun , Meng Zhaoting , Zhao Lujun
Published: June 2022

8579

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for limited-stage small-cell lung cancer (LS-SCLC). However, LS-SCLC remains an area of high unmet medical need. Anlotinib is an antiangiogenic multi-target tyrosine kinase inhibitor. In the phase II ALTER-1202 trial, anlotinib significantly improved clinical outcomes in advanced small-cell lung cancer. We report here a phase 1 trial of anlotinib with CCRT for LS-SCLC. Methods: This is a prospective, single-arm, phase I clinical trial using a 3+3 design. Patients aged between 18 and 75 with previously untreated LS-SCLC, PS 0-1 and adequate organ function are eligible. Patients received anlotinib (12mg, qd, d1-14, q3w) and chemotherapy (etoposide, 100 mg/m2, d1-3, q3w and cisplatin, 25 mg/m2, d1-3, q3w) for cycle 1, then anlotinib [dose escalation at 3 levels (DL1-3) 8mg, 10mg and 12mg, qd, d1-14, q3w], chemotherapy (etoposide, 50 mg/m2, d1-5, q4w and cisplatin, 25 mg/m2, d1-3, q4w) and thoracic radiotherapy (60-66 Gy in 30-33 daily 2-Gy fractions starting on day 1 of cycle 2) for cycles 2–3, then anlotinib (12mg, qd, d1-14, q3w) and chemotherapy (etoposide, 100 mg/m2, d1-3, q3w and cisplatin, 25 mg/m2, d1-3, q3w) for cycles 4-6. Cycles 5-6 were given as appropriate according to the patient's physical condition. Prophylactic cranial radiation was given according to the judgment of the investigator after CCRT. The purpose of this study is to determine the maximum tolerated dose (MTD) of anlotinib when combination with CCRT. Results: Twelve patients were enrolled from May 2020 to September 2021. No DLTs were observed in DL1 (3 patients) or DL2 (3 patients). At DL3 (6 patients), 1 patient had a DLT of grade 3 pulmonary embolism. Grade 3 adverse events were white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, hypertension, albumin decreased and pulmonary embolism. One patient had grade 3 pulmonary embolism and grade 4 neutrophil count decreased in DL3 at cycle 1. One patient had grade 2 radiation pneumonitis after cycle 5 and grade 1 radiation esophagitis at cycle 3 in DL3. One patient had grade 2 radiation esophagitis at cycle 3 in DL2. The MTD was not reached. Conclusions: Combined treatment with anlotinib and CCRT for limited-stage small cell lung cancer is well tolerated and further clinical investigation is warranted. Clinical trial information: NCT04882033.
Three days of CIV rh-Endostatin in combination with PD-1 antibody plus chemotherapy as first-line regimen for EGFR/ALK-negative, advanced or metastatic, non-squamous non–small cell lung cancer (NSCLC): A open label, multicenter, phase II and cohort study (ENPOWER).
Authors: Wang Dong , Feng Yan , Bai Yuju , Ma Hu , Huang Li , Zhu Tienian , Qian Haihong , Li Yanping , Fang Xinjian , Ren Biyong
Published: June 2022

