Early Evidence Supporting KRAS G12C as a Druggable Target: High Response Rate for AMG 510 in Advanced NSCLC

The following article features coverage from the IASLC 2019 World Conference on Lung Cancer meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Initial data from the phase 1 study evaluating the efficacy of AMG 510, an oral, specific inhibitor of KRAS G12C, in patients with advanced solid tumors showed a 100% disease control rate (DCR) in the subgroup of evaluable patients with advanced non-small cell lung cancer (NSCLC) treated with the 960 mg dose. These findings were presented at the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer held in Barcelona, Spain.^1-3

Mutations in KRAS have been identified as oncogenic drivers of many types of solid tumors. In particular, KRAS mutations encoding for alterations in the amino acid at position 12 in the KRAS protein are common. Nevertheless, previous attempts to therapeutically target mutant forms of KRAS have been unsuccessful, largely due to the lack of suitable drug-binding pockets on the protein.

In its active form, KRAS binds to GTP and is a key mediator in signaling pathways involved in cellular proliferation. Under normal circumstances, KRAS then cycles to an inactive form through enzymatic conversion of GTP to GDP. However, oncogenic forms of KRAS remain in the active conformation.

AMG 510 is a first-in-class, orally administered KRAS inhibitor that was designed to specifically and covalently bind to the cysteine-12 residue which replaces glycine-12 in 1 mutant form of KRAS (G12C). Its mechanism of action has been associated with “locking [KRAS] in an inactive GDP-bound state.”²

This ongoing open-label, nonrandomized phase 1/2 study (ClinicalTrials.gov Identifier: NCT03600883), is enrolling adult patients with advanced solid tumors characterized by KRAS G12C. The phase 1 portion of the study involves enrollment of patients into 1 of 4 different AMG 510 oral monotherapy dose cohorts (180 mg, 360 mg, 720 mg, and 960 mg once daily). The primary end point of the study is safety with pharmacokinetics, objective response rate (ORR), and DCR as some of the key secondary study end points.

Thus far, 76 patients with pretreated locally advanced or metastatic solid tumor cancers have been enrolled in the study, including 34 patients with NSCLC.³ Of the 23 patients with NSCLC who were evaluable for efficacy, the ORR was 48%, with a DCR of 96%.

In the subgroup of patients with NSCLC treated with the 960 mg dose of AMG 510 who were also evaluable for efficacy, the ORR was 54% (all partial responses), with 46% of patients achieving stable disease, for a DCR of 100%.^2,3

Regarding safety, AMG 510 was well tolerated in the overall cohort of patients with NSCLC. Treatment-related grade 1/2 and grade 3 adverse events were reported in 26.5% and 8.8% of these patients, respectively. No grade 4 treatment-related adverse events, dose-limiting toxicities, or adverse events leading to treatment discontinuation were reported.

“There is a need for targeted treatments for specific driver mutations of cancer that do not have an approved therapy,” noted Ramaswamy Govindan, MD, principal investigator of this study and professor at Washington University School of Medicine in St Louis, Missouri, in a conference press release. “These data continue to show encouraging antitumor activity with AMG 510, underscoring the potential to close the treatment gap for non-small cell lung cancer patients with previously treated KRAS G12C-mutation NSCLC.”²

Read more of Cancer Therapy Advisor‘s coverage of the IASLC annual meeting by visiting the conference page.

References

1. Govindan R, Fakih MG, Price TJ, et al. Phase I study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS G12C inhibitor, evaluated in NSCLC. Presented at: IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02
2. Amgen. Amgen announces new clinical data evaluating novel investigational KRASG12C inhibitor in larger patient group at WCLC 2019 [press release]. Published September 8, 2019. Accessed September 9, 2019.
3. International Association for the Study of Lung Cancer. IASLC World Conference on Lung Cancer – press briefing summary for Sunday, September 8^th. Accessed September 8, 2019.