Olomorasib earned breakthrough therapy status as a monotherapy for adults with previously treated, KRAS G12C-mutant advanced pancreatic cancer.
The FDA has granted breakthrough therapy designation to the next-generation, KRAS G12C inhibitor, olomorasib as a monotherapy for the treatment of patients with advanced pancreatic cancer harboring a KRAS G12C mutation, as determined by an FDA-approved test, who have received at least 1 prior systemic therapy, according to a news release from.1
The designation was based on preliminary findings from the phase 1/2 LOXO-RAS-20001 trial (NCT04956640) study evaluating olomorasib in patients with KRAS G12C–mutant advanced solid tumors, including those with pancreatic cancer.1
"This breakthrough therapy designation reflects the early potential we're seeing with olomorasib in this setting and the critical need for new treatment options,” Jacob Van Naarden, executive vice president and president of Lilly Oncology said in a news release. “With now 2 breakthrough therapy designations across pancreatic and lung cancers, olomorasib continues to demonstrate broad potential clinical evidence across KRAS G12C-driven tumors and reflects our commitment to bringing meaningful new treatment options to patients living with these cancers."
No currently approved therapies specifically target KRAS G12C-mutations in pancreatic cancer, and the regulatory decision marks the second breakthrough therapy designation granted to olomorasib, following one awarded in
The open-label, multicenter study enrolled patients with KRAS G12C-mutant advanced solid tumors and an ECOG performance status of 1 or less.3 Patients also needed to have adequate organ function, resolved all adverse effects from prior treatments, evidence of KRAS G12C mutations via circulating tumor DNA or tumor tissue, and measurable disease via RECIST 1.1 criteria.
If patients had disease that was suitable for local therapy with curative intent, infections, serious cardiac conditions, a second primary malignancy, untreated active central nervous system metastases, or received prior KRAS G12C small molecule inhibitors, they were not included in the trial.
Patients in the trial received olomorasib as a monotherapy or in combination with other treatments like pembrolizumab, cetuximab (Erbitux), or chemotherapy regimens.
The trial includes a phase 1a dose-escalation portion assessing olomorasib monotherapy and a phase 1b dose-expansion and optimization portion evaluating the agent both as monotherapy and in combination regimens.
Primary end points of the trial were determining the recommended phase 2 dose of olomorasib monotherapy, safety, and antitumor activity. Whereas overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival were secondary end points.
Data from the trial evaluating the combination in KRAS G12C–mutated NSCLC (n = 46) yielded an ORR of 74% (95% CI, 59.8%-85.7%) and a disease control rate (DCR) of 91% (95% CI, 79.2%-97.6%).4 The median DOR was not evaluable (NE; 95% CI, 10.5-NE), the median PFS was also NE (95% CI, 12.0-NE). Although, PFS rates at 6 and 12 months were 80.2% (95% CI, 64.1%-89.6%) and 66.7% (95% CI, 40.9%-83.2%), respectively.
Moreover, in patients with a PD-L1 expression level of at least 50% (n = 20), an ORR of of 90% (95% CI, 68.3%-98.8%) was reached alongside a 95% DCR (95% CI, 75.1%-99.9%).
Olomorasib combination regimens are being separatedly evaluated in the phase 3 SUNRAY-01 trial (NCT06119581) which is assessing frontline olomorasib plus pembrolizumab with or without chemotherapy as first-line treatment for KRAS G12C-mutant advanced NSCLC, in addition to the phase 3 SUNRAY-02 trial (NCT06890598), which is evaluating olomorasib alongside standard-of-care immunotherapy in patients with resected or unresectable KRAS G12C-mutant NSCLC.5,6
