Marwan G. Fakih, M.D.
Phase 1 Trial of Sotorasib (AMG 510) in Advanced, Heavily Pretreated Solid Tumors
Kirsten rat sarcoma viral oncogene homolog (KRAS), the most frequently mutated oncogene in human cancers, confers resistance to targeted cancer therapies. The KRASG12C mutation occurs in approximately 13% of nonsmall cell lung cancer (NSCLC) and 1% to 3% of colorectal cancer and other solid cancers. Despite three decades of scientific effort, no selective KRAS inhibitor has been approved.
“Since its discovery in 1982, the mutated KRAS protein has been deemed ‘undruggable’ due to its high affinity for GTP and lack of accessible binding pockets, as well as toxicities associated with other KRAS-targeting approaches,” said Marwan G. Fakih, M.D., director of the Gastrointestinal Cancer Program at City of Hope and co-lead author in a recent New England Journal of Medicine publication that reported results of the first in-human study of sotorasib, a small-molecule KRASG12C inhibitor.
Sotorasib plugs a specific pocket (P2), blocking the ability of this mutated KRAS protein from driving tumor growth and spread. This phase 1 study evaluated the safety of various doses of sotorasib (180 mg, 360 mg, 720 mg and 960 mg) orally once a day. Patients had refractory metastatic NSCLC (n=59), colorectal cancer (n=42) or other tumor types (n=28).
Inclusion criteria included:
- Age ≥18 years
- Histologically confirmed, locally advanced or metastatic malignancy with KRASG12C mutation
- Eastern Cooperative Oncology Group (ECOG) performance status of 0–2
- NSCLC patients: previous platinum-based combination therapy or targeted therapies
- Colorectal cancer: ≥2 prior lines of systemic therapy in the metastatic
setting (nivolumab or pembrolizumab if clinically applicable in microsatellite instabilityâhigh)
- Other solid tumors: ≥1 prior line of systemic therapy
- Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
Promising Anticancer Activity in Heavily Pretreated Patients With KRASG12C Mutant Solid Tumors
Sotorasib was administered to patients who had a median of three prior lines of anti-cancer therapy (61% had received ≥3 prior lines) until progressive disease, intolerance, withdrawal of consent or the end of the study. Their average age was 62, and the median follow-up was 12 months. The KRASG12C inhibitor produced lasting clinical benefits with mostly minor side effects that affected the gastrointestinal tract and included diarrhea (30%), fatigue (23%) and nausea (21%).
In the NSCLC patient subset, confirmed response was documented in 32%; 88% achieved disease control for a few months or more, leading to a median progression-free survival of 6.3 months. Most patients with colorectal cancer achieved disease control, with 5.4 months median duration of stable disease and 4.0 months median progression-free survival.
Treatment outcome in similar populations with NSCLC or colorectal cancer is generally poor. With present therapies, the response rate for patients with NSCLC in the 2nd or 3rd line setting is approximately 9-18%, with a median progression-free survival of 2.5-4.0 months.
Treatment outcome in similar populations with NSCLC or colorectal cancer is generally poor. With present therapies, the response rate for patients with NSCLC in the 2nd or 3rd line setting is approximately 9-18%, with a median progression-free survival of 2.5-4.0 months. For patients with previously treated colorectal cancer, the response rate with standard therapies approximates 1-1.6%, and median progression-free survival is 1.9-2.1 months.
“KRAS mutations have been linked with worse treatment outcomes in a variety of cancers, including lung and colorectal cancers,” Fakih added. “We have finally shown that RAS targeting and inhibition is feasible. This proof-of-concept study has, in some cases, demonstrated a median progression-free survival that is two times longer than what we encounter in patients today.”
Added to the superior survival outcomes provided by City of Hope at all stages of NSCLC and colorectal cancers in comparison to those of the Greater Los Angeles region,* results from this first-in-human multisite phase 1 clinical trial of the KRASG12C inhibitor sotorasib (AMG 510) show promise of new hope for patients with these and other refractory solid tumor cancers.
Dr. Fakih is involved in two sotorasib clinical trials with a total of six treatment arms to evaluate use of sotorasib as a monotherapy or combination treatment in patients with non-small cell lung cancer (NCT04303780) and other solid tumors, including colorectal cancer (NCT04185883).
*Based on the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) Program data on Los Angeles Regional Cancer Facilities and City of Hope’s cancer registry (CNeXT).