What treatment approach is recommended for a patient with relapsed colon cancer, microsatellite stable (MSS), KRAS G12C mutation, and BRAF wild type?

From the Guidelines

For a patient with relapsed colon cancer that is microsatellite stable (MSS) with a KRAS G12C mutation and BRAF wild type, the recommended treatment approach is sotorasib or adagrasib, which are specific KRAS G12C inhibitors, and should be given in combination with cetuximab or panitumumab, or considered as a single agent if toxicities from EGFR inhibitors are a concern. The treatment of relapsed colon cancer has evolved with the introduction of KRAS G12C inhibitors, such as sotorasib and adagrasib, which have shown promising results in clinical trials 1. Key points to consider in the treatment approach include:

• The combination of sotorasib or adagrasib with cetuximab or panitumumab has been shown to improve response rates and progression-free survival compared to monotherapy 1.
• The standard dosing for sotorasib is 960 mg orally once daily, while adagrasib is typically given as 600 mg orally twice daily.
• The presence of the KRAS G12C mutation provides a specific therapeutic target that can be exploited with these newer targeted agents, which specifically bind to the mutated cysteine at position 12, locking KRAS in its inactive state and preventing downstream signaling that drives cancer growth.
• Since the tumor is MSS, immunotherapy would not be a primary consideration as these tumors typically do not respond well to immune checkpoint inhibitors compared to microsatellite instability-high (MSI-H) tumors.
• The results from the CodeBreaK 100 and KRYSTAL-1 trials have demonstrated the efficacy and safety of sotorasib and adagrasib in patients with KRAS G12C-mutated metastatic colorectal cancer, with response rates ranging from 7.1% to 46% and median progression-free survival ranging from 5.6 to 6.9 months 1.

From the FDA Drug Label

The efficacy of LUMAKRAS in combination with panitumumab was evaluated in CodeBreaK 300 [NCT05198934], a multicenter, randomized, open-label, active-controlled study conducted in previously treated patients with KRAS G12C-mutated mCRC Key eligibility criteria included patients 18 years of age or older, who had received at least one prior line of therapy for mCRC, and who had received fluoropyrimidine, oxaliplatin, and irinotecan for metastatic disease unless there was a medical contraindication The trial demonstrated a statistically significant improvement in PFS for patients randomized to LUMAKRAS 960 mg in combination with panitumumab compared to the investigator's choice SOC.

For a patient with relapsed colon cancer, microsatellite stable (MSS), KRAS G12C mutation, and BRAF wild type, the treatment approach is to consider LUMAKRAS (sotorasib) 960 mg orally once daily in combination with panitumumab, as it has shown a statistically significant improvement in progression-free survival (PFS) compared to the investigator's choice of standard of care (SOC) in the CodeBreaK 300 study 2.

• Main points:
  • LUMAKRAS in combination with panitumumab has shown efficacy in patients with KRAS G12C-mutated mCRC.
  • The recommended dosing regimen is LUMAKRAS 960 mg orally once daily in combination with panitumumab 6 mg/kg IV every 2 weeks.
  • Patients should have received at least one prior line of therapy for mCRC and have received fluoropyrimidine, oxaliplatin, and irinotecan for metastatic disease unless there was a medical contraindication.
• Important considerations:
  • The patient's KRAS G12C mutation and BRAF wild type status should be confirmed through molecular testing.
  • The patient should be closely monitored for adverse reactions, including rash, dry skin, diarrhea, stomatitis, fatigue, and musculoskeletal pain.

From the Research

Interpretation of Oncology Note

The oncology note states "MSS, KRASG12C, BRAF wild type" for a patient with relapsed colon cancer. This indicates that the patient's tumor is:

• Microsatellite stable (MSS), meaning it does not have a high level of microsatellite instability
• Has a KRAS G12C mutation, which is a specific mutation in the KRAS gene
• Has a wild-type BRAF gene, meaning it does not have a mutation in the BRAF gene

Treatment Approach

Based on the evidence, the treatment approach for a patient with relapsed colon cancer, MSS, KRAS G12C mutation, and BRAF wild type is:

• Sotorasib, a KRAS G12C inhibitor, in combination with panitumumab, an EGFR inhibitor, has shown promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer 3, 4
• The combination of sotorasib and panitumumab has been shown to improve progression-free survival and overall response rate compared to standard treatment 3
• Sotorasib monotherapy has also shown modest anti-tumor activity and manageable safety in heavily pretreated chemorefractory patients with KRASG12C-mutant colorectal cancer 5, 6

Key Considerations

• The patient's tumor is MSS, which means that immunotherapy may not be an effective treatment option
• The patient has a KRAS G12C mutation, which is a targetable mutation with sotorasib
• The patient has a wild-type BRAF gene, which means that BRAF inhibitors may not be an effective treatment option
• The combination of sotorasib and panitumumab may be an effective treatment option for this patient, but it is important to consider the potential toxicities and side effects of this treatment regimen 3, 4