scholarly journals Independent Drug Action in Combination Therapy: Implications for Precision Oncology

2022 ◽  
pp. candisc.0212.2021
Author(s):  
Deborah Plana ◽  
Adam C Palmer ◽  
Peter K Sorger
2011 ◽  
Vol 55 (9) ◽  
pp. 4461-4464 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Enny Kenangalem ◽  
...  

ABSTRACTFerroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potentin vitroefficacy against chloroquine (CQ)-resistantPlasmodium falciparumand CQ-sensitiveP. vivax. In the current study,ex vivoFQ activity was tested in multidrug-resistantP. falciparumandP. vivaxfield isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistantP. falciparumandP. vivax(median 50% inhibitory concentrations [IC50s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (forP. falciparum,r= 0.546 to 0.700,P< 0.001; forP. vivax,r= 0.677 to 0.821,P< 0.001). The observedex vivocross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of bothP. falciparumandP. vivaxhighlights a promising role for FQ as a lead antimalarial against CQ-resistantPlasmodiumand a useful partner drug for artemisinin-based combination therapy.


2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 39-39
Author(s):  
Junhua Yu ◽  
Kanwal Pratap Singh Raghav ◽  
Aparna Raj Parikh ◽  
David Hanna ◽  
Enrique Marino ◽  
...  

39 Background: Clinical insights gained from real-world data have led to numerous advances in oncology including new and expanded drug approvals and an understanding of real-world clinical utilization. In this precision oncology age, integrating real-world clinical data with genomic data can lead to further advancements. We aimed to understand the genomic and treatment landscape in advanced colorectal cancer (aCRC) by leveraging a uniquely large and detailed clinical-genomic database. Methods: The GuardantINFORM (Guardant Health) database comprises aggregated commercial payer health claims and de-identified records from over 100,000 individuals with comprehensive ctDNA results (Guardant360). GuardantINFORM was queried for patients (pts) with a diagnosis of CRC. Pts with fewer than two pharmacy claims prior to or after the first ctDNA test were excluded from the regimen analysis. Latest claims data was truncated as of 8/31/2020. Results: 10,845 pts had a total of 13,510 ctDNA tests (1 – 19 tests/pt). The first ctDNA test date was from 06/2014 - 06/2020. The majority of pts had one ctDNA test (86.7%) while 5% had three or more tests. 87.9% of ctDNA tests had at least one genomic alteration identified, with the distribution of alterations consistent with prior reports (Table). 78% of pts had at least two pharmacy claims before and/or after the first ctDNA test. Of those pts with at least one CRC treatment, the most commonly prescribed CRC regimens up to one year prior to the first ctDNA test were FOLFOX +/- bevacizumab (16%, 18%), FOLFIRI +/- bevacizumab (17%, 11%), capecitabine (15%), 5-FU (12%), and regorafenib (5.2%). Anti-EGFR mono and combination therapy was reported in 6% and 16% of pts pre ctDNA testing. Immune checkpoint inhibitor (ICPi) mono and combination therapy was reported in 2% and 0.5% of pts. The most commonly prescribed CRC regimens post first ctDNA test were capecitabine (16%), FOLIRI +/- bevacizumab (15%, 13%), tipiracil and trifluridine (15%), FOLFOX +/- bevacizumab (12%, 14%), 5-FU (11%), and regorafenib (10%). Anti-EGFR mono and combination therapy was reported in 8% and 18% of pts post ctDNA testing. ICPi mono and combination therapy was reported in 5% and 1% of pts. Conclusions: Using a large and uniquely detailed clinical-genomic dataset, we produced results that replicate the observed distribution of ctDNA identified mutations present in aCRC. This genomic information combined with real-world clinical data provides valuable insights into the variety of longitudinal treatments, including before and after comprehensive ctDNA genomic profiling, allowing for detailed outcomes research, especially focused on precision oncology. [Table: see text]


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9117-TPS9117
Author(s):  
Martin Gutierrez ◽  
Matthew David Hellmann ◽  
Matthew A. Gubens ◽  
Charu Aggarwal ◽  
Daniel Shao Weng Tan ◽  
...  

TPS9117 Background: Pembrolizumab-based combination immunotherapy aims to improve clinical outcomes over pembrolizumab monotherapy. A biomarker-based therapeutic approach may be associated with improved response to different combination therapies of immune checkpoint inhibitors and may improve overall outcomes in NSCLC. The randomized, multicenter, open-label, phase 2 KEYNOTE-495 trial ( NCT03516981 ) will evaluate the clinical usefulness of biomarker-informed, pembrolizumab-based combination therapy in patients with treatment-naive, advanced NSCLC. Methods: This is a group-sequential, adaptive randomization trial. Patients will have histologically or cytologically confirmed treatment-naive, advanced NSCLC, documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements, measurable disease per RECIST v1.1, and ECOG PS 0-1. Tumor tissue from patients will be initially screened for 2 validated, independent, next-generation biomarkers: T cell–inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on results of biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab 200 mg Q3W intravenously (IV) combined with either MK-4280 200 mg Q3W (anti–LAG-3) IV or lenvatinib 20 mg orally once daily, with the randomization assignment adaptively modified based on interim efficacy analyses. Response will be assessed by imaging every 9 weeks for the first year and every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. Treatment arms may be terminated during the interim analysis due to safety, prespecified futility criteria, or both. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries. Clinical trial information: NCT03516981.


2008 ◽  
Vol 39 (2) ◽  
pp. 69
Author(s):  
CAROLINE HELWICK
Keyword(s):  

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