9031

Background: rh-Endostatin, an antiangiogenic agent, in combination with chemotherapy is recommended by the CSCO guideline as the first-line treatment for EGFR/ALK-negative, advanced or metastatic, non-squamous non–small-cell lung cancer (NSCLC). However, evidence supporting the application of rh-Endostatin plus PD-1 antibody in clinical settings has been limited. The ENPOWER study is an open-label, multicenter, phase II and cohort study to evaluate the efficacy and safety of three days of continuous intravenous infusion (CIV) of rh-Endostatin in combination with PD-1 antibody plus chemotherapy as the first-line regimen for EGFR/ALK-negative, advanced or metastatic, non-squamous NSCLC. Methods: ENPOWER was an open label, multicenter, phase II and cohort study. Patients with EGFR/ALK-negative, advanced or metastatic, non-squamous NSCLC were enrolled and assigned into the following two cohorts. Patients in Cohort 1 (PD-1 combination) received rh-Endostatin plus PD-1 antibody plus standard chemotherapy (Carboplatin or Cisplatin plus Pemetrexed) during the induction period up to 4 - 6 cycles and rh-Endostatin plus PD-1 antibody during the maintenance period until disease progression or intolerable adverse events. Those in cohort 2 different from in cohort 1 was not subject to PD-1 antibody. Results: 43 subjects were evaluable for efficacy analysis, with 15 in Cohort 1 (PD-1 combination) and 28 in Cohort 2. ORR and DCR was 53% and 93% in Cohort 1 (CR, 0; PR, 8; SD, 6; PD,1) and 39% and 86% in Cohort 2 (CR 0; PR 11; SD, 13; PD, 4), respectively. 50 subjects were included in safety analysis. The overall incidence of AEs of any grade was 89%. 92% of the patients in the cohort 1 and 85% in the cohort 2. The majority of AEs was grade 1 or 2. Adverse events of any grade that occurred in at least 10% of patients were neutropenia（76%），nausea/vomiting (61%), AST/ALT abnormal (33%), palpitate (28%), anemia (22%) and skin hypersensitivity (11%) in the cohort 1 and neutropenia（68%），nausea/vomiting (59%), AST/ALT abnormal (21%), palpitate (16%), anemia (40%) in the cohort 2, respectively. Adverse events of grade 3 or higher found in the cohort 1 were neutropenia (23%) and those were neutropenia (19%), AST/ALT abnormal (3%) and anemia (3%) in the cohort 2. Seemingly, Adverse events that occurred more frequently in the cohort 1 than in the cohort 2 were AST/ALT abnormal, palpitate and skin hypersensitivity. Conclusions: Three days of CIV rh-Endostatin in combination with PD-1 antibody plus chemotherapy for the first line treatment of EGFR/ALK negative, advanced or metastatic, non-squamous NSCLC could obtain the better improvement in the efficacy and result in the higher frequent in some of AEs. Clinical trial information: NCT: 04063449.
Effect of performance status (ECOG PS) on treatment outcome with second-line (2L) nintedanib (NIN) + docetaxel (DOC) for patients (pts) with lung adenocarcinoma after first-line (1L) immune checkpoint inhibitor (ICI) combination therapy.
Authors: Grohé Christian , Wehler Thomas , Henschke Sven , Dittrich Ina , Hammerschmidt Stefan , Aulmann Christoph , Dechow Tobias , Schiefer Conrad , Zander Ingo , Schuette Wolfgang , Atz Judith , Kaiser Rolf
Published: June 2022

9092

Background: ICIs with or without chemotherapy represent 1L standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Given the paucity of prospective randomized trials assessing second-line treatment options post-immunochemotherapy, non-interventional data may help support clinical decision making. Patients with ECOG PS > 1 are generally underrepresented in clinical trials relative to routine clinical practice. We therefore examined treatment outcomes with 2L NIN + DOC after 1L ICI combination therapy with respect to ECOG PS at baseline. Methods: In this analysis of Cohort C of the ongoing, non-interventional VARGADO study (NCT02392455), eligible pts had locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC and received 2L NIN+DOC in routine clinical practice after failure on 1L ICI in combination with chemotherapy. The primary endpoint is 1-year survival rate (not yet mature). Tumor response was according to investigator review. Results: In 164 pts enrolled in Cohort C, median age was 63 years (range: 37 – 84), 100 pts (61.0%) were men, and 123 pts (75.0%) were ECOG PS 0–1. 146 pts (89.0%) had received prior 1L pembrolizumab-based combination therapy. Objective response rate (ORR) with 2L NIN+DOC was 35.4% (40/113 pts) in the overall population and 41.2%, 30.8% and 28.6% for pts with ECOG PS 0, 1 and > 1, respectively. Disease control rate (DCR) was 67.3% (76/113 pts) in the overall population and 76.5%, 65.4% and 50.0% for pts with ECOG PS 0, 1 and > 1, respectively. Median PFS was 4.7 months (95% CI: 3.4 – 5.3) in the overall population and 5.1 months (95% CI: 2.8 – 8.3), 3.7 months (95% CI: 2.5 – 5.3) and 2.1 months (95% CI: 1.3 – 6.5) for pts with ECOG PS 0, 1 and > 1, respectively. The median OS was 8.1 months (95% CI: 6.3 – 11.2) in the overall population and 9.1 months (95% CI: 5.4 – 14.5), 10.5 months (95% CI: 6.3 – 14.9) and 4.0 months (95% CI: 2.5 – 6.3) for pts with ECOG PS 0, 1 and > 1, respectively. Conclusions: Our results support 2L NIN+DOC as an effective treatment option in pts with advanced adenocarcinoma NSCLC following 1L ICI in combination with chemotherapy. ECOG PS > 1 was associated with lower ORR, DCR and shorter PFS and OS. These findings warrant further evaluation of the effect of ECOG PS on 2L treatment outcomes in patients after 1L ICI combination therapy. Clinical trial information: NCT02392455.
Clinical response to tepotinib according to circulating tumor (ct) DNA biomarkers in patients with advanced NSCLC with high-level MET amplification (METamp) detected by liquid biopsy (LBx).
Authors: Le Xiuning , Paz-Ares Luis , Van Meerbeeck Jan , Viteri Ramirez Santiago , Cabrera Galvez Carlos , Vicente Baz David , Kim Young-Chul , Kang Jin-Hyoung , Stroh Christopher , Juraeva Dilafruz , Bruns Rolf , Otto Gordon , Johne Andreas , Paik Paul K.
Published: June 2022

