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Oncodrivers in Advanced or Metastatic NSCLC: Current and Future Standards of Care - Episode 4

Targeting KRAS: Emerging Frontline Options for Patients With NSCLC

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Panelists discuss how KRAS G12C inhibitors are moving into frontline combination therapy with immunotherapy, highlighting KRYSTAL-7 data showing impressive efficacy in PD-L1–high patients (~28 months progression-free survival) but more modest results in PD-L1–low patients, with ongoing studies exploring optimal combination strategies.

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    First-Line KRAS G12C Combination Therapy Data

    The KRYSTAL-7 study represents a pivotal advancement in first-line KRAS G12C treatment, combining pembrolizumab with adagrasib for treatment-naive patients. In patients with high PD-L1 expression (≥50%), the combination demonstrated impressive efficacy with a 59% overall response rate, 26-month duration of response, and nearly 28-month median progression-free survival. These results suggest substantial promise for combination therapy in the frontline setting for appropriately selected patients.

    However, efficacy in PD-L1–low patients (0-49%) proved more modest, with response rates of 34%, 18-month duration of response, and 6.9-month median progression-free survival. This disparity highlights the continued importance of PD-L1 biomarker testing in treatment selection. The differential outcomes between PD-L1 high and low populations emphasize the need for tailored therapeutic approaches based on immune biomarker status.

    Ongoing research explores various combination strategies for PD-L1–low patients, including sotorasib plus chemotherapy versus standard chemoimmunotherapy. The complexity of integrating chemotherapy, KRAS G12C inhibitors, and immunotherapy in frontline treatment requires careful evaluation through randomized trials. Future studies will determine optimal combination approaches for different patient subsets based on PD-L1 expression and other relevant biomarkers.

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