Amgen's KRAS Inhibitor Sotorasib Shows 32.2% ORR in NSCLC Cohort in Pivotal Phase 1 Trial

Text: Manhua

KRAS mutations occur in approximately 25% of cancer cases and are associated with a very poor prognosis. Therefore, scientists consider blocking KRAS signaling to be a potential anticancer strategy. However, research over the past several decades has suggested that this protein may be an “undruggable” target, as its surface is largely smooth except for a GTP-binding pocket, making it difficult for drug developers to identify binding sites for small-molecule candidates.

In 2013, a paper published in Nature by the team of Kevan Shokat, a chemical biologist at the University of California, San Francisco, marked a significant turning point in the development of KRAS-targeted drugs. Shokat and his colleagues reported for the first time the feasibility of using small molecules to covalently bind to the KRAS G12C mutant [1]. They designed a covalent small-molecule inhibitor capable of irreversibly targeting the cysteine residue at codon 12 of KRAS, thereby locking the protein in an inactive state.

KRASG12C mutation, referring to the substitution of glycine at position 12 of KRAS with cysteine, is present in approximately 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors. Due to the high reactivity of the newly introduced cysteine residue, which readily forms covalent bonds, small molecules can covalently bind to the KRASG12C mutant, thereby holding promise for the treatment of patients harboring this specific KRAS mutation.

The groundbreaking discovery by the Shokat team confirmed that KRAS is more druggable than previously thought, significantly advancing the development of KRAS G12C inhibitors. Among these, Amgen’s KRAS G12C inhibitor Sotorasib (AMG 510) entered clinical studies in August 2018, becoming the first KRAS G12C inhibitor to undergo clinical testing.

At last year’s ESMO Congress, Amgen announced preliminary data from the Phase I/II trial of sotorasib. Among the 13 patients with non-small cell lung cancer (NSCLC) treated with sotorasib, 7 (54%) achieved a partial response, characterized by tumor shrinkage, while the remaining 6 patients experienced stable disease. Furthermore, sotorasib appeared to be well tolerated, with no dose-limiting toxicities observed.

Source: NEJM

On September 20, Amgen published the full results of the Phase I trial of Sotorasib in the New England Journal of Medicine (NEJM) [2]. This Phase I trial (NCT03600883) enrolled patients with advanced solid tumors harboring KRAS G12C mutations. Patients received oral Sotorasib once daily at one of four dose levels: 180 mg, 360 mg, 720 mg, or 960 mg. The primary endpoint of the study was safety, and the key secondary endpoints were pharmacokinetics and objective response rate.

Baseline Patient Characteristics (Source: NEJM)

Specifically, a total of 129 patients were enrolled in the trial, including 59 with non-small cell lung cancer (NSCLC), 42 with colorectal cancer, and 28 with other types of solid tumors. The majority of patients had undergone extensive prior treatment; 78 patients (60.5%) had previously received three or more lines of therapy.

The study results showed that, in terms of safety, no dose-limiting toxicities or treatment-related deaths were observed. Treatment-related adverse events (TRAEs) occurred in 73 patients (56.6%), including 15 patients (11.6%) who experienced grade 3 or 4 TRAEs. The most common TRAEs included diarrhea, fatigue, and nausea. Grade 3 TRAEs included elevated alanine aminotransferase levels (4.7%), diarrhea (3.9%), and anemia (3.1%).

Efficacy of Sotorasib Across All Tumor Types (Source: NEJM)

In terms of efficacy, anticancer activity was observed across all dose groups in the non-small cell lung cancer (NSCLC) cohort, with 32.2% (19 patients) achieving a confirmed objective response (complete response [CR] or partial response [PR]), and 88.1% (52 patients) achieving disease control (objective response or stable disease). The median progression-free survival (PFS) was 6.3 months. In the colorectal cancer cohort, 7.1% (3 patients) achieved a confirmed response, 73.8% (31 patients) achieved disease control, and the median PFS was 4.0 months. Responses were also observed in patients with pancreatic cancer, endometrial cancer, appendiceal cancer, and melanoma (one patient each).

Changes in Tumor Burden in NSCLC Patients Receiving Sotorasib Treatment (Source: NEJM)

Researchers believe that these data indicate sotorasib demonstrates promising anticancer activity in patients with advanced solid tumors harboring KRAS G12C mutations. The trial results provide key clinical evidence confirming that KRAS is indeed “druggable.”

Efficacy of Sotorasib in Patients with NSCLC (Source: NEJM)

An accompanying perspective article in the New England Journal of Medicine (NEJM) on the results of this phase I trial noted that the overall survival of patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC) or colorectal cancer is approximately 1 to 2 years. This striking data has driven nearly four decades of industry research into KRAS-targeted therapies. Early strategies aimed at preferentially binding to the KRAS–GTP pocket failed due to KRAS’s picomolar affinity for GTP and the high intracellular concentration of GTP (KRAS is in its active state when bound to GTP, and aberrant KRAS activation is closely associated with various cancers). Other approaches attempted to disrupt KRAS activity by preventing its membrane localization or inhibiting downstream kinase signaling, but these also failed due to resistance mediated by compensatory signaling pathways. To date, no therapy targeting KRAS mutations in cancer has been approved for market release.

However, thanks to the landmark findings published in Nature by Shokat’s team, industry interest in developing therapeutic strategies that directly target KRAS has been rekindled. The favorable safety profile of sotorasib observed in this Phase I study, along with positive data demonstrating anticancer activity across multiple doses, indicates its potential for combination with other therapies. In summary, the results of this trial are highly encouraging, representing a critical step forward in targeting previously “undruggable” targets.

References:

[1]Jonathan M. Ostrem etal.K-Ras(G12C)inhibitors allosterically control GTP affinity and effector interactions. Nature（2013）.[2]David S. Hong et al.KRASG12CInhibition with Sotorasib in Advanced Solid Tumors. NEJM(2020).

[3]Clinical Data From Full Phase 1 Cohort Of Investigational Sotorasib Published In New England Journal Of Medicine