9121

Background: Tepotinib, a potent, highly selective, oral, MET inhibitor, showed meaningful activity in patients (pts) with NSCLC with high-level METamp by LBx in VISION. Exploratory biomarker analyses are presented herein. Methods: Pts had 0–2 prior therapy lines, high-level METamp by LBx (Guardant360; MET copy number ≥2.5), and no MET exon 14 skipping or EGFR/ ALK alterations. Pts received tepotinib 500 mg once daily (450 mg active moiety). Primary endpoint was objective response by independent review; data cut-off: Aug 20, 2021. Exploratory biomarker analysis included LBx at baseline (BL), on treatment, and end of treatment (EOT). Early molecular response (eMR) was defined as undetectable METamp 6–8 weeks on treatment. Results: 24 pts were enrolled (median age: 63.4 years [yrs]; smokers: 88%; ECOG PS 1: 88%; adenocarcinoma: 67%). Treatment duration was ≥1 yr in five pts and ≥2 yrs in two pts (both ongoing). Overall, objective response rate (ORR) was 41.7% (95% CI: 22.1, 63.4). Treatment-naïve pts (n=7) had an ORR of 71.4% (29.0, 96.3), median (m) DOR was 14.3 months (2.8, not estimable [ne]), and mPFS was 15.6 months (1.4, ne). BL biomarker analyses according to clinical benefit (CR/PR/SD [n=11] vs PD/NE [n=13]) showed association with better outcomes in pts with focal METamp, or without MYCamp or RB1 mutation (Table). MYCamp/ RB1 mutation was detected in 4/7 pts with neuroendocrine/not otherwise specified histology; MYCamp in 2/3 pts with neuroendocrine histology. Low BL ctDNA mutant allele frequency (MAF) was associated with better outcomes. 14 pts had eMRs (ORR 71.4%); persistent METamp (n=4) was associated with lack of clinical response. 2/9 pts with EOT biomarker profiles had emerging resistance mechanisms (MET kinase domain mutations Y1230 and D1228); both had METamp re-emergence. Treatment-related adverse events included edema (composite term; any grade: 46%; Grade 3: 13%) and constipation (any grade: 17%; Grade ≥3: 0%). Conclusions: Tepotinib showed meaningful activity, especially in first line, in the first trial of a MET inhibitor in EGFR WT NSCLC with high-level METamp to enroll based on a convenient LBx assay. BL biomarker analyses indicated focal METamp, MYC/RB1 WT, and low ctDNA MAF were associated with improved outcomes. Serial LBx could monitor molecular response and evaluate resistance. Clinical trial information: NCT02864992. [Table: see text]
Merkel polyoma virus specific T-cell receptor transgenic T-cell therapy in PD-1 inhibitor refractory Merkel cell carcinoma.
Authors: Veatch Joshua , Paulson Kelly , Asano Yuta , Martin Lauren , Lee Bo , Hall Evan Thomas , Bhatia Shailender , Nghiem Paul , Chapuis Aude
Published: June 2022

