Joshua K. Sabari, MD

Panelists discuss how the ROS1 inhibitor landscape has evolved from crizotinib to entrectinib and now repotrectinib as the current standard of care, with repotrectinib showing impressive 35.7-month median PFS in treatment-naive patients despite increased dizziness toxicity, while next-generation agents like NVL-520 aim to spare TRK toxicity.

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.

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.

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.

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.

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.

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.

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.

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.

Panelists discuss how medical professionals envision the future of early-stage non–small cell lung cancer (NSCLC) treatment evolving through the integration of novel therapies, predictive biomarkers, and personalized strategies to address current gaps in care, emphasizing the need for continued research to optimize outcomes and tailor interventions in resectable disease.

Joshua Sabari, MD, explains the rationale behind targeting c-MET in nonsquamous EGFR wild-type advanced NSCLC.

Panelists discuss how targeted therapy with osimertinib has revolutionized treatment approaches for unresectable early-stage non–small cell lung cancer (NSCLC) patients with EGFR mutations, offering new hope for a previously underserved patient population.

Panelists discuss how PD-L1 expression levels significantly impact treatment decisions in unresectable early-stage non–small cell lung cancer (NSCLC), with consensus that biomarker status should be evaluated before finalizing treatment approaches.

Panelists discuss how advanced radiotherapy techniques, including stereotactic body radiation therapy (SBRT), combined with immunotherapy, have emerged as preferred treatment approaches for unresectable early-stage non–small cell lung cancer (NSCLC).

Panelists discuss how the diagnostic workup for unresectable stage III non–small cell lung cancer (NSCLC) requires comprehensive staging including imaging studies (PET-CT, brain MRI), tissue sampling through bronchoscopy or endobronchial ultrasound (EBUS), molecular and biomarker testing, and multidisciplinary evaluation to guide optimal treatment planning.

Panelists discuss how to treat patients who do not achieve a pathological complete response or major pathological response after neoadjuvant chemoimmunotherapy, considering options such as adjuvant therapy, close surveillance, or clinical trial enrollment based on individual risk factors and disease characteristics.

Panelists discuss how circulating tumor DNA could serve as a potential marker for minimal residual disease (MRD) in this setting, offering a noninvasive and sensitive method for monitoring treatment response and detecting relapse.

Joshua K. Sabari, MD, discusses how phase 1 efficacy data with zongertinib in HER2-mutant NSCLC lay the foundation for future research with the agent.

Panelists discuss how medical professionals are integrating targeted therapies, such as those for EGFR, ALK, and other mutations like RET and ROS1, into the treatment of resectable early-stage non–small cell lung cancer (NSCLC), with a focus on incorporating the ADAURA and ALINA regimens into clinical practice.

Panelists discuss how medical professionals identify patients who should receive neoadjuvant immune checkpoint inhibitors (ICI) before surgery based on tumor characteristics, patient health, and treatment response, and how factors such as surgical outcomes, recurrence risk, and molecular markers guide decisions on the need for additional adjuvant therapy post surgery.

Panelists discuss how the latest efficacy and safety data from AEGEAN, CheckMate 816, CheckMate 77T, and KEYNOTE-671, along with recent approvals in early-stage non–small cell lung cancer (NSCLC) treatment, are shaping optimized treatment approaches and influencing clinical practice.

Panelists discuss how a multidisciplinary team—including oncologists, thoracic surgeons, radiologists, and pathologists—collaborates to streamline the diagnostic process for patients with resectable non–small cell lung cancer (NSCLC), ensuring timely evaluation, accurate staging, and personalized treatment planning.

Panelists discuss how a multidisciplinary team (MDT) approach to resectable non–small cell lung cancer (NSCLC) involves an initial diagnostic workup with imaging (CT, PET-CT), histologic confirmation via biopsy, staging with mediastinal assessment (endobronchial ultrasound or mediastinoscopy), and timely molecular testing (eg, EGFR, ALK, PD-L1) integrated early in the process to guide perioperative treatment decisions.

Panelists discuss how a multidisciplinary approach enhances the early diagnosis of non–small cell lung cancer (NSCLC) by integrating insights from oncology, radiology, pathology, and surgery.

Panelists discuss how comprehensive biomarker testing in early-stage disease settings provides crucial molecular insights that guide surgical planning and inform critical decisions about neoadjuvant, perioperative, and adjuvant treatment strategies.

Panelists discuss how collaboration between pathologists, oncologists, and pulmonologists is essential for timely next-generation sequencing (NGS) testing in early-stage non–small cell lung cancer (NSCLC), emphasizing that molecular testing should ideally be ordered at diagnosis with prioritization of EGFR, ALK, ROS1, BRAF, MET, KRAS, RET, and NTRK biomarkers to guide treatment decisions before surgical intervention.

Panelists discuss how medical professionals frequently encounter tissue adequacy challenges in comprehensive genomic profiling for early-stage non–small cell lung cancer (NSCLC), employing strategies such as optimized biopsy techniques, efficient tissue triage protocols, and complementary liquid biopsies to ensure sufficient material for complete molecular analysis.

Panelists discuss how medical professionals currently approach molecular testing in early-stage non–small cell lung cancer (NSCLC) through comprehensive biomarker analysis, including targeted next-generation sequencing (NGS), to identify actionable mutations that guide adjuvant therapy decisions and improve patient outcomes.

Joshua K. Sabari, MD, discusses key considerations when testing for HER2 alterations in non–small cell lung cancer

Joshua K. Sabari, MD, discusses FDA approval of first-line amivantamab plus lazertinib for locally advanced or metastatic EGFR-mutated non–small cell lung cancer.