tbuckley/cabot-search huggingface dataset:
Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.
Authors: Torsten Dahlén, Gunnar Larfors, Hans Lennernäs, Charlotta Liljebris, Mikael Von Euler, Magnus Brisander, Per Andersson, Leif Stenke
Journal: Journal of Clinical Oncology (2024)

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, C max and AUC 0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]
A phase II randomized trial evaluating consolidative nivolumab in locally advanced non-small cell lung cancer post neoadjuvant chemotherapy plus nivolumab and concurrent chemoradiotherapy (GASTO-1091).
Authors: Hui Liu, Bo Qiu, Yuanyuan Zhao, Wen-zhuo He, Weineng Feng, Weijing Zeng, Jun Jia, Fanjun Meng, DaQuan Wang, FangJie Liu, JinYu Guo, YingYi Zou, SuPing Guo, YingJia Wu, QiaoTing Luo, Ji-Bin Li, Yunpeng Yang, Liang-Ping Xia, Li Zhang
Journal: Journal of Clinical Oncology (2024)

8008 Background: Enhancing clinical outcomes in resectable non-small cell lung cancer (NSCLC) has been associated with neoadjuvant or perioperative administration of nivolumab. However, the efficacy and safety of consolidation nivolumab versus observation following neoadjuvant chemotherapy plus nivolumab, hypofractionated radiotherapy and concurrent chemotherapy (hypo-CCRT) in patients with unresectable stage III NSCLC remain underexplored. Methods: Conducted as a randomized, multi-center, phase 2 trial in patients with unresectable stage IIIA-C NSCLC, this study enrolled individuals aged 18 to 75 with an ECOG performance status of 0 or 1. Neoadjuvant therapy consisted of docetaxel, cisplatin, and nivolumab (360mg every 3 weeks for 2 cycles), followed by hypo-CCRT. Patients without disease progression or G2+ pneumonitis after hypo-CCRT were randomly assigned to receive nivolumab (360 mg every 3 weeks for up to 12 months) or undergo observation. Randomization factors included age, sex, smoking history, and EGFR mutation status. The primary endpoint was progression-free survival (PFS) from randomization, with preplanned analysis results reported herein. The trial is registered with ClinicalTrials.gov, NCT04085250. Results: Between Dec 3rd, 2019, and Aug 18th, 2023, 264 patients underwent neoadjuvant therapy, 242 received hypo-CCRT, and 172 were randomly assigned to nivolumab consolidation (n = 86) or observation (n = 86) post hypo-CCRT. At the January 31, 2024, data cutoff, the median follow-up for all randomized patients was 22.8 months. Nivolumab consolidation exhibited significantly longer PFS compared to observation (median not reached vs. 12.2 months [95% CI 6.2-18.1]; hazard ratio 0.49 [95% CI 0.31-0.79], p = 0.002). The 12-month and 18-month PFS rates were 72.6% and 64.8% in the consolidation group, contrasting with 52.5% and 42.3% in the observation group. Grade 3-4 nonhematological adverse events occurred in 14.0% (37/264) during neoadjuvant therapy and hypo-CCRT. Following randomization, grade 3-5 adverse events occurred in 7.0% (6/86) with consolidation (G3 pneumonitis, 2.3%; G5 pneumonitis, 1.2%; G3 proximal bronchial tree toxicity, 3.5%) and 4.6% (4/86) with observation (G3 pneumonitis, 2.3%; G3 proximal bronchial tree toxicity, 2.3%). Conclusions: Consolidation with nivolumab after neoadjuvant chemotherapy plus nivolumab and hypo-CCRT demonstrates effectiveness and tolerability for patients with unresectable stage III NSCLC. Extended follow-up is essential for confirming these findings. Clinical trial information: NCT04085250 .
Impact of complete cytogenetic response on survival in patients with myelodysplastic syndromes.
