Sotorasib monotherapy is safe and effective in heavily pretreated advanced pancreatic cancer patients with KRASG12C mutations-individuals who have limited treatment options and poor prognosis. Despite decades of research, limited progress has been made to improve survival in pancreatic cancer. There are currently no FDA-approved treatment options for patients with pancreatic cancer that has progressed on first- and second-line chemotherapy.
There is a significant unmet need for new therapies that improve quality of life and survival in pancreatic cancer. FDA-approved second-line therapy for pancreatic ductal adenocarcinoma (PDAC) has shown about a 6-month survival and 16 percent response. After progression on first-line and second-line chemotherapy, no therapies have demonstrated survival benefit.
Sotorasib is active and well-tolerated in patients with metastatic pancreatic cancer with a KRASG12C mutation, according to research presented at the February 2022 American Society of Clinical Oncology (ASCO) Plenary Series session. Lead author John H. Strickler, MD, Associate Professor of Medicine at Duke University Medical Center, presented the data from the largest dataset to date evaluating a KRASG12C-inhibitor in patients with pre-treated KRASG12C-mutated pancreatic cancer (Abstract 360490).
About 90 percent of PDAC tumors harbor a KRAS mutation, with G12C found in 1-2 percent of these mutations, he said. Currently, no targeted therapies are approved for the treatment of patients with KRASG12C-mutated PDAC. Sotorasib is a selective and irreversible KRASG12C inhibitor that has already shown efficacy and is FDA-approved for the treatment of lung cancers with a KRASG12C mutation.
CodeBreaK100 is an international, single-arm, open-label Phase I/II study evaluating the efficacy and safety of sotorasib in patients with advanced solid tumors with a KRASG12C mutation, including pancreatic cancer. The trial included patients who had received at least one prior systemic therapy and patients who were not eligible or not able to tolerate available therapies. The primary efficacy endpoint was confirmed objective response rate, and secondary endpoints included duration of response (DOR), disease control rate, progression-free survival (PFS), and overall survival (OS).
As of November 1, 2021, a total of 38 patients, mean age 65 years, with advanced pancreatic cancer from the combined Phase I/II study received 960 mg sotorasib once daily. Stage IV disease was present in 55.3 percent of patients at diagnosis and in all patients at enrollment. Baseline ECOG scores were 0, 1, or 2 in 31.6 percent, 57.9 percent, and 10.5 percent of patients, respectively. Most patients (79%) had two or more prior lines of therapy.
After a median follow-up of 16.8 months, eight patients (21.1%) had a confirmed partial response to treatment. The percentage of patients in which the cancer improved or remained stable was 84.2 percent. Median duration of response was 5.7 months. Median treatment duration was 4.1 months. Two patients had ongoing responses at the time of data cutoff.
"Thirty out of 38 patients experienced a decrease in the sum of diameters of RECIST lesions compared with baseline," Strickler stated. Estimated median PFS was 4 months and estimated median OS was 6.9 months.
Overall, sotorasib was well-tolerated and most treatment-related adverse events (TRAEs) were Grade 2 and manageable, Strickland noted. TRAEs of any grade occurred in 16 (42.1%) patients. Grade 3 TRAEs occurred in six patients: diarrhea (two patients); fatigue (two patients); as well as abdominal pain, ALT increase, AST increase, pleural effusion, and pulmonary embolism (one patient each). No TRAEs were fatal or resulted in discontinuation.
"Sotorasib demonstrated clinically meaningful activity in heavily pretreated patients with KRASG12C-mutated pancreatic cancer," Strickland concluded. "Sotorasib once daily was well-tolerated. These data support further exploration of sotorasib in this patient population."
Kimmie Ng, MD, MPH, Associate Professor of Medicine at Harvard Medical School, and ASCO Expert in pancreatic cancer, stated: "Pancreatic cancer is one of the most difficult-to-treat cancers, and KRAS has-until recently-been thought to be 'undruggable.' The data presented here for sotorasib carry huge potential as a future targeted treatment option for patients with refractory KRASG12C pancreatic cancer and will hopefully open the doors for the development of other novel RAS inhibitors for this and other cancers."
ASCO discussant E. Gabriella Chiorean, MD, Professor of Medicine at the University of Washington School of Medicine, noted: "Targeting KRAS has been the elephant in the room for many decades for pancreatic cancer. KRAS may be responsible for causing significant chemotherapy and immunotherapy resistance in pancreatic cancer patients."
The new data "are a stepping stone for future combination approaches with sotorasib. We also need to bring these approaches earlier in the disease treatment stage. Earlier lines of therapy will enable more patients to have access to treatment because very few patients reach third-line therapy," Chiorean said. "The efficacy we see in pancreatic cancer is remarkable in the refractory setting. Response rates of 20 percent with a DOR of 6 months and encouraging OS of 7 months in third-line and beyond is unheard of in pancreatic cancer. Having access to sotorasib is extremely meaningful."
Molecular and genomic profiling should be performed for all pancreatic cancer patients, and these patients should be encouraged to enroll in clinical trials of KRASG12C inhibitors, she said.
Mark L. Fuerst is a contributing writer.