What is the treatment approach for KRAS (Kirsten rat sarcoma viral oncogene homolog) mutated metastatic non-small cell lung cancer (NSCLC)?

Treatment of KRAS Mutated Metastatic Lung Cancer

For patients with KRAS G12C-mutated metastatic non-small cell lung cancer (NSCLC), first-line therapy should be based on PD-L1 expression levels with immunotherapy-based regimens, while sotorasib or adagrasib are recommended as subsequent therapy options after disease progression on first-line treatment. 1

First-Line Treatment Approach

• PD-L1-guided therapy: Treatment selection for first-line therapy should be determined by PD-L1 expression levels, with immunotherapy-based regimens (either alone or in combination with chemotherapy) as the preferred approach 1
• Immunotherapy benefit: KRAS-mutated NSCLC patients are likely to derive significant benefit from immunotherapy-based regimens in the first-line setting, with evidence showing a positive association between PFS and PD-L1 expression in patients receiving immune checkpoint inhibitor monotherapy 1
• No first-line targeted therapy: Unlike other oncogenic drivers (such as EGFR or ALK), targeted therapies are not recommended as first-line treatment options for KRAS G12C-mutated metastatic NSCLC 1
• Standard approach: Follow standard first-line treatment with immune checkpoint inhibitor therapy and/or chemotherapy as recommended in the non-driver alteration guidelines 1

Subsequent Therapy Options

• KRAS G12C inhibitors: For patients who experience disease progression after first-line therapy, two FDA-approved targeted therapies are available for KRAS G12C mutations:

  • Sotorasib: FDA-approved for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy 1, 2
  • Adagrasib: FDA-approved for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy 1, 3

• Efficacy data for sotorasib:

  • Phase II study showed median OS of 12.5 months and objective response rate of 37.1% in previously treated patients 1
  • Phase III trial demonstrated improved PFS compared to docetaxel (5.6 vs 4.5 months; HR 0.66) 1
  • Complete response was reported in 4 patients in the phase II study 1

• Efficacy data for adagrasib:

  • Phase II study showed median OS of 12.6 months and objective response rate of 42.9% 1
  • Intracranial response rate of 33.3%, which may be important for patients with brain metastases 1

• Third-line and beyond: Sotorasib or adagrasib may also be used as third-line therapy or beyond if the patient has not previously received a KRAS G12C-targeted therapy 1

Important Considerations and Caveats

• KRAS mutation prevalence: Approximately 25% of patients with adenocarcinomas in North American populations have KRAS mutations, making it the most common mutation in this population 1

• Smoking association: KRAS mutations are associated with cigarette smoking, unlike many other actionable mutations such as EGFR mutations or ALK rearrangements 1

• Specific mutation targeting: Current targeted therapies (sotorasib and adagrasib) are only effective for the KRAS G12C mutation, which accounts for approximately 40% of all KRAS mutations in NSCLC 4, 5

• No switching between similar agents: The NCCN panel notes that switching between agents with a similar mechanism of action (sotorasib to adagrasib or vice versa) at the time of progression is not recommended 1

• Adverse events monitoring:

  • For sotorasib: Monitor for diarrhea, increased liver enzymes, dyspnea, and pneumonitis 1, 2
  • For adagrasib: Monitor for anemia, pneumonia, dyspnea, kidney injury, hyponatremia, fatigue, nausea, and increased liver enzymes 1, 3

• Testing requirements: Selection of patients for KRAS G12C inhibitor therapy requires FDA-approved testing to confirm the presence of the KRAS G12C mutation in tumor or plasma specimens 2, 3

Future Directions

• Resistance mechanisms: Mechanisms of resistance to KRAS G12C inhibitors are highly heterogeneous, including both on-target and off-target resistance as well as morphologic switching 4

• Combination approaches: Clinical trials are exploring combination strategies to overcome or delay resistance, including combinations with immunotherapy, chemotherapy, or other targeted agents 5, 6

• Non-G12C mutations: New approaches are being developed to target other KRAS mutations beyond G12C, such as G12D inhibitors 5