Authors: Samuel Urrutia, Koji Sasaki, Hagop M. Kantarjian, Elias Jabbour, Kelly Sharon Chien, Danielle Hammond, Carlos E. Bueso-Ramos, Joseph Khoury, Keyur P. Patel, Guillermo Montalban-Bravo, Yue Wei, Simona Colla, Nicholas James Short, Naval Guastad Daver, Gautam Borthakur, Tapan M. Kadia, Sherry Pierce, William G. Wierda, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2024)

6567 Background: Response to therapy prolongs survival in patients with myelodysplastic syndromes (MDS). The aim of this study is to evaluate the impact of complete cytogenetic response (CCyR) on survival in patients with MDS and abnormal cytogenetics. Methods: We reviewed 2311 consecutive patients with MDS and cytogenetic abnormalities who were treated at our institution from 2006 to 2023. Results: CCyR was observed in 330 patients (14%), complete response (CR) in 208 (9%), CR with bilineage recovery (CRbi) in 255 (11%), CR with unilineage recovery (CRuni) in 151 (7%), CR with incomplete hematologic recovery (CRh) in 4 (0.2%), and non-CR in 1363 (59%). With a median follow-up of 59 months, the median overall survival (mOS) was 14 months. Ten months for non-CR, 19 months for CRh/CRbi/CRuni, 21 months for CR, and 26 months for patients with CCyR (p &lt; 0.001). With stem cell transplant (SCT) censoring, mOS was 15 months. Eleven months in non-CR, 19 months in CRh/CRbi/CRuni, 19 months in CR, and 27 months for patients with CCyR (p &lt; 0.001). In low-risk MDS by the International Prognostic Scoring System (IPSS), mOS with SCT censoring was 87 months for CCyR, compared to 40 months for non-CR, 38 months for CRh/CRbi/CRuni, and 36 months for CR (p &lt; 0.001). In intermediate/high-risk MDS mOS with SCT censoring mOS was 25 months in CCyR, compared to 9 months in non-CR, 15 months in CRh/CRbi/CRuni, and 17 months in CR (p &lt; 0.001). In a multivariate regression analysis, age &gt; 75 years (HR 3.1, p &lt; 0.001), complex karyotype (HR 2.15, p &lt; 0.001) performance status 3-4 (HR 1.48, p &lt; 0.001), hemoglobin &lt; 8 g/dL (HR 1.48, p=0.003), creatinine &gt; 1.3 g/dL (HR 1.44, p &lt; 0.001), therapy-related AML (HR 1.41, p &lt; 0.001), infection at diagnosis (HR 1.34, p =0.003), white blood cells &gt; 50 x10 9 /L (HR 1.31, p &lt;0.001), cardiac comorbidities (HR 1.26, p &lt; 0.001), platelets &lt; 20 x10 9 /L (HR 1.26, p=0.001), pneumonia at diagnosis (1.22, p =0.006), and core-binding factor cytogenetics (HR 0.48, p &lt; 0.001) were independently prognostic for survival in this select group. Conclusions: Achievement of CCyR in patients with MDS and abnormal cytogenetic abnormalities leads to improved survival. Given poor outcomes in older patients with MDS, CCyR can be used as a valid surrogate for long-term outcomes.
Efficacy of immunotherapy retreatment in patients with non-small cell lung cancer receiving consolidative durvalumab.
Authors: Allison Baker Carroll, Lindsay Renee Kohler, Amber Britton Cipriani, Shetal Arvind Patel, Kevin Yanjun Chen
Journal: Journal of Clinical Oncology (2024)

8625 Background: The standard of care for patients with stage III, unresectable non-small cell lung cancer (NSCLC) is curative intent chemoradiation followed by durvalumab consolidation. However, most patients progress necessitating further treatment. Although immunotherapy (IO) is the cornerstone of treatment in advanced/metastatic disease, the benefit in patients who received prior durvalumab is unclear. Clinical trials excluded prior IO exposure and current guidelines do not provide specific recommendations. This study aims to characterize the efficacy of post-durvalumab IO treatment. Methods: This was a retrospective cohort study conducted at the University of North Carolina (UNC) Medical Center. Adult patients with unresectable NSCLC who received chemoradiation and consolidative durvalumab followed by subsequent systemic therapy for disease progression between February 2018 to May 2023 were included. Patients were excluded if they received targeted therapy as subsequent systemic treatment. The primary endpoint was real-world progression-free survival (rwPFS) of post-durvalumab treatment. Key secondary outcomes included physician assessed response, overall survival (OS), and subgroup analyses to identify biomarkers which may predict benefit from IO retreatment. Results: A total of 66 patients met inclusion criteria, of which 39 (59%) received