9549

Background: Merkel cell carcinoma is an aggressive neuroendocrine tumor of skin origin with most cases caused by the Merkel polyoma virus (MCPyV). While many patients benefit from PD-1/PD-L1 axis blockade, most patients do not respond or develop resistance. We sought to ask whether adoptive transfer of autologous T cells transduced with MCPyV specific T cells could lead to clinical responses in PD-1 inhibitor refractory patients. Methods: Five MCPyV positive, HLA-A02 patients with PD-1 inhibitor refractory metastatic Merkel cell carcinoma were treated with adoptive transfer of CD62L+ CD8+ and CD4+ autologous T cells transduced with a T cell receptor (TCR) targeting an HLA-A0201 restricted MCPyV epitope. Two different strategies were used to facilitate T cell expansion: In 3 patients, single fraction radiation was administered to a subset of lesions prior to T cell transfer. In 2 patients, lymphodepleting chemotherapy with cyclophosphamide and fludarabine was administered prior to T cell transfer. Anti PD-1/PD-L1 therapy was given 14 days after T cell infusion. Transgenic T cells were visualized in tumor biopsies by multiplex immunohistochemistry. Results: 5 patients were treated, with 4 patients receiving 100 million tetramer positive CD8+ T cells and one patient receiving 500 million cells. 3 patients received second infusions with between 300 million and 900 million tetramer positive cells. No dose limiting toxicities or cytokine release syndrome were observed. T cell persistence was lower in the 2 patients treated with lymphodepleting chemotherapy relative to the 3 patients treated with single fraction radiation. Transgenic T cells persisted at tumor sites greater than 1 month following transfer. 4 patients experienced progressive disease, and a single patient had a mixed response and greater than 1 year disease free interval following local therapy of an isolated site of progression. The responding patient was the only patient with class I MHC staining on tumor cells prior to treatment, and the site of local progression in that patient showed the presence of TCR transgenic T cells but loss of class I MHC expression. Conclusions: MCPyV specific transgenic T cells are safe, traffic to tumor sites, and can result in a clinical response, but their clinical activity may be limited by down-regulation of class I MHC expression on tumors. A future trial will address strategies to increase class I MHC expression on Merkel tumors. Clinical trial information: NCT03747484.
Outcomes of neoadjuvant (NA) and adjuvant (A) chemotherapy in geriatric patients with stage I-III triple-negative breast cancer (TNBC): A single institution experience.
Authors: Sam Christine , Sehovic Marina , Extermann Martine
Published: June 2022

e12522

Background: Older breast cancer patients have greater risk for toxicity with perioperative chemotherapy and poorer outcomes for stage I-III TNBC due to medical comorbidities and declining organ function. It is not clear whether use of anthracycline based chemotherapy regimens (ABC) delivers better outcomes than non-anthracycline taxane-based chemotherapy regimens (TBC) in this population. Methods: A single institution retrospective review of TNBC patients ≥65 treated with adjuvant and neoadjuvant chemotherapy at Moffitt Cancer Center from 2009 to December 2018 was conducted. Demographic, comorbidity, treatment, and toxicity variables were collected. Treatment toxicity was defined as dose reductions, dose delays, early discontinuations, unplanned hospitalizations, and grade 3-4 heme and non-heme toxicities. Eligible patients had stage I-IIII TNBC, were ≥65, and received NA or A chemotherapy at MCC. A validated frailty index (FI) was used to calculate comorbidity score. Kaplan Meier was used to estimate overall survival by regimen received, with log rank test to compare ABC and TBC groups. Results: A total of 79 patients met criteria for analysis, with mean age of patients receiving treatment was 71 (range 65-88). 41.8% of patients had stage I disease, 36.7% with stage II, and 21.5% with Stage III. 76% of patients with Stage III, 51.7% of Stage II, and 18% of stage I disease received ABC. There was a trend toward higher toxicity events in patients receiving ABC compared to TBC regimens, although not statistically significant (see Table). The mOS for patients receiving ABC was 43.5mo and 63.0 mo for patients receiving TBC, although not statistically significant (p=0.212). Conclusions: Geriatric patients with stage I-III TNBC were mostly able to successfully receive NA or A chemotherapy, although TBC may have better tolerability. Patients receiving TBC also had better survival, although not statistically significant and potentially confounded by patients with earlier stage or less aggressive tumors receiving TBC.[Table: see text]
A prospective real-world study to assess the effectiveness and safety of trastuzumab biosimilar in the adjuvant treatment of HER2-positive breast cancer: Preliminary safety results.
Authors: Cardoso Ana Carolina Ferreira , Gagliato Debora De Melo , Brito Natália Mesquita , Lapa Maura Gonzaga , Magaton Érida Aparecida Pinto , Santos Renata Virgínia Cavalcanti , Castilho Vivienne Carduz
Published: June 2022

