What is the recommended treatment approach for a patient with stage 3A adenocarcinoma (lung cancer) with a KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C mutation and high PD-L1 (Programmed Death-Ligand 1) expression?

From the Guidelines

For a patient with stage 3A adenocarcinoma lung with KRAS G12C mutation and high PD-L1 expression, the recommended treatment approach is concurrent chemoradiation therapy followed by consolidation immunotherapy with durvalumab, as high PD-L1 expression predicts a better response to immunotherapy 1. The initial treatment consists of platinum-based chemotherapy (typically cisplatin or carboplatin combined with etoposide, vinorelbine, or pemetrexed) administered concurrently with definitive radiation therapy (60-66 Gy in 30-33 fractions) over 6-7 weeks. Following completion of chemoradiation and if there is no disease progression, consolidation immunotherapy with durvalumab (10 mg/kg every 2 weeks or 1500 mg every 4 weeks) should be administered for 12 months. Key considerations in this approach include:

• The use of PD-L1 level to determine the appropriate first-line systemic therapy regimen, as recommended by the NCCN NSCLC Panel 1
• The potential for targeted therapy with sotorasib or adagrasib as subsequent therapy options for patients who experience disease progression after treatment with first-line systemic therapy 1
• The importance of not switching between agents with a similar mechanism of action at the time of progression, as noted by the NCCN panel 1 This multimodal approach combines local control through chemoradiation with systemic immune enhancement via durvalumab, addressing both the local disease and potential micrometastases. The treatment leverages the immunogenic effects of radiation while targeting the specific molecular characteristics of the tumor, particularly the high PD-L1 expression which predicts better response to immunotherapy. Additionally, for patients with KRAS G12C mutations who later develop metastatic disease, targeted therapy with sotorasib (960 mg daily) or adagrasib (600 mg twice daily) would be appropriate options, as indicated by recent clinical data 1.

From the FDA Drug Label

KEYTRUDA may be used alone as your first treatment when your lung cancer: has not spread outside your chest (Stage III) and you cannot have surgery or chemotherapy with radiation or your NSCLC has spread to other areas of your body (advanced NSCLC), and your tumor tests positive for “PD-L1”, and does not have an abnormal “EGFR” or “ALK” gene

The recommended treatment approach for a patient with stage 3A adenocarcinoma (lung cancer) with a KRAS G12C mutation and high PD-L1 expression is pembrolizumab (KEYTRUDA) alone as the first treatment, since the tumor has not spread outside the chest and tests positive for PD-L1 2.

• Main considerations:
  • The patient's tumor must test positive for PD-L1.
  • The patient's tumor must not have an abnormal EGFR or ALK gene.
  • The patient's cancer is stage 3A, which means it has not spread outside the chest.
• Key treatment:
  • Pembrolizumab (KEYTRUDA) alone as the first treatment.

From the Research

Treatment Approach for Stage 3A Adenocarcinoma with KRAS G12C Mutation and High PD-L1 Expression

• The treatment approach for a patient with stage 3A adenocarcinoma (lung cancer) with a KRAS G12C mutation and high PD-L1 expression involves considering targeted therapies and immunotherapies 3, 4, 5, 6, 7.
• Targeted therapies, such as sotorasib, have shown significant clinical benefit in patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) 4, 6.
• Sotorasib, a specific inhibitor of KRAS G12C mutant protein, has been approved for the treatment of patients with KRAS G12C-mutated NSCLC who have received at least one prior systemic therapy 4.
• Immunotherapies, such as immune checkpoint inhibitors (ICIs), may also be effective in patients with high PD-L1 expression, as seen in KRAS G12C-mutant NSCLC 5, 7.
• The combination of chemotherapy and ICIs with anti-angiogenesis inhibitors or multi-target inhibitors may not significantly improve progression-free survival (PFS) in patients with KRAS G12C-mutant NSCLC 7.

Clinical Characteristics and Treatment Outcomes

• Patients with KRAS G12C-mutant NSCLC tend to have a higher tumor mutation burden and higher PD-L1 expression compared to those with KRAS non-G12C mutations 5.
• The comutation patterns of STK11 and KEAP1 are similar between KRAS G12C and KRAS non-G12C mutations 5.
• The median overall survival from diagnosis is similar for KRAS G12C and KRAS non-G12C mutations 5.
• ICIs treatment can significantly prolong PFS in NSCLC patients with KRAS G12C mutation, especially those with TP53 mutation 7.

Ongoing Research and Development

• Various studies are ongoing to evaluate the efficacy of KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy 6.
• The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC, and further research is needed to improve clinical outcomes 6.