subsequent chemotherapy alone and 27 (41%) received IO-containing therapy. Of those who received IO-containing treatments, 18 received chemotherapy plus IO (chemoIO) and 9 received IO alone. Durvalumab was discontinued for therapy completion (chemotherapy: 18%, IO: 26%), disease progression (chemotherapy: 54%, IO: 48%), or side effects (chemotherapy: 26%, IO: 19%). No significant difference was observed between median rwPFS of chemotherapy versus IO-containing therapy (7.0 months vs 5.8 months, respectively; p = 0.9419) or OS (13.0 months vs 12.6 months, respectively; p = 0.5769). Notably, patients in our cohort who received IO alone had a numerically longer rwPFS compared to chemoIO (12.6 months vs 5.8 months, respectively; p = 0.3951), as well as a numerically longer OS (12.6 months vs 6.4 months, respectively; p = 0.8885). Conclusions: This study found that there were no statistically significant differences in median rwPFS or OS between chemotherapy or IO-based regimens following the conclusion of durvalumab consolidation. Interestingly, we observed a numerically improved rwPFS and OS in those who received IO alone compared to chemoIO, which suggests there may be key clinical or molecular features that may help identify patients who benefit from IO therapy. We acknowledge the limitations of this small, retrospective study. The efficacy of IO-based regimens post-durvalumab warrants further investigation in a larger, prospective manner to assess the risks and benefits of IO retreatment.
Efficacy of imetelstat on red blood cell (RBC)-transfusion independence (TI) in the absence of platelet transfusions or myeloid growth factors in IMerge.
Authors: Amer Methqal Zeidan, Valeria Santini, Uwe Platzbecker, Mikkael A. Sekeres, Michael R. Savona, Pierre Fenaux, Yazan Madanat, Azra Raza, Qi Xia, Libo Sun, Jennifer Riggs, Sheetal Shah, Shyamala Chendeal Navada, Tymara Berry, Rami S. Komrokji
Journal: Journal of Clinical Oncology (2024)

6566 Background: In the IMerge trial (NCT02598661) of RBC transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory to or ineligible for erythropoiesis stimulating agents, imetelstat showed significant efficacy vs placebo (PBO) for 8-wk, 24-wk, and 1-y TI endpoints, with neutropenia and thrombocytopenia as the most common adverse events (Platzbecker. Lancet 2024). Supportive care was given to all pts as needed, per investigator discretion. Here we report RBC-TI rates in the absence of platelet transfusions or myeloid growth factor use. Separately, RBC-TI with mean central hemoglobin (Hb) rise of ≥1.5 g/d was assessed in all pts. Methods: Pts were randomized 2:1 to receive imetelstat (n=118) 7.5 mg/kg or PBO (n=60) Q4W IV until disease progression. Primary endpoint was 8-wk RBC-TI; 24-wk RBC-TI was a key secondary endpoint. Primary analysis cutoff was Oct 2022, with Oct 2023 cutoff for 1-y RBC-TI analyses. Results: Overall, 21/118 (18%) pts in the imetelstat group and 1/60 (2%) pts in the PBO group needed platelet transfusions; 41/118 (35%) and 2/60 (3%) pts received myeloid growth factors, respectively. Significantly higher percentages of pts achieved 8-wk, 24-wk, and 1-y RBC-TI with imetelstat vs PBO in the absence of either platelet transfusions or growth factor support (Table). In a separate analysis, 8-wk, 24-wk, and 1-y RBC-TI and concurrent Hb rise of ≥1.5 g/dL with imetelstat vs PBO occurred in 28% vs 2%, 23% vs 0%, and 17% vs 0% of pts, respectively (Table). Among responders, imetelstat increased median central Hb levels compared with PBO: 3.6 g/dL vs 0.8 g/dL for 8-wk, 4.2 g/dL vs 1.1 g/dL for 24-wk, and 5.2 g/dL vs 1.7 g/dL for 1-y RBC-TI. Conclusions: Results from this subanalysis confirm that pts who achieve RBC-TI with imetelstat do so without developing severe neutropenia and thrombocytopenia (functionally defined as needing myeloid growth factors or platelet transfusions, respectively), therefore not negating the clinical benefit of the drug. Imetelstat also led to significant rise in Hb levels in RBC-TI responders, particularly long-term responders. These data further support the efficacy of imetelstat in TD pts with LR-MDS. Clinical trial information: NCT02598661 . [Table: see text]
BEAT-SC: A randomized phase III study of bevacizumab or placebo in combination with atezolizumab and platinum-based chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC).
