Browsing by Subject "combination therapy"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer
    (Elsevier, 2018) Borghaei, Hossein; Langer, Corey J.; Gadgeel, Shirish; Papadimitrakopoulou, Vassiliki A.; Patnaik, Amita; Powell, Steven F.; Gentzler, Ryan D.; Martins, Renato G.; Stevenson, James P.; Jalal, Shadia I.; Panwalkar, Amit; Yang, James Chih-Hsin; Gubens, Matthew; Sequist, Lecia V.; Awad, Mark M.; Fiore, Joseph; Saraf, Sanatan; Keller, Steven; Gandhi, Leena; Medicine, School of Medicine
    Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.
  • Thumbnail Image
    Item
    Is There a Role for Immunotherapy in Prostate Cancer?
    (MDPI, 2020-09-08) Rizzo, Alessandro; Mollica, Veronica; Cimadamore, Alessia; Santoni, Matteo; Scarpelli, Marina; Giunchi, Francesca; Cheng, Liang; Lopez-Beltran, Antonio; Fiorentino, Michelangelo; Montironi, Rodolfo; Massari, Francesco; Pathology and Laboratory Medicine, School of Medicine
    In the last decade, immunotherapy has revolutionized the treatment landscape of several hematological and solid malignancies, reporting unprecedented response rates. Unfortunately, this is not the case for metastatic castration-resistant prostate cancer (mCRPC), as several phase I and II trials assessing programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits. Moreover, despite sipuleucel-T representing the only cancer vaccine approved by the Food and Drug Administration (FDA) for mCRPC following the results of the IMPACT trial, the use of this agent is relatively limited in everyday clinical practice. The identification of specific histological and molecular biomarkers that could predict response to immunotherapy represents one of the current challenges, with an aim to detect subgroups of mCRPC patients who may benefit from immune checkpoint monoclonal antibodies as monotherapy or in combination with other anticancer agents. Several unanswered questions remain, including the following: is there—or will there ever be—a role for immunotherapy in prostate cancer? In this review, we aim at underlining the failures and promises of immunotherapy in prostate cancer, summarizing the current state of art regarding cancer vaccines and immune checkpoint monoclonal antibodies, and discussing future research directions in this immunologically “cold” malignancy.
  • Thumbnail Image
    Item
    MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma
    (Elsevier, 2017-12-11) Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A.; Pangeni, Rajendra P.; Wan, Xuechao; Song, Xiao; Shi, Taiping; Yang, Yongyong; Sastry, Namratha; Horbinski, Craig M.; Lu, Songjian; Stupp, Roger; Kessler, John A.; Nishikawa, Ryo; Nakano, Ichiro; Sulman, Erik P.; Lu, Xinghua; James, Charles David; Yin, Xiao-Ming; Hu, Bo; Cheng, Shi-Yuan; Pathology and Laboratory Medicine, School of Medicine
    ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy., • MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells • MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383 • Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy • Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models , Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.
  • Thumbnail Image
    Item
    Some basic facts on combination therapy
    (Association of Kenya Physicians, 2007) Kokwaro, Gilbert; Association of Kenya Physicians Scientific Conference (11th : Mar. 2007 : Eldoret, Kenya)
    What are the problems with malaria? • The disease • The drugs • The policies • The finance COMBINATION THERAPY: DEFINITION • CT is the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasites • • CTs can be either fixed ratio combinations or multiple-drug therapy, in which components are co-administered in separate tablets or capsules.