Literature

Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published December 6, 2023

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Did treatment with sotorasib in combination with panitumumab increase progression-free survival as compared with standard-care therapy in the trial by Fakih et al.?

Fakih et al. conducted a phase 3 trial that evaluated the efficacy and safety of two different doses of sotorasib in combination with panitumumab as compared with standard-care therapy (trifluridine–tipiracil or regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation who had never received a KRAS G12C inhibitor. Read the NEJM Original Article here.

Clinical Pearls

Q: How common is metastatic colorectal cancer with KRAS G12C mutation?

A: The Kirsten rat sarcoma viral oncogene homologue (KRAS) glycine-to-cysteine mutation at codon 12 (KRAS G12C) is a driver mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer and may be associated with poor prognosis. In patients with disease that is refractory to initial therapies (fluoropyrimidine-based chemotherapy with or without bevacizumab), the standard treatments (trifluridine–tipiracil or regorafenib) have shown limited efficacy.

Q: What was the rationale for combining sotorasib and an epidermal growth factor receptor (EGFR) inhibitor in this trial?

A: Dual KRAS G12C and EGFR blockade was designed to overcome treatment resistance to KRAS G12C inhibition in patients with colorectal cancer with KRAS G12C mutation. Sotorasib selectively and irreversibly inhibits the KRAS G12C protein to block downstream proliferation and survival signaling. Although single-agent KRAS G12C inhibitors (sotorasib and adagrasib) have shown improved outcomes in patients with non–small-cell lung cancer with KRAS G12C mutation, KRAS G12C inhibition alone has shown limited activity in patients with colorectal cancer. Treatment-induced resistance selective to KRAS G12C inhibition develops primarily through upstream reactivation of the EGFR pathway and is supported by the synergistic activity of concomitant KRAS G12C and EGFR inhibition in preclinical models.

Morning Report Questions

Q: Did treatment with sotorasib in combination with panitumumab increase progression-free survival as compared with standard-care therapy in the trial by Fakih et al.?

A: Treatment with sotorasib at a dose of either 960 mg or 240 mg, in combination with panitumumab, resulted in significantly longer progression-free survival than standard-care treatment. The median progression-free survival as assessed by blinded independent central review was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib–panitumumab and 240-mg sotorasib–panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib–panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P=0.006). The hazard ratio in the 240-mg sotorasib–panitumumab group as compared with the standard-care group was 0.58 (95% CI, 0.36 to 0.93; P= 0.03). At the time of data cutoff, the data on overall survival were not mature.

Q: What were the common treatment-related adverse events of grade 3 or higher in the trial?

A: Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of the patients in the 960-mg sotorasib–panitumumab, 240-mg sotorasib–panitumumab, and standard-care groups, respectively. The most common (incidence of ≥5%) treatment-related adverse events of grade 3 or higher were dermatitis acneiform (11.3%), hypomagnesemia (5.7%), and rash (5.7%) in the 960-mg sotorasib–panitumumab group; hypomagnesemia (7.5%) and diarrhea (5.7%) in the 240-mg sotorasib–panitumumab group; and neutropenia (23.5%), anemia (5.9%), and hypertension (5.9%) in the standard-care group.

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