Authors: Yuichiro Ohe, Baohui Han, Makoto Nishio, Satoshi Watanabe, Xiubao Ren, Shuji Murakami, Nong Yang, Isamu Okamoto, Gaofeng Li, Nobuyuki Katakami, Xianling Liu, Naoyuki Nogami, Yuki Nakagawa, Morihiko Hayashi, Toshihiro Nanki, Chunyu Qian, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2024)

8001 Background: Atezolizumab combined with carboplatin and etoposide is approved as first-line treatment for patients with ES-SCLC, based on results from the Phase I/III IMpower133 trial (NCT02763579). The VEGF inhibitor bevacizumab (bev) is approved for the treatment of many tumor types and has synergistic effects when combined with atezolizumab, as demonstrated by the Phase III IMpower150 study (NCT02366143) in non-small cell lung cancer. BEAT-SC (jRCT2080224946) is evaluating the efficacy and safety of bev combined with atezolizumab and platinum-based chemotherapy in patients with ES-SCLC from Japan and China. Here, we report the primary analysis for progression-free survival (PFS) and the first interim analysis for overall survival (OS) from BEAT-SC. Methods: Eligible patients had measurable ES-SCLC, were aged ≥20 y (≥18 y for patients from China), had an ECOG performance status of 0 or 1 and had no prior systemic treatment for ES-SCLC. Patients were randomized 1:1 to receive 4 cycles (21 days/cycle) of induction therapy with bev combined with atezolizumab + cisplatin or carboplatin + etoposide (ACE) or placebo combined with ACE, followed by maintenance therapy with bev + atezolizumab or placebo + atezolizumab, respectively. The primary endpoint was investigator-assessed PFS (INV-PFS). Key secondary endpoints included OS and safety. Results: The ITT population comprised 333 patients with a median age of 65.0 y; 82.6% of the patients were male, 57.7% were from China, 91.8% received carboplatin and 87.6% were current or former smokers. At data cutoff (June 30, 2023; median follow-up, 10.2 mo), median INV-PFS was 5.7 mo for bev + ACE vs 4.4 mo for placebo + ACE (HR, 0.70; 95% CI: 0.54, 0.90; P=0.0060; 2-sided α boundary=0.05). Median OS was 13.0 mo for bev + ACE vs 16.6 mo for placebo + ACE (HR, 1.22; 95% CI: 0.89, 1.67; P=0.2212; 2-sided α boundary=0.0079). Among the safety analysis population (n=330), bev + ACE was well-tolerated and treatment-related adverse events (TRAEs) were generally similar between treatment arms (Table). Conclusions: BEAT-SC met its primary endpoint, demonstrating that the addition of bev to ACE significantly increased PFS vs placebo + ACE. OS data were immature at the first interim OS analysis, and the numerical OS improvement of bev + ACE was not shown vs placebo + ACE; OS follow-up will continue. No new safety signals were observed. Clinical trial information: jRCT2080224946 . [Table: see text]
Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC).
