Sotorasib Reveals Anti-Tumor Efficacy in KRAS G12C-Positive Advanced Pancreatic Cancer

David S. Hong, MD

KRAS inhibition with sotorasib (Lumakras) demonstrated anti-tumor activity in patients with KRAS p.G12C-mutated advanced pancreatic cancer, while displaying an acceptable safety profile, according to results published from the phase 1/2 CodeBreaK 100 clinical trial (NCT03600883).^1,2

Results for the primary end point showed that sotorasib achieved an objective response rate (ORR) of 21% (95% CI, 10%-37%). All responses were partial responses and the median time-to-response was 1.5 months. Sixty-three percent of patients had stable disease and 13% had progressive disease for a disease control rate of 84% (95% CI, 69%-94%). The median duration of response, a key secondary end point, was 5.7 months (95% CI, 1.6-not evaluable).²

“These are encouraging early data because they point toward establishing that KRAS inhibitors can work in pancreatic cancers, which have been difficult to crack from a targeted therapy standpoint,” said principal investigator David S. Hong, MD, professor of Investigational Cancer Therapeutics at University of Texas MD Anderson Cancer Center, in a press release.¹ “We look forward to data from larger trials as we continue working to bring much-needed new therapies to these patients.”

CodeBreaK 100 is evaluating patients with KRAS p.G12C-mutated advanced solid tumors on treatment with sotorasib monotherapy or sotorasib plus an anti-PD-L1 agent. For the advanced pancreatic cancer cohort, 38 patients were enrolled. The patients all had metastatic disease and received a median of 2 prior lines of therapy. The cohort had a median age of 65.5 years. Most patients in the cohort (76.3%) were male, and 55.3% of patients had stage IV disease at initial diagnosis.^1,2

In addition to good responses, sotorasib showed change in tumor burden, as well as long progression-free survival (PFS) and overall survival (OS), which are secondary end points in CodeBreaK 100.

Tumor shrinkage in target lesions from baseline was observed in 79% of the patients treated with sotorasib. The median PFS observed with the agent was 4.0 months (95% CI, 2.8-5.6 months). At 6 months, the PFS rate was 31.6% (95% CI, 16.7%-47.7%), and at 9 months the PFS rate was 9.9% (95% CI, 2.0%-25.6%). The median OS was 6.9 months (95% CI, 5.0-9.1 months) and it was estimated that the 12-month OS rate would be 19.6% (95% CI, 7.2%-36.3%).

The safety analysis results from the advanced pancreatic cancer cohort were similar with what was observed in other CodeBreaK 100 cohorts. All patients with advanced pancreatic cancer experienced any-grade adverse events (AEs). The most common AEs seen in the cohort were abdominal pain (37%), diarrhea (24%), nausea (24%), vomiting (21%), and pyrexia (21%). Grade 3 or higher AEs occurred in 63% of patients, and grade 4 or higher AEs occurred in 37%.

Any-grade treatment-related AEs (TRAEs) were observed in 42% of the cohort, and grade 3 or higher TRAEs occurred in 16% of patients. No grade 4 or higher TRAEs occurred, but serious TRAEs were seen in 8% of patients.

AEs led to dose reduction or interruption in 42% of patients, and 8% discontinued treatment due to AEs. Fatal AEs were seen in 58% of the cohort. TRAEs led to dose reductions and interruptions in 13% of patients.

Overall, CodeBreaK 100 investigators determined that the efficacy of sotorasib in the advanced pancreatic cancer population was encouraging but did not have as much promise as it does in KRAS p.G12C–mutated non–small-cell lung cancer (ORR: 37.1%) Moreover, sotorasib achieved a higher ORR in the advanced pancreatic cancer population compared with the KRAS p.G12C–mutated colorectal cancer population (ORR: 9.7%).

“It’s gratifying to see results like this, since targeting mutant KRAS seemed virtually impossible just a few years ago. Still, we must continue our research efforts to make progress against other common KRAS mutations found in pancreatic and other cancer types,” Hong said, in the press release. “Trials have recently begun on drugs targeting KRAS G12D, a much more common mutation in pancreatic cancer, as well as some pan-RAS therapies, which target multiple mutations.”

_REFERENCES:

_{1. Sotorasib shows clinically meaningful activity in KRAS G12C-mutated advanced pancreatic cancer. News release. MD Anderson Cancer Center. December 21, 2022. Accessed January 4, 2023. https://bit.ly/3vz16Ip}

_{2. Stirckler JH, Satake H, George TJ, et al. Sotorasib in KRAS p.G12C–mutated advanced pancreatic cancer. N Engl J Med. Published December 21, 2022. doi:10.1056/NEJMoa2208470.}