E. Gabriela Chiorean, MD
The invited discussant of the CodeBreaK 100 data, E. Gabriela Chiorean, MD, Professor of Medicine at the University of Washington and Fred Hutchinson Cancer Research Center, and Clinical Director of the Gastrointestinal Medical Oncology program at Seattle Cancer Care Alliance, found the efficacy of the KRAS G12C inhibitor sotorasib “remarkable” in treatment-refractory advanced pancreatic cancer.1 “A 21% response rate, a 6-month duration of response, and an overall survival of about 7 months in the third-line setting is unheard of in pancreatic cancer,” said Dr. Chiorean.
Although the efficacy of sotorasib as a single agent is less robust in pancreatic cancer than in non–small cell lung cancer, she acknowledged: “Pancreatic cancer is not lung cancer, and we are happy with these results…. The findings are a stepping stone for future combinatorial approaches…. The implication is that molecular and genomic profiling should be performed on all patients, and patients should be encouraged to enroll in clinical trials of KRAS G12C inhibitors.”
“KRAS may be responsible, in part, for causing significant resistance to chemotherapy, radiation, and immunotherapy. Targeting KRAS, therefore, has been a huge endeavor in pancreatic cancer and many other tumors,” she pointed out.
A unique feature of KRAS G12C–mutated pancreatic cancer is its ability to maintain GTPase activity, through which the active GTP-bound state converts back to the inactive GDP-bound state. KRAS G12C inhibitors allosterically control GTP affinity and effector interactions, such that mutant KRAS is trapped in an inactive GDP state.
Growing Evidence for KRAS G12C Inhibitors
The first signal of activity for sotorasib in pancreatic cancer came from a study of 12 patients, 1 of whom had a partial response and 9 who achieved stable disease.2 This was followed by a study of another KRAS G12C inhibitor, adagrasib, in which 5 of 10 (50%) evaluable patients responded, and all (100%) achieved disease control.3 With adagrasib, median duration of response was 7.0 months, and progression-free survival was 6.6 months.
“Strickler and colleagues have brought us more robust data with sotorasib in a study of 38 patients, where we saw a response rate of 21% and a very significant disease control rate of 84%. Time on treatment was also very significant, with many patients having responses and stable disease for more than 6 months,” Dr. Chiorean noted.
“The progression-free survival and overall survival are encouraging and are comparable with what we expect to see with chemotherapy in the second-line setting for pancreatic cancers,” she added.
Safety results with sotorasib and adagrasib are also encouraging, with relatively low rates of grade 3 adverse events and almost no grade 4 toxicities. Diarrhea, fatigue, nausea, and slight increases in transaminases are the main side effects with both agents; additionally, with adagrasib, some QT prolongation has been observed.
Next Steps
Asked during the discussion period to comment on what appear to be more favorable outcomes with adagrasib, Dr. Chiorean said those findings were from a much smaller study with 10 patients, “and one cannot assume the data will pan out in a larger patient population.” She also noted the drugs have different pharmacokinetics and dosing: specifically, adagrasib has a longer half-life and is dosed twice daily rather than once daily. Whether these differences affect response is unclear.
“We need to wait for data on more patients before we declare one superior to the other,” she said. “The data with sotorasib and adagrasib support the fact that KRAS G12C inhibitors are here to stay, and we can only build upon these results moving forward.”
Dr. Chiorean expects future combinations to include agents targeting other relevant pathways important for KRAS signaling. She also acknowledged that new molecular alterations, such as mutations and fusions, are already emerging as resistance develops to KRAS G12C inhibitors. “These acquired mutations and alterations are definitely food for thought for the next steps in how to prevent resistance and how to combine targeted therapeutics,” she said.
Numerous clinical trials with KRAS-targeted therapies are underway. The CodeBreaK 101 study (ClinicalTrials.gov identifier NCT04085883) of nearly 1,300 patients will evaluate sotorasib in combination with a variety of targeted agents, PD-1 inhibitors, and chemotherapy. “It is important to refer our patients to these trials…. We also need to bring these approaches into earlier disease stages, as this will enable more patients to have access. Today, few patients with pancreatic cancer reach third-line therapy.”
DISCLOSURE: Dr. Chiorean has received institutional research funding from Boehringer-Ingelheim, BioMed Valley, Clovis, Corcept, Fibrogen, Lonza, Merck, Rafael, Roche, and Stemline; and has served in scientific/advisory roles for Bayer, BioNTech, Cardiff, Ipsen, Novartis, Noxxon, Pfizer, and Stemline.
REFERENCES
1. Strickler JH, Satake H, Hollebecque A, et al: First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety. 2022 ASCO Plenary Series. Abstract 360490. Presented February 15, 2022.
2. Hong DS, Fakih MG, Strickler JH, et al: KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.
3. Bekaii-Saab TS, Spira AI, Yaeger R, et al: KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients with unresectable or metastatic pancreatic cancer and other gastrointestinal tumors harboring a KRAS G12C mutation. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 519. Presented January 21, 2022.
