The Food and Drug Administration (FDA) approved Krazati (adagrasib) plus Erbitux (cetuximab) for patients with previously treated KRAS G12C-mutant locally advanced or metastatic colorectal cancer (CRC), according to the agency.
Locally advanced disease is when the cancer grows beyond the original site to nearby organs, whereas metastatic disease is when cancer spreads to other parts of the body.
“KRAS mutations are very common and have been historically undruggable with targeted therapies. With this approval, we have a KRAS-directed therapy available for the first time for patients with colorectal cancer,” Dr. Rona Yaeger, gastrointestinal oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center said in an interview with CURE. “Now the presence of KRAS G12C mutation no longer serves to exclude patients from a treatment option (i.e, EGFR inhibitors), but rather it is a positive biomarker for selecting a matched therapy.”
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The approval is based off findings from the phase 1/2 KRYSTAL-1 clinical trial, which were published in the journal Cancer Discovery. The trial included 94 patients with KRAS G12C-mutant locally advanced or metastatic CRC that was not eligible to be surgically removed.
“The combination of [Krazati] and [Erbitux] led to disease control in nearly all patients with colorectal cancer participating in the phase 1/2 KRYSTAL-1 trial and responses in about a third of patients,” Yaeger said.
Findings showed that the confirmed objective response rate (ORR; percentage of patients whose disease shrinks or disappears from treatment) was 34% for patients treated with Krazati plus Erbitux, with a disease control rate (percentage of patients whose disease disappears, shrinks or stops growing after treatment) of 85.1%. The median duration of response, which describes how long patients live before experiencing growth or complications from their cancer, was 5.8 months. Further, 31% of patients who responded to treatment had a duration of response that lasted six months or longer.
Additionally, the progression-free survival (PFS; time patients live before disease worsening) was 6.9 months for those who received Krazati plus Erbitux. The median overall survival (OS; time from treatment until death of any cause) was 15.9 months.
All patients on the trial experienced a side effect of any severity. The most frequent treatment-related side effects were nausea, vomiting, diarrhea, a type of skin rash called dermatitis acneiform, fatigue, dry skin, low levels of magnesium in the blood, headache and rash.
More than one fourth (29.8%) of patients experienced a treatment-related side effect that led to a dose reduction of Krazati, while side effects caused 6.4% of patients to undergo a dose reduction of Erbitux. Dose interruptions (temporarily stopping the drug) for Krazati and Erbitux occurred in 36.2% and 35.1% of patients, respectively. Eight patients (8.5%) completely stopped therapy with Erbitux due to side effects. No patients had to permanently stop Krazati treatment.
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