OA02.02 Phase 1 Study of Safety, Tolerability, PK and Efficacy of AMG 510, a Novel KRASG12C Inhibitor, Evaluated in NSCLC

Govindan, Ramaswamy; Fakih, Marwan; Price, Timothy; Falchook, Gerald S.; Desai, Jayesh; Kuo, James; Strickler, John H.; Krauss, John C.; Li, B.; Denlinger, C.S.; Durm, Greg Andrew; Ngang, Jude; Henary, H.; Ngarmchamnanrith, Gataree; Rasmussen, Erik; Morrow, Phuong Khanh; Hong, David S.

doi:10.1016/j.jtho.2019.08.412

Cited by 35 publications

(23 citation statements)

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“…Phase I clinical trials of the single agent were associated with a partial response in two patients with advanced cancers (lung and colon). Further, recent results from this clinical trial have shown a partial response in four patients and stable disease in the rest of the evaluable patients (n = 12) at the time of analysis [26]. These preliminary observations with KRAS inhibitors provide hope for their use in PDAC.…”

Section: Kras Inhibitors As Novel Anti-cancer Agents For Pdacmentioning

confidence: 69%

“…These encouraging results have led AMGEN to initiate a phase I/II clinical trial involving 533 participants with KRAS G12C mutations suffering from various advanced solid tumors, investigating the efficacy of AMG 510 as monotherapy or in combination with an anti-PD-1 immune checkpoint blocker. The initial results from this clinical trial are promising, with all patients (locally advanced or metastatic NSCLC patients treated with multiple failed prior therapies) treated at the highest/target dose (960 mg) achieving disease control (54% demonstrating partial response and 46% demonstrating stable disease) [26]. Only 35.3% of patients reported treatment-related adverse events, which were predominantly grade 1 and 2 nausea and vomiting [26].…”

Section: Kras Inhibitors As Novel Anti-cancer Agents For Pdacmentioning

confidence: 96%

“…The initial results from this clinical trial are promising, with all patients (locally advanced or metastatic NSCLC patients treated with multiple failed prior therapies) treated at the highest/target dose (960 mg) achieving disease control (54% demonstrating partial response and 46% demonstrating stable disease) [26]. Only 35.3% of patients reported treatment-related adverse events, which were predominantly grade 1 and 2 nausea and vomiting [26]. Although these results are encouraging for cancers that majorly harbor KRAS G12C mutations (e.g., lung cancers [27]), their utility for PDAC is limited, with only~2% KRAS G12C mutation observed [15].…”

Section: Kras Inhibitors As Novel Anti-cancer Agents For Pdacmentioning

confidence: 99%

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Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?

Gillson

Ramaswamy

Singh

et al. 2020

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Overall, we propose that the antitumor effects from novel KRAS inhibitors along with strategies to overcome drug delivery issues could be a new therapeutic way forward in PDAC.

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Section: Kras Inhibitors As Novel Anti-cancer Agents For Pdacmentioning

confidence: 69%

Section: Kras Inhibitors As Novel Anti-cancer Agents For Pdacmentioning

confidence: 96%

Section: Kras Inhibitors As Novel Anti-cancer Agents For Pdacmentioning

confidence: 99%

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Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?

Gillson

Ramaswamy

Singh

et al. 2020

Cancers

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“…The grade 3 TEAEs were anemia and diarrhea. The most common AEs were decreased appetite and diarrhea [65,66].…”

Section: Kras G12c Inhibitormentioning

confidence: 99%

Emerging therapeutic agents for advanced non-small cell lung cancer

et al. 2020

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Advanced non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a poor prognosis and no known cure. Survival time is often short because of limited treatment options. Recent advances in targeted therapy and immunotherapy have changed the landscape for the treatment of advanced NSCLC. In the last 10 years, the US Food and Drug Administration (FDA) has approved more than 17 new medications for this devastating disease and more are coming. Molecular and immunogenic testing makes personalized medicine possible for patients with advanced NSCLC. The new medications provide promising efficacy and safety resulting in improved long-term survival for a significant number of patients. In this review, we summarize the recent advances in advanced/metastatic NSCLC therapeutics with a specific focus on first inhuman or early-phase I/II clinical trials. These drugs either offer better alternatives to current standard drugs in the same class or are a completely new class of drugs with novel mechanisms of action. Advances are divided into (1) targeted agents, (2) antibody-drug conjugates, and (3) immunotherapies. Finally, we present a brief review of the emerging agents and ongoing clinical studies.

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“…For example, the development of mutant KRAS-targeted drugs has proven problematic over the previous three decades (13). Although recently, treatment with AMG510, a novel inhibitor against KRAS G12C, resulted in a promising response rate in patients with lung cancer harboring this specific type of mutation, development of drugs targeting other types of KRAS mutations have not yet been successful (14)(15)(16). In addition, mutations in driver oncogenes in a number of types of human cancer have not been identified (17).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic screening using large‑scale genomic libraries to identify drug targets for the treatment of cancer (Review)

Sato

2020

Oncol Lett

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During malignant progression to overt cancer cells, normal cells accumulate multiple genetic and non-genetic changes, which result in the acquisition of various oncogenic properties, such as uncontrolled proliferation, drug resistance, invasiveness, anoikis-resistance, the ability to bypass oncogene-induced senescence and cancer stemness. To identify potential novel drug targets contributing to these malignant phenotypes, researchers have performed large-scale genomic screening using various in vitro and in vivo screening models and identified numerous promising cancer drug target genes. However, there are issues with these identified genes, such as low reproducibility between different datasets. In the present study, the recent advances in the functional screening for identification of cancer drug target genes are summarized, and current issues and future perspectives are discussed.

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OA02.02 Phase 1 Study of Safety, Tolerability, PK and Efficacy of AMG 510, a Novel KRASG12C Inhibitor, Evaluated in NSCLC

Cited by 35 publications

References 0 publications

Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?

Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?

Emerging therapeutic agents for advanced non-small cell lung cancer

Phenotypic screening using large‑scale genomic libraries to identify drug targets for the treatment of cancer (Review)

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