KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors
David S Hong1, Marwan G Fakih1, John H Strickler1
1From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.).
Background:
No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.
Methods:
We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
Results:
A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.
Conclusions:
Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Insights
Sotorasib shows promise for treating cancers with the KRAS p.G12C mutation, demonstrating anticancer activity with manageable side effects in heavily pretreated patients. This targeted therapy offers a new option for non-small-cell lung cancer and colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The KRAS p.G12C mutation is present in 13% of non-small-cell lung cancers (NSCLCs) and 1-3% of other cancers, with no approved targeted therapies.
- Sotorasib is a novel small molecule designed to selectively and irreversibly inhibit the KRAS p.G12C protein.
Purpose of the Study:
- To evaluate the safety and efficacy of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation.
- To assess the pharmacokinetics and objective response rates of sotorasib in this patient population.
Main Methods:
- A Phase 1 clinical trial involving dose escalation and expansion cohorts.
- 129 patients with advanced solid tumors (including NSCLC, colorectal cancer, and others) with KRAS p.G12C mutation received oral sotorasib daily.
- Safety was assessed by dose-limiting toxicities and treatment-related adverse events; efficacy by objective response and disease control per RECIST v1.1.
Main Results:
- No dose-limiting toxicities or treatment-related deaths were observed; 11.6% of patients experienced grade 3 or 4 treatment-related adverse events.
- In NSCLC patients, objective response rate was 32.2% and disease control was 88.1%, with a median progression-free survival of 6.3 months.
- In colorectal cancer patients, objective response rate was 7.1% and disease control was 73.8%, with a median progression-free survival of 4.0 months. Responses were also noted in other cancer types.
Conclusions:
- Sotorasib demonstrated encouraging anticancer activity in heavily pretreated patients with advanced solid tumors harboring the KRAS p.G12C mutation.
- The observed toxic effects were generally manageable, with 11.6% of patients experiencing grade 3 or 4 events.
- Sotorasib represents a promising targeted therapy for cancers with the KRAS p.G12C mutation, warranting further investigation.
More Related Videos
09:29Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
05:29A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity
02:56Treatment Resistant Cancers