e12524

Background: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) defines a biosimilar as a biological molecule product that is highly similar to and has no clinically meaningful differences from an existing approved reference product. The trastuzumab biosimilar was the first oncology biosimilar approved in Brazil for HER2-positive breast cancer (BC) and advanced gastric cancer treatment. This study aimed to assess the effectiveness and safety of trastuzumab biosimilar (named as Zedora in Brazil) in the adjuvant setting among HER2-positive BC patients treated in Brazil. Methods: This is a national, multicentric, observational, and prospective real-world study. Patients with early-stage HER2-positive BC who received at least one dose of trastuzumab biosimilar as adjuvant therapy were eligible. At the present date, 126 of 170 planned patients were recruited. Here, we present the preliminary safety data of the first 42 patients recruited in the study. The safety endpoint is the occurrence of adverse events (AEs), and the safety population included all patients who received at least one dose of trastuzumab biosimilar. We analyzed the AEs collected from the signature of the consent form until the end of adjuvant treatment. Results: Baseline patient characteristics among the 42 evaluated patients included a median age of 48.5 years, with 78.6% of them having a node-negative disease. Most patients had hormone-receptor-positive tumors (71.4% estrogen-receptor-positive and 57.1% progesterone-receptor-positive). The number of patients undergoing conservative surgery (59.5%) was higher than mastectomy (40.5%). The most frequent histological BC subtype was invasive ductal carcinoma (97.6%). Neoadjuvant therapy included the trastuzumab biosimilar administration (25%) and the dual anti-HER2 block (trastuzumab biosimilar + pertuzumab) (68.8%). Only 6.3% of patients received the reference trastuzumab in neoadjuvant therapy. In total, 25/42 (59,5%) patients had at least one AE, two of them were serious AEs (4.8%). The incidence of grade 3 or 4 AEs was 35.7%, and no death occurred. The table lists the most reported AEs according to SOC (System Organ Class). Conclusions: The nature and severity of AEs observed were consistent with the known safety profile of trastuzumab. Clinical trial information: NCT03892655. [Table: see text]
Genomic and immunological characterization between primary and recurrent breast cancer.
Authors: Liu Danni , Zhang Jing , Peisu Suo , Chen Shifu , Peng Xiufan
Published: June 2022

e12553

Background: A large number of breast cancer patients suffered cancer recurrence. Survival was seriously worse in recurred tumor. Immune microenvironment and pathways inducing drug resistance were closely related to tumor recurrence. It is necessary to clarify the recurrence mechanisms and improve recurrence detection. Methods: Somatic mutation, expression matrix and clinical information of primary (n = 1177) and recurred (n = 803) breast tumors in METABRIC were downloaded from cBioPortal. The Kaplan-Meier method of survival analysis was used to display overall survival. Significantly mutated genes (SMG) identified by MutSig2CV (v3.11) with Qvalue < 0.05. R packages CIBERSORT was applied to calculate the proportion of tumor-infiltrating immune cell using mRNA expression microarray data. Student's t-test was used to compare the SMGs expression log intensity levels of two groups. Results: Overall survival were significantly difference between the primary and recurred patients (log-rank test, P value < 0.0001). The immune cell components of primary and recurred breast tumors presented different patterns. Macrophages were significantly enriched in primary patients (Kruskal-Wallis test, P value < 0.05). PIK3R1, SMAD4, ATR and FLT3 were uniquely significantly mutated and expressed at lower levels in recurred group. These SMGs were identified as being associated with recurrence in other cancer studies. For example, PIK3R1 regulates the transduction of PI3K/Akt pathway, which disrupting the balance between induction and prevention of apoptosis, causing drug resistance. In the other, SMAD4 acts as a central mediator of TGF-β/SMAD4 signaling pathway that usually impedes immune cell activation. Conclusions: Recurred breast tumors presented different genetic mutation frequency and microenvironment. Tumor immune factors are associated with recurrence. Detecting uniquely SMGs of recurred breast tumors may be a feasibility way to monitor disease recurrence.
Quality initiative (QI) to improve molecular testing in newly diagnosed (ND) stage 4 non-small cell lung cancer (NSCLC-4): An Integra Connect (IC) database study.
Authors: Gart Mike , Choksi Rushir J. , Petro Daniel P. , Scott Jeffrey A. , Varughese Prateesh , Stockton Matt , Smith Robert E.
Published: June 2022

