Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation

1. The overall objective response rate was 35.1% in patients with initial measurable disease, all of which were partial responses, and had occurred in all cancer types except for appendiceal cancer.

2. Treatment-related adverse events of grade 3 or higher occurred in about 27% of patients and included fatigue and QT prolongation.

Evidence Rating Level: 2 (Good)

Study Rundown: The KRASG12C mutation occurs can be found in patients with non-small cell lung cancer (NSCLC), colorectal cancer (CRC), as well as in other solid tumours. Adagrasib, a small molecule covalent inhibitor, has demonstrated clinical activity and tolerability in previously treated patients with KRASG12C-mutated NSCLC and CRC. This study investigates a phase II trial of adagrasib in advanced solid tumours other than NSCLC or CRC. The primary endpoint was objective response rate (ORR), and the secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The overall ORR was 35.1%, which were all partial responses and had occurred in all cancer types except for appendiceal cancer. The median time to respond was 1.4 months and the median DoR was 5.3 months. The median PFS was 7.4 months with the median OS being 14.0 months. The OS rate at 1 year was 53.5%. With regards to safety, 96.8% of patients experienced treatment-related adverse events, with grade 3 events representing 25.4% and grade 4 representing 1.6%. The most common adverse events included nausea (49.2%), diarrhea (47.6%), fatigue (41.3%), and vomiting (39.7%). The most common grade 3 events were fatigue (6.3%) and electrocardiogram QT prolongation (6.3%). The strengths of this study included the diversity of tumour types, and the limitations of this study included its small sample size and its single-arm design. Overall, this phase II trial shows some evidence of efficacy in KRASG12C-mutated advanced solid tumours other than NSCLC and CRC.

Click to read the study in JCO

Relevant Reading: Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation

In-Depth [prospective cohort]: This open-label, single-arm, non-randomized phase II trial investigated the clinical activity of adagrasib (600mg PO BID) in 64 adult patients with histologically confirmed KRASG12C-mutated advanced solid tumours (excluding NSCLC and CRC). Advanced solid tumours included pancreatic, biliary tract, appendiceal, ovarian cancer etc. The median follow-up time was 16.8 months. The overall ORR was 35.1% in patients with initial measurable disease, all of which were partial responses, and had occurred in all cancer types except for appendiceal cancer. The median time to respond was 1.4 months and the median DoR was 5.3 months (95%CI, 2.8-7.3) according to a blinded review panel. The median PFS was 7.4 months (95%CI, 5.3 to 8.6) with the median OS being 14.0 months (95%CI, 8.5 to 18.6). The OS rate at 1 year was 53.5% (95%CI, 37.9 to 66.9). With regards to safety, 96.8% of patients experienced treatment-related adverse events, with grade 3 events representing 25.4% and grade 4 representing 1.6%. The most common adverse events included nausea (49.2%), diarrhea (47.6%), fatigue (41.3%), and vomiting (39.7%). The most common grade 3 events were fatigue (6.3%) and electrocardiogram QT prolongation (6.3%). Overall, this phase II trial shows some evidence of benefit of KRASG12C targeted inhibition in advanced solid tumours other than NSCLC and CRC.

Image: PD

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