AMG 510 Demonstrates Early Promise in Advanced KRAS G12C-Mutant Solid Tumors

Early signals of anti-tumor activity and safety were demonstrated with the novel KRAS G12C inhibitor, AMG 510, in multiple advanced solid tumors that harbor KRAS G12C mutations, according to results presented at the 2020 ASCO Virtual Scientific Program.¹

In a cohort of 25 patients treated with AMG 510 confirmed partial responses were observed in 3 patients who had appendiceal cancer, melanoma, and endometrial cancer, respectively. Thirteen patients achieved stable disease and included 6 patients with pancreatic cancer, 2 with appendiceal cancer, 1 with ampullary cancer, and 1 with bile duct cancer, 1 with endometrial cancer, 1 with sinonasal cancer, and 1 with unknown primary cancer.

The safety profile was consistent with previously reported data, and toxicities were mild and manageable with treatment related adverse events (AEs).

“In the phase 1, first-in-human study, we saw encouraging anti-cancer activity in multiple tumor types with G12C, and the toxicities were tolerable,” said David S. Hong, MD during a poster presentation.

AMG 510 is a small molecule that specifically and irreversible binds to switch II pocket region of the KRAS G12C protein, said Hong, deputy chair of Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.

Previously, AMG 150 demonstrated a favorably toxicity profile and preliminary efficacy in patients with NSCLC and CRC harboring KRAS G12C. The updated analyses examined the efficacy of the agent in other KRAS G12C-mutant solid tumors.

CodeBreak 100, a phase 1/2 study (NCT03600883), evaluated AMG 510 in patients with locally-advanced or metastatic KRAS G12C–mutant solid tumors. Enrolled patients were pretreated with at least 2 or more prior lines of treatment, consistent with their tumor type and stage of disease.

In this analysis, data were evaluated for 25 pretreated patients with advanced KRAS G12C-mutant solid tumors other than CRC or NSCLC. These patients had received a median 3 prior lines of therapy with a median follow-up of 4.3 months. The primary end point was safety; key secondary end points included pharmacokinetics and objective response rate as assessed per RECIST 1.1 criteria. Response was assessed every 6 weeks for 24 weeks then every 12 weeks thereafter. Patients were enrolled in 4 dose cohorts: 180 mg, 360 mg, 720 mg and 960 mg, taken orally once a day.

Six of 8 evaluable patients with pancreatic cancer achieved stable disease, and 3 had approximately a 30% reduction in tumor burden from baseline. Eight of 22 patients were still on treatment as of cutoff, January 8, 2020.

No dose-limiting toxicities, grade 4 or higher, or fatal treatment-related AEs were reported, and no treatment-related adverse events led to therapy discontinuation. Twenty patients (80%) experienced an AE, and 9 patients (36%) experienced a treatment-related AE. Grade 3 treatment-related AEs included diarrhea and pneumonia occurring in 1 patient each.

Continued Efficacy in CRC and NSCLC

Anti-tumor activity has continued to be observed in patients with NSCLC and CRC in CodeBreak 100. Updated findings of patients with CRC were reported as part of the 2020 ASCO Virtual Scientific Program.

Across all dose levels patients with heavily pretreated advanced KRAS G12C-mutant CRC (n = 42) the objective response rate (ORR) and disease control rate (DCR) were 7.1% and 76.2%. Disease stability was maintained for a median of 4.2 months. Median progression-free survival (PFS) was 4.0 months and median overall survival (OS) was 10.1 months. Tumor shrinkage was observed in 18 of 39 patients with available post-baseline tumor data across all doses.

In the dose-expansion cohort, defined as those patients receiving 960 mg once-daily target dose, the ORR was 12% (3/25) and the DCR was 80% (20/25). Median PFS was 4.2 months and OS had not been reached after a median follow-up of almost 8 months. Further, tumor shrinkage was observed in 11 of 23 patients with available post-baseline tumor data.²

In September 2019, the FDA granted AMG 510 a fast track designation for the treatment of patients with previously treated metastatic NSCLC harboring a KRAS G12C mutation. The designation was based on follow-up data for a subset of 34 NSCLC patients, 23 of whom were evaluable for efficacy. Thirteen of the evaluable patients received the target dose of 960 mg once daily, of which 7 (54%) achieved a partial response at one or more timepoints and 6 (46%) achieved stable disease, for a disease control rate of 100%.³

Single-arm phase 2 trials in both NSCLC and CRC (also part of CodeBreak 100) are now fully enrolled. A phase 2 trial in NSCLC is on track for data readout in 2020.2 The phase 2 CRC trial is expected to have a data readout in early 2021. Phase 1b combination studies across various advanced solid tumors (CodeBreak 101) are currently enrolling. In addition, a randomized global phase 3 confirmatory study in NSCLC (CodeBreak 200) has been initiated.

_References:

_{1. Hong D. Kuo J. Sacher A, et al. CodeBreak 100: phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Poster presented at: 2020 American Society of Clinical Oncology Virtual Scientific Meeting. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/185094/poster}

_{2. Fakih M, Desai J, Kuboki Y, et al. CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. Poster presented at: 2020 American Society of Clinical Oncology Virtual Scientific Meeting. Accessed May 30, 2020. https://meetinglibrary.asco.org/record/185490/poster}

_{3. Amgen announces new clinical data evaluating novel investigational KRAS(G12C) inhibitor in larger patient group at WCLC 2019. Press release. Thousand Oaks, CA: Amgen; September 8, 2019. Accessed May 30, 2020. bit.ly/2kqnxi4}

_{4. Amgen presents new AMG 510 clinical data across multiple solid tumors during ASCO20 virtual scientific program. Press release. Thousand Oaks, CA: Amgen; May 29, 2020. Accessed May 29, 2020 https://bit.ly/3cf8zQG}