AMG 510

KRAS G12C IS A NEW ONCOGENIC DRIVER MUTATION

KRASG12C is an oncogenic driver mutation, and the most common KRAS mutation in NSCLC.1,2,3 KRASG12C occurs in 13% of patients with NSCLC, and in 1 to 3 % in patients with colorectal or other solid tumors. G12C is a point mutation, where at codon 12, glycine is substituted by a cysteine. This favors the active status of KRAS and amplifies the signal cascades, leading to oncogenesis.3

KRAS G12C -MUTATION: TARGET FOR NEW THERAPEUTIC OPTIONS

video-g12c-protein
Mode of action and inhibition of KRAS G12C protein

SOTORASIB, A KRAS p.G12C INHIBITOR UNDER INVESTIGATION

Sotorasib, formerly AMG 510, specifically and irreversibly binds to cysteine-12 in a small pocket of the KRASG12C protein.3,4,5

Clinical Trial Programme of AMG 510 in Advanced Solid Tumors

SOTORASIB CONGRESS DATA

ESMO 2020: Phase 1 Results of CodeBreaK100 showed that AMG 510 demonstrated durable disease control in heavily pre-treated patients with NSCLC with a favorable safety profile.

Oral (abstract #1257) by Hong et al.

ESMO 2020: Largest real-world dataset for NSCLC patients with KRAS G12C mutations (n=743) from the Flatiron Health-Foundation Medicine Clinico-Genomic database shows PFS and OS outcomes are poor (mPFS 2L 4.0 mo), consistent with overall NSCLC.

Poster (abstract 1339) by Aggarwal et al.

ASCO 2020: in the phase I study with Sotorasib (AMG 510), a KRASG12C inhibitor, clinical anticancer activity has been seen in patients with advanced multiple solid tumor types (other than CRC and NSCLC) with mutant KRAS p.G12C, with a tolerable toxicity profile (Codebreak 100 trial)

Material90
510 Poster discussion #3511, Hong et al., ASCO 2020
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ASCO 2020: A further analysis of the CRC cohort of the phase 1 CodeBreak 100 showed that 7.1% patients with heavily pretreated KRAS p.G12C mutant metastatic CRC had confirmed durable partial responses to sotorasib (AMG 510)

Details about this recruiting trial in Switzerland are found here.

ESMO 2019: Phase 1 study data of AMG 510 in advanced solid tumors with KRAS p. G12C mutation

AMG 510 has been found to have a favorable safety profile at the dose levels tested and demonstrated early promising antitumor activity in patients with advanced CRC and NSCLC harboring KRAS p. G12C mutation.
Material90
Poster presentation 446PD by R. Govindan et al.

WCLC 2019: Phase 1 study of AMG 510 showed an 48% Overall Response Rate in patients with advanced NSCLC

and a favorable safety profile with Dose Limiting Toxicities.
Oral presentation (abstract #OA02.02) by R. Govindan et al.

ASCO 2019: Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 510

References:

  1. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Nat Rev Drug Discov. 2014;13(11):828-851.
  2. Downward J. Nat Rev Cancer. 2003;3(1):11-22.
  3. Ryan MB, Corcoran RB. Nat Rev Clin Oncol. 2018;15(11):709-720
  4. Shea M, et al. Ther Adv Respir Dis. 2016;10:113–29.
  5. Kris MG, et al. JAMA. 2014;311: 1998–2006. 10

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