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

Joshua Sabari, MD; Christine Bestvina, MD; Hatim Husain, MD; and Julia Rotow, MD, discuss how targeted therapies for KRAS G12C and ALK::ROS1 fusion-positive advanced non–small cell lung cancer are evolving from second-line treatments to promising frontline combinations with immunotherapy, emphasizing the critical importance of comprehensive biomarker testing and the management of unique toxicity profiles as these next-generation inhibitors demonstrate improved efficacy and central nervous system penetration.

EP. 1: KRAS G12C-Mutated NSCLC: Current Treatment Paradigms

June 18th 2025

Panelists discuss how critical broad-panel next-generation sequencing is for all patients with non–small cell lung cancer to enable biomarker-guided treatment, with focus on KRAS G12C mutations found in 12% to 14% of patients and consideration of PD-L1 expression levels and comutations when selecting frontline therapy.

EP. 2: Evaluating Efficacy Outcomes of TKI Therapies in KRAS G12C-Mutated NSCLC

June 18th 2025

Panelists discuss how 2 FDA-approved KRAS G12C inhibitors (adagrasib and sotorasib) perform in second-line therapy after immunotherapy and chemotherapy, with both showing improved progression-free survival versus docetaxel despite modest gains, leading to their adoption as standard of care due to better tolerability profiles.

EP. 3: Managing KRAS Inhibitor Safety and Hepatotoxicity

June 25th 2025

Panelists discuss how KRAS G12C inhibitors differentiate in their toxicity profiles, with sotorasib carrying higher hepatotoxicity risk especially post–checkpoint inhibitor therapy, while adagrasib shows more gastrointestinal toxicities, and the importance of washout periods to mitigate liver toxicity.

EP. 4: Targeting KRAS: Emerging Frontline Options for Patients With NSCLC

June 25th 2025

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.

EP. 5: CNS Surveillance and Management of Brain Metastases in Patients With KRAS G12C NSCLC

July 2nd 2025

CNS Metastases Management in KRAS G12C Patients Central nervous system (CNS) metastases affect approximately 40% of patients with KRAS G12C positive non–small cell lung cancer, presenting significant management challenges. Unlike EGFR- and ALK-positive patients who benefit from highly CNS-penetrant targeted agents, KRAS G12C patients have limited systemic options with proven intracranial activity. Stereotactic radiosurgery often becomes the preferred approach for CNS lesions, particularly when systemic options are exhausted after platinum-based chemotherapy and immunotherapy. For asymptomatic, small CNS metastases (≤5 mm without edema), systemic therapy initiation with close monitoring represents a reasonable approach. Immunotherapy and chemoimmunotherapy combinations demonstrate modest CNS response rates, while KRAS G12C inhibitors show approximately 40% to 43% intracranial response rates in untreated brain metastases. However, these response rates remain below 50%, necessitating careful patient monitoring and readiness for local ablative therapy. Surveillance strategies for CNS metastases vary among practitioners, with baseline MRI universally recommended but routine follow-up imaging practices differing. Some oncologists perform periodic surveillance scans for high-risk patients, while others monitor symptomatically. The lack of robust CNS activity from systemic agents emphasizes the importance of early detection and prompt local therapy intervention when CNS progression occurs.

EP. 6: New Frontiers in KRAS Inhibition for Patients With NSCLC

July 2nd 2025

Panelists discuss how next-generation KRAS G12C inhibitors like divarasib, lifirafenib, and RMC-6291 (a RAS-ON inhibitor) show promising enhanced potency with response rates in the 50% range and extended PFS, offering hope for more effective treatment options and potential sequencing strategies.

EP. 7: Decoding Efficacy and Safety Outcomes Among Second- and Third-Generation ALK Inhibitors

July 9th 2025

Panelists discuss how lorlatinib has become the new standard of care for ALK-positive patients based on CROWN trial data showing unprecedented 5-year progression-free survival (60% at 5 years, median not reached) and superior central nervous system control compared with earlier agents like alectinib, despite unique metabolic and neurocognitive toxicities requiring careful management.

EP. 8: Emerging Strategies for Overcoming On/Off-Target Resistance in ALK-Positive NSCLC

July 9th 2025

Panelists discuss how resistance mechanisms in ALK-positive disease are driving development of next-generation inhibitors like NVL-655 that spare TRK to reduce neurocognitive toxicity while targeting compound resistance mutations, though the success of lorlatinib makes frontline trials challenging due to extremely long progression-free survival requiring decade-long studies.

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