e13507

Background: In August 2019 IC partnered with University of Pittsburg Medical Center (UPMC) on a QI aimed at improving outcomes in stages 3 and 4 NSCLC. This report details the findings, interventions, and results in the stage 4 cohort to date. Guidelines advocate broad molecular profiling and completion of biomarker testing prior to initiation of initial therapy (KF Mileham,2022). However, real world data has shown a high rate of treatment initiation without biomarker testing due to low rate of testing and, if tested, treatment prior to results reporting (H West,2021; J Nicholas, 2021) in this disease state having a 5-year survival of only 7% (N Howlander). Based on analysis of the US Oncology Network it was found that only 46% of patients (pts) with metastatic NSCLC received testing for PD-L1, EGFR, ALK, ROS1, and BRAF-V600E (J Nicholas, 2021). Methods: By querying the UPMC and IC databases, 847 patients (pts) with ND NSCLC-4 were identified who received an initial line of therapy, excluding squamous carcinoma pts unless documented never-smokers, during 1/1/2017- 12/31/2021. Date of EGFR test ordered, date of test result report to electronic health record, and date of treatment initiation were captured. Also included were test orders for the NCCN recommended biomarker panel of PD-L1, ALK, ROS1, BRAF, RET, MET, and NTRK. The data were evaluated in three time periods for the QI: Phase 1 of 1339 days (1/1/2017-8/31/2020) for baseline, Phase 2 of 122 days (9/1/2020-12/31/20) post physician leadership intervention, and Phase 3 of 272 days (1/1/2021-9/30/2021) performance measurement period. Baseline and on-going measurement of testing metrics was performed with physician leadership intervention for identified gaps in care. Additionally, surveys were implemented to assess caregiver perceptions. The use of chart curation and software-based monitoring tools powered by IC enabled providers to understand current levels of testing and track performance over time. Results: Median age was 68 (range 36 - 89) and 49% male. As shown in Data Table, EGFR testing at baseline was 94% and increased to 96%. Testing of the entire biomarker panel noted above increased from 52% baseline to 76% at this point in Phase 3. While only 72% had treatment initiated after EGFR result at baseline, this improved to 88% during Phase 3. Conclusions: This QI led to improvement in rates of broad biomarker testing and initiation of treatment only after results were made available in this NSCLC-4 population. While this initiative was not designed to evaluate outcomes, one would expect outcome improvement over baseline with higher guideline adherence.[Table: see text]
Enhancing accrual to clinical trials of minority patients with gynecologic malignancy.
Authors: Lara Olivia , Pothuri Bhavana
Published: June 2022

