Sotorasib active, safe for certain patients with advanced pancreatic cancer
Sotorasib demonstrated clinically meaningful anticancer activity in patients with heavily pretreated KRAS G12C-mutated advanced pancreatic cancer, according to study results presented during the ASCO Plenary Series.
The KRAS inhibitor also proved tolerable among patients in the international, single-arm, phase 1/2 CodeBreaK100 study.
“These data are promising for [patients with pancreatic cancer] with high unmet medical need who have limited treatment options,” John H. Strickler, MD, associate professor and medical oncologist at Duke University Medical Center, said in a press release.
Background
Strickler and colleagues pursued the research because no FDA-approved treatment options exist for patients with pancreatic cancer who experience progression on first- and second-line chemotherapy. Additionally, KRAS mutations occur in 90% of pancreatic ductal adenocarcinomas, with p.G12C accounting for 1% to 2% of these mutations.
Sotorasib (Lumakras, Amgen) is a small molecule that specifically and irreversibly inhibits KRAS, blocking certain enzymes that cancer cells need to grow and may kill cancer cells. It has demonstrated efficacy for treatment of KRAS G12C-mutated lung cancer, for which it is FDA approved.
Thus, researchers sought to test efficacy and safety among patients with pretreated KRAS G12C-mutated pancreatic cancer.
Methodology
The analysis included 38 patients (76.3% men; mean age, 65 years; range, 45-81) who had received one or more prior systemic therapies, unless intolerant to or ineligible for available therapies. Researchers administered sotorasib, dosed at 960 mg once daily, for a median duration of 4.1 months, with median follow-up of 16.8 months.
Confirmed objective response rate, assessed by blinded independent central review, served as the primary efficacy endpoint. Researchers also evaluated duration of response, disease control rate, PFS and OS as secondary endpoints.
Key findings
Results showed eight patients had a confirmed partial response to treatment (ORR = 21.1%; 95% CI, 9.55-37.32). Researchers reported a disease control rate of 84.2%, median PFS of 3.98 months and median OS of 6.87 months.
No treatment-related adverse events resulted in death or in sotorasib discontinuation. Sixteen patients (42.1%) experienced treatment-related adverse events and six experienced grade 3 or higher adverse events, including diarrhea, fatigue, abdominal pain, alanine aminotransferase increase, aspartate aminotransferase increase, pleural effusion and pulmonary embolism.
Implications
Strickler called the findings “clinically meaningful” in what he referred to as the largest data set evaluating efficacy and safety of a KRAS inhibitor in patients with pretreated KRAS G12C-mutated pancreatic cancer.
“These data support further exploration of sotorasib in this patient population with high unmet medical need,” Strickler said.
References:
Strickler JH, et al. Abstract 360490. Presented at: ASCO Plenary Series; Feb. 15, 2022.
Sotorasib shows promise for patients with certain advanced pancreatic cancer. https://www.asco.org/about-asco/press-center/news-releases/sotorasib-shows-promise-patients-certain-advanced-pancreatic. Published Feb. 14, 2022. Accessed Feb. 15, 2022.
Perspective
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KRAS may be responsible for causing significant chemoresistance, radiation resistance and immunotherapy resistance for patients with pancreatic cancer. Therefore, targeting KRAS had been a huge endeavor for many years in pancreatic cancer and many other tumors.
These clinical trials are extremely encouraging and it’s very important to be aware that they exist. Our patients should be referred moving forward to participate in them as much as possible.
The lessons learned and take-home messages are that sotorasib is safe and effective for KRAS G12C-mutated pancreatic cancers. The data presented by Strickler and colleagues are a stepping stone for future combination approaches with sotorasib.
We also need to bring these approaches into the early disease treatment stage. Earlier lines of therapy will enable more patients to have access to treatment, because very few patients reach third-line therapy.
The efficacy we see in pancreatic cancer is remarkable in the refractory setting. Response rates of 20% with a duration of response of 6 months and encouraging survival rates of 7 months in the third line and beyond are unheard of in pancreatic cancer.
How does this compare with sotorasib for lung cancer? Clearly, we see better efficacy with monotherapy in lung cancer. But pancreatic cancer is not lung cancer. And we are happy with these results. No standard treatment options are available to date for third-line treatment of pancreatic cancer, so having access to sotorasib is extremely meaningful.
Molecular and genomic profiling should be performed for all of our patients, and they should be encouraged to enroll in clinical trials with KRAS G12C inhibitors.
University of Washington School of Medicine
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Strickler JH, et al. Abstract 360490. Presented at ASCO Plenary Series, Feb. 15, 2022.