Authors: Marina Chiara Garassino, Heather A. Wakelee, Jonathan Spicer, Moishe Liberman, Terufumi Kato, Masahiro Tsuboi, Se-Hoon Lee, Ke-Neng Chen, Christophe Alfons Dooms, Margarita Majem, Ekkehard Eigendorff, Gastón L. Martinengo, Olivier Bylicki, Delvys Rodriguez-Abreu, Jamie E. Chaft, Jing Yang, Ashwini Arunachalam, Josephine M Norquist, Steven M. Keller, Shugeng Gao
Journal: Journal of Clinical Oncology (2024)

8012 Background: Neoadjuvant pembrolizumab + cisplatin-based chemotherapy (neoadj pembro + chemo), resection, and adjuvant (adj) pembro (pembro arm; n=397) significantly improved EFS, OS, pCR, and mPR and had an expected safety profile versus neoadj placebo (pbo) + chemo, resection, and adj pbo (pbo arm; n=400) in patients (pts) with resectable stage II, IIIA, or IIIB (N2) NSCLC. We present prespecified pt-reported outcome (PRO) endpoints from KEYNOTE-671. Methods: Pts completed EORTC QLQ-C30 and QLQ-LC13 questionnaires at baseline (BL), the last scheduled presurgery visit, adj cycles 1-4, 7, 10, and 13, and each post treatment visit. A constrained longitudinal data analysis model was used to estimate least squares mean (LSM) score changes from BL to neoadj wk 11 and adj wk 10 (latest time of ≥60% completion and ≥80% compliance) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), role functioning (RF), and dyspnea and QLC-LC13 cough and chest pain in all treated pts who completed ≥1 PRO assessment. Data are from interim analysis 2 (10 Jul 2023 cutoff). Results: Across arms, questionnaire completion was ≥87% at neoadj wk 11 and ≥62% at adj wk 10; compliance was ≥87% and ≥92%, respectively. There were no differences in LSM change from BL in the neoadj or adj phase for any PRO score (Table). Conclusions: Adding perioperative pembro maintained HRQoL in both the neoadj and adj settings versus neoadj chemo and surgery alone in pts with resectable early-stage NSCLC. Together with the significant efficacy improvements and absence of new safety signals, HRQoL data support the perioperative pembro regimen as a new standard of care. Clinical trial information: NCT03425643 . [Table: see text]
Efficacy and safety of taletrectinib in patients with advanced or metastatic ROS1+ non–small cell lung cancer: The phase 2 TRUST-I study.
Authors: Wei Li, Anwen Xiong, Nong Yang, Huijie Fan, Qitao Yu, Yanqiu Zhao, Yongsheng Wang, Xue Meng, Jingxun Wu, Ziping Wang, Yunpeng Liu, Xicheng Wang, Xintian Qin, Kaihua Lu, Wu Zhuang, Yizhong Ren, Xianyu Zhang, Bing Yan, Christine M. Lovly, Caicun Zhou
Journal: Journal of Clinical Oncology (2024)

8520 Background: Taletrectinib, a highly potent, next-generation, central nervous system–active, selective ROS1 tyrosine kinase inhibitor (TKI), was previously reported to provide high overall and intracranial (IC) response rates, prolonged progression-free survival (PFS), and activity against G2032R with favorable tolerability. We report updated data from the TRUST-I study (NCT04395677), the largest clinical trial to date conducted in patients living with ROS1+ NSCLC. Methods: TRUST-I, a multicenter, single-arm, open-label, pivotal phase 2 study of taletrectinib conducted in China, had 2 cohorts: TKI-naïve and TKI-pretreated. The primary endpoint was objective response rate (ORR) by Independent Review Committee (IRC) per RECIST 1.1. Secondary endpoints included duration of response (DoR), PFS, overall survival (OS), and safety. Results: As of November 2023, 173 patients were enrolled (median age: 55 y; 58% female; 73% never smoked; TKI-naïve: n = 106; TKI-pretreated: n = 67). In TKI-naïve patients, 21% had prior chemotherapy, and 17% had brain metastases; in TKI-pretreated patients, 34% had prior chemotherapy, and 42% had brain metastases. In TKI-naïve patients, the ORR was 91% (95% CI: 83, 95) and IC-ORR was 88% (7/8; 95% CI: 47, 100). In TKI-pretreated patients, the ORR was 52% (95% CI: 40, 65) and IC-ORR was 75% (12/16; 95% CI: 48, 93). In patients with G2032R mutation, 8 of 12 patients (67% [95% CI: 35, 90]) responded. DoR and PFS remain durable, with median follow-up of 23.5 months in TKI-naïve patients and 9.7 months in TKI-pretreated patients (Table). Among all patients (n = 173), the most frequent treatment-emergent adverse events (TEAEs) were AST increase (76%), diarrhea (70%), and ALT increase (68%). Rates of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuation (5%) and dose reductions (19%) due to TEAEs were low. Conclusions: With longer follow-up, taletrectinib continues to show high and durable overall responses, robust intracranial and G2032R activity, and a favorable safety profile with a low incidence of neurologic AEs. An additional ongoing pivotal phase 2 study, TRUST-II (NCT04919811), is further evaluating the efficacy and safety of taletrectinib in patients in the US, Europe, and Asia. Clinical trial information: NCT04395677 . [Table: see text]