e13535

Background: Central to improving survival of patients with gynecologic malignancy is participation in therapeutic, surgical and preventative clinical trials. Minority population accrual is particularly poor representing a disparity in cancer care. We sought to evaluate enrollment of minority populations at an urban NCI-designated Comprehensive Cancer Center before and after the NCI call to action June 2020. Methods: Data on patient enrollment in gynecologic oncology clinical trials (14 therapeutic and 4 non-therapeutic) was obtained from Perlmutter NCI-designated Comprehensive Cancer Center. Primary outcomes were the proportion of newly accrued patients by race participating in trials between January 2019 to September 2021. Results: Over the entire study period 154 total patients were enrolled in therapeutic and non-therapeutic clinical trials. Enrollment by cancer type included 100 (71.4%) ovarian, 16 (7.1%) uterine, 12 (7.9%) cervical and 26 (13.5%) solid tumor trials. White patients comprised 69% (69 of 100) of patients on ovarian cancer trials. Uterine cancer trials by race consisted of 50 % White, 37.5% Black, 6.2% Asian and 6.2% Other race patients. Eighty-eight patients were enrolled into clinical trial prior to the NCI alert. By race these patients were: White, 65.9% (58 of 88); Black, 3.4% (3 of 88); Asian, 11.4% (10 of 88) and Other race, 19.3% (17 of 88). Hispanic patients comprised 13.6% (12 of 88) of the population. Following the call to action an additional 66 patients were enrolled in clinical trial. This included 42 (63.6%) White, 14 (21.2%) Black, 5 (7.57%) Asian, 5 (7.6%) Other race and 8 (12.12%) Hispanic patients. The percentage of Black patients enrolled in clinical trial increased four -fold over the time period (3.4% vs 21.2%, p < 0.05). Conclusions: Overall during this time period we found an increase in number of Black patients accrued to clinical trial. This indicates disparities in clinical trial enrollment can be modified by institutional awareness. The role of patient education, financial and logistical barriers and language discordance to minority participation in clinical trials should be studied further.
A novel risk-scoring model developed based on tertiary lymphoid structure related genes predict the prognosis and immunotherapeutic efficacy in cutaneous melanoma.
Authors: Wang Bin , Liu Jie , Jiang Yu
Published: June 2022

e13574

Background: Emerging evidence has proven that tertiary lymphoid structures (TLSs) are predictive biomarkers of favorable clinical outcomes in melanoma, whereas the exact role of TLS-related genes remained unclear. In the present study, we aimed to establish a novel risk-scoring model based on TLS-related genes to predict the prognosis and immunotherapeutic efficacy in cutaneous melanoma. Methods: Patients in the TCGA-SKCM cohort (n = 468) were clustered into two subtypes based on the prognosis-related genes associated with TLSs though consensus clustering analysis, and differentially expressed genes were screened between two clusters. By univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, a 13-gene signature was selected to construct a prognostic risk-scoring model. The median risk score served as the unified cutoff to divide patients into high- and low-risk groups. GSE65904 (n = 220) and GSE544467 (n = 79) cohorts were used for external validation. Univariate and multivariate cox analysis were used to select significant variables for construction of nomogram. The nomogram model was evaluated by concordance index, time-dependent receiver operating characteristics (ROC) curve, calibration curve and decision curve analysis (DCA). GSEA, CIBERSORT, Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenoscore (IPS) were utilized to explore the potential mechanism of immune-related process and immunotherapy. Results: Thirteen signature genes (CCL8, DLX3, CNTFR, CNFN, BCAN, CD33, HAPLN3, ABCB1, CLIC2, GCNT1, FGF1, A2ML1, GBP2) were developed to construct a risk-scoring model. Melanoma patients could be grouped into high- and low-risk groups, and low-risk patients showed better survival than high-risk patients. Area under the curve values of 1, 3, and 5 years were 0.76, 0.72, and 0.73 in the training set, respectively, indicating a good predictive efficacy. In addition, based on independent prognostic factors including risk score, age, stage, T and N Staging after univariate and multivariate Cox regression analyses, a nomogram was constructed to better estimate individual survival. For the prediction of 1, 3, and 5-year overall survival probability according to the nomogram, the area under the receiver operating characteristic curve was 0.81, 0.80 and 0.76, respectively. Furthermore, we explored the correlation of the prognostic risk-scoring model with tumor microenvironment (TME) and immunotherapeutic efficacy. Patients in the low risk group featured immunoactive TME, higher IPS scores and lower TIDE scores, and was regarded as the potential beneficiaries of immunotherapy. Conclusions: The 13-gene risk score proposed in the research may provide new insights into the individualized evaluation of cutaneous melanoma prognosis and Immunotherapeutic Efficacy
Diagnostic accuracy of the CxPREVENTIVE breast model for early detection of breast cancer.
Authors: Calleja Sergio J , Patiño Édgar C
Published: June 2022

