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Amgen Expanding Enrollment in Lumakras Trial After Promising Data in KRAS-Mutant Pancreatic Cancer


NEW YORK – Amgen will further investigate Lumakras (sotorasib) in KRAS G12C-mutant pancreatic cancer after the drug showed efficacy in heavily treated, advanced pancreatic cancer patients who have no standard treatment options.

At the American Society of Clinical Oncology's Genitourinary Cancers Symposium this week, John Strickler, associate professor of medicine at Duke University Medical Center, presented the first data from pancreatic cancer patients enrolled in the Phase I/II CodeBreaK 100 trial, which is a basket study that includes patients with any solid tumor harboring a KRAS G12C mutation. Based on the activity seen in pancreatic cancer patients, Amgen plans to enroll more patients with this tumor type in the CodeBreaK 100 trial, hoping to "better understand the efficacy and safety of Lumakras in tumors outside of non-small cell lung and colorectal cancers," David Reese, executive VP of research and development at Amgen, said in a statement.

The results, presented during a plenary program at the ASCO meeting, included data from 38 evaluable patients with advanced pancreatic cancer. Nearly 80 percent of patients had received two or more prior lines of therapy, representing a group of patients who don't currently have a standard treatment, according to Strickler.

"For this patient population, there is a significant unmet need for new therapies that improve quality of life and survival," he continued, estimating that in the second-line setting, the average survival with the current US Food and Drug Administration-approved chemotherapy is about six months, with a response rate of 16 percent. "After progression on first- and second-line chemotherapy, there are no therapies with a demonstrated survival benefit [in pancreatic cancer]."

KRAS mutations occur in 95 percent of pancreatic tumors and may drive resistance to chemotherapy, radiation therapy, and immunotherapy, said Gabriela Chiorean, who discussed the data at the ASCO plenary and was not involved with the CodeBreaK 100 study. She noted that the most commonly occurring KRAS mutations in pancreatic cancer are G12D, G12V, and G12R. KRAS G12C, the subtype targeted by Lumakras, show up in only 1 percent to 2 percent of pancreatic cancers.

In this study, KRAS G12C-mutated pancreatic cancer patients on Lumakras monotherapy had an objective response rate of 21 percent, with two patients achieving a complete response. The disease control rate, including patients who responded and patients who had stable disease, was 84 percent.

With a median follow-up of 16.8 months, progression-free survival was four months, and the median overall survival was 6.8 months. The median duration of response was 5.7 months. Patients remained on treatment for a median of 4.1 months; one patient was on treatment for 11 months.

Last year, Lumakras became the first KRAS inhibitor to receive regulatory approval in the US for previously treated, locally advanced or metastatic NSCLC with a KRAS G12C mutation. That approval was also based on data from the CodeBreaK 100 study, in which Lumakras-treated NSCLC patients had an objective response rate of 36 percent.

Recently released CodeBreaK 100 results in KRAS G12C-mutant colorectal cancer patients also informed the company's strategy to explore Lumakras combinations in this setting. Amgen pivoted to a combination study in colorectal cancer after the drug showed modest efficacy in patients with KRAS G12C-mutated advanced colorectal cancer, with only a 9.7 percent response rate among 62 patients. Now, the company is exploring Lumakras combinations with its EGFR inhibitor Vectibix (panitumumab) as a third-line regimen for KRAS G12C-mutant colorectal cancer and other solid tumors.

Amgen is also exploring Lumakras' efficacy in KRAS-mutant solid tumors with Merck's checkpoint inhibitor Keytruda (pembrolizumab), Revolution Medicines' SHP2 inhibitor RMC-4630, and BridgeBio Pharma's SHP2 inhibitor BBP-398.

Chiorean, a professor in the clinical research division at Fred Hutchinson Cancer Research Center, said that the CodeBreaK 100 results were significant for pancreatic cancer and could be a "steppingstone" for future Lumakras combination approaches.

"The efficacy we see in pancreatic cancer is remarkable," Chiorean said. "In the refractory setting, a response rate of 21 percent with the duration of response of nearly six months and encouraging survival rates of seven months in the third line is unheard of in pancreatic cancer."

Strickler said that combination approaches with KRAS inhibitors and anti-PD-1 drugs have shown in other cancers to address the immune suppressive tumor microenvironment. While pancreatic cancer is known to have a highly immune suppressed tumor microenvironment, he noted that research is still ongoing to determine if the effects of KRAS inhibition on the microenvironment are similar to other cancer types.

Combination approaches could also help address emerging resistance to KRAS inhibition, Chiorean said. Strickler highlighted that CodeBreaK 100 trial investigators are exploring how KRAS resistance mechanisms in pancreatic cancer might differ from other tumor types such as in the lung. He noted that data will be presented at a future meeting.

"We are learning so much that the activity of KRAS inhibitors really differ depending on the disease subtype and we cannot assume that all that's true for lung cancer is going to be true for pancreas cancer," Chiorean said. "Nevertheless, we do see some similar resistance mechanisms between colon and lung cancer, so some mechanisms will be probably very similar in other tumor types as well."

The CodeBreaK 100 results are the largest data set of KRAS inhibitor treatment in KRAS G12C-mutant pancreatic cancer so far. However, previous studies of another KRAS G12C inhibitor in development, Mirati Therapeutics' adagrasib, also showed promising efficacy in this population.

Results presented in January showed that half of the patients in a smaller pancreatic cancer cohort from Mirati's Phase I/II KRYSTAL-1 trial responded to treatment with adagrasib. Among 10 patients in that trial with previously treated, advanced KRAS G12C-mutated pancreatic cancer, the median progression-free survival was 6.6 months.

Chiorean cautioned that results from more patients are needed before comparing the efficacy of Lumakras and adagrasib in pancreatic cancer.

"The good news for both molecules is that clearly there is substantial activity for a patient population that desperately needs breakthroughs," Strickler said. "I'm excited, both as an investigator and as a clinician, that we are hopefully going to have some real options for patients who desperately need them."