Sotorasib shows anticancer activity in KRAS G12C-mutated NSCLC
Click Here to Manage Email Alerts
Sotorasib demonstrated encouraging anticancer activity among patients with heavily pretreated advanced non-small cell lung cancer who harbor KRAS G12C mutations, according to phase 1 study results presented at ESMO Virtual Congress 2020.
“Despite the discovery of the KRAS oncogene almost 4 decades ago, there is no approved therapy targeting this,” David S. Hong, MD, deputy chair of the department of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, said during a presentation of the findings, published simultaneously in The New England Journal of Medicine. “KRAS G12C is found in approximately 13% of NSCLC, 3% to 5% of colorectal cancer and 1% to 3% of other solid tumors.”
Sotorasib (AMG 510, Amgen) — a highly selective, first-in-class KRAS G12C inhibitor — showed anticancer activity and acceptable safety in previous studies of patients with KRAS G12C-mutant solid tumors.
In the current multicenter, open-label study, Hong and colleagues assigned 59 patients with advanced KRAS G12C-mutated NSCLC (median age, 68 years; range, 49-83; 59.3% women) to sotorasib dose-escalation and dose-expansion cohorts. Most patients (74.6%) had two or more prior lines of therapy.
Patients received sotorasib at once-daily doses of 180 mg (n = 3), 360 mg (n = 16), 720 mg (n = 6) or 960 mg (n = 34).
Safety served as the primary endpoint.
Objective response rate, duration of response, PFS, disease control rate and stable disease served as secondary endpoints.
Median follow-up was 11.7 months (range, 4.8-21.2). At that time, 14 patients remained on treatment; 45 had discontinued sotorasib due to disease progression (n = 35), death (n = 5), patient request (n = 4) or adverse events (n = 1).
Thirty-seven patients (62.7%) experienced grade 3 or higher adverse events, including 18.6% of patients with grade 3 or grade 4 treatment-related adverse events. However, no dose-limiting toxicities or treatment-related fatal adverse events occurred.
Among all patients, 19 achieved a confirmed partial response, 33 had stable disease and five had progressive disease (ORR = 32.2%; 95% CI, 20.6-45.6). Among the 34 patients who received the 960 mg dose, 12 achieved a confirmed partial response, 19 had stable disease and two had progressive disease (ORR = 35.3%; 95% CI, 19.8-53.5).
Researchers observed a slightly higher disease control rate in the 960 mg cohort vs. all patients (91.2% vs. 88.1%) and identified 960 mg as the recommended phase 2 dose.
Tumor reduction occurred across dose levels. Median duration of response was 10.9 months (range, 1.1-13.6) among the 19 patients who achieved confirmed partial response and 4 months (range, 1.4-10.9) among the 33 patients with stable disease.
Median PFS was 6.3 months (range, 0-14.9).
“Sotorasib now demonstrates clinical activity in NSCLC across a range of KRAS G12C mutations, PD-L1 expression levels, tumor mutational burden plasma levels and co-mutational profiles,” Hong said. “Additional [studies] evaluating sotorasib as monotherapy or in combination with other anticancer agents are currently underway.”
References:
- Hong DS, et al. Abstract 1257O. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
- Hong DS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1917239.
Perspective
Back to Top
Fred R. Hirsch, MD, PhD
Sotorasib is a very promising drug. We have been struggling for decades to target KRAS, which is an infrequent abnormality in lung cancer.
G12C in lung cancer is the most frequent subtype of KRAS mutation. Having a drug that can finally target this is a huge advantage and advancement in this field. We now have good data for treatment in the second line and later.
So where do we go with this drug in the future? In my opinion, we need to test this in the first line. I’m excited to see if it will work there.
Sotorasib is not the only drug on the market that targets KRAS. All of the drugs have very promising preliminary data. What we need to see are larger trials testing this in the first-line setting.
Perspective
Back to Top
Jorge J. Nieva, MD
Mutations in KRAS account for about one-quarter of NSCLC cases in Western countries, and the G12C mutation is the most commonly observed aberration, making up about 40% of the KRAS variants in lung cancer.
Targeting RAS in general has been unsuccessful until the recent development of mutation-specific inhibitors, such as sotorasib. The study presented by Hong and colleagues describes the outcome of 59 patients with refractory NSCLC who received sotorasib. The ORR of 32.2% is good, if not great, and the median PFS of 6.3 months represents an advance for patients with lung cancer, given the low toxicity of the agent relative to what we would expect with chemotherapy in this population.
We anticipate the response rate and PFS to improve as this drug is moved into earlier lines of therapy. However, given the favorable response rates and potential for long-term remission with checkpoint inhibitor-based therapy, these data suggest that sotorasib will not replace checkpoint inhibitors as the preferred first-line therapy for KRAS-mutated disease. Therefore, it will be important to understand the impact of regimens that combine sotorasib with other immunotherapy agents, as well as with chemotherapy. Nonetheless, the data are better than we would expect from taxane-based chemotherapy, and we can be hopeful that there will soon be a low-toxicity option for patients with G12C-mutated KRAS-driven lung cancer.
Collapse
Hong DS, et al. Abstract 1257O. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
Click Here to Manage Email Alerts