e13578

Background: Despite different available methods for breast cancer (BC) screening (mainly mammographies for ages between 50 and 65 yr.), and their proven benefits, morbidity, and mortality of this malignancy are still high, partly due to technical limitations and low compliance with screening. The aim of the present study was to assess the diagnostic accuracy for early detection of BC using a modeling algorithm based on multiple blood and urine biomarkers. Methods: In this retrospective cohort study, clinical and blood and urine markers-based algorithms with predefined cutoff values were applied to a generally healthy asymptomatic outpatient cohort of women aged 23 years or older undergoing mammography and histopathology for routine breast cancer screening. We used a modeling algorithm based on two different frameworks (Multiple Biomarkers Disease Activity Algorithm MBDAA [Bioprognos], and Artificial Intelligence Recursive Algorithm AIRA [Mintlot] both in Barcelona, Spain). Both algorithms compute information from a wide number of analytes, tumor markers (CA 15.3, CEA, EGFR, NGAL, NSE and 8-OHdG), and additional clinical data (age, weight, height, and BMI). MBDAA includes Barcelona Criteria (four criteria to correctly interpret the cause of the increase in tumor markers, benign or malignant, defined by the Spanish Society of Clinical Biochemistry and Molecular Pathology, Commission of Biological Markers of Cancer). To assess the association between the modelling algorithm and downstream diagnosis we used logistic regression to compute receiver operating characteristic curves (ROC). Exact binomial confidence limits were calculated to test accuracy, sensitivity, and specificity. Results: 123 women (median age 48 yr. [IQR 40-63]) who underwent mammography at the Juan Ramón Jiménez Hospital (Huelva, Spain), were included in this analysis. Based on mammography and histopathologic findings, BC was diagnosed in 61 (49.5%) women, and absence of pathological findings (control group) was seen in 62 (51.5%). The diagnostic intervention for BC yielded an area under the curve (AUC) of 1 among the entire specimen set, accuracy 1 (95% CI 0.990,1), Se 1 (0.991, 1) and Sp 1 (0.991, 1). Conclusions: Using mammography as a gold standard, our data suggest that an innovative newly designed non-invasive blood and urine-based biomarker algorithm CxPREVENTIVE Breast may provide a timely diagnosis of BC with very high accuracy, especially for those women under 50 and over 65yr., where up to 60% of all BC are concentrated. Our findings warrant further investigation, and we are planning large-scale (n 10,000), fully powered study to inform clinical practice.
Canadian oncology residents’ knowledge of and attitudes towards artificial intelligence and machine learning.
Authors: Kennedy Thomas , Collie Laura , Nabhen Jacqueline J. , Ynoe de Moraes Fabio
Published: June 2022

e13587

Background: The use of artificial intelligence (AI) and machine learning is becoming more common and is expected to expand further in order to meet the needs of our ever-evolving healthcare system. In oncology, AI and machine learning are already being explored in various applications. Despite AI’s importance, there is sparse formal teaching on AI incorporated into medical schools’ curricula and residency training programs. In this study, we examined the perceptions and knowledge of Canadian oncology residents and fellows with respect to AI technologies. Methods: An electronic, anonymous, questionnaire-based survey was distributed to residents and fellows in medical and radiation oncology programs across Canada. Survey questions spanned areas of demographics, familiarity with AI, personal attitudes towards AI, and perspectives regarding AI use in different specialties. Approval was obtained from the Queen’s Research Ethics Board prior to conducting this study. Mixed-methods statistical analysis is ongoing. Qualitative data will be analyzed using thematic analysis. Univariable and multivariable regressions will be conducted to identify any correlation between perception or knowledge of AI and demographic factors. Results: Fifty-seven participants responded in total. Most residents (67%) agreed or strongly agreed that it was important they learn about AI. Seventy percent indicated that, if given the chance, they would like to learn more about AI, yet the majority of participants (88%) indicated they had not received formalized teaching. Disciplines that were felt to be most associated with AI were radiology (98%), radiation oncology (84%), and pathology (58%). With respect to the field of radiation oncology, 98% of respondents felt that AI had the potential to replace some, most, or all medical activities. A perceived barrier to understanding AI was a lack of knowledge of mathematics and programming (63%). Respondents indicated that their preferred formats for learning about AI would be workshops (78%), lectures (60%), and collaborative activities with other departments (46%). Conclusions: Our results show that Canadian oncology residents’ sense that AI is important and relevant to their area of training. Despite this, they have not received education on these topics. Thus, formalized teaching, such as lectures and workshops, would be perceived as beneficial by most Canadian oncology residents.