Hatim Husain, MD

This segment examines how comprehensive genomic profiling is now being used earlier in the lung cancer disease course.

This segment focuses on how clinicians decide between tissue biopsy and blood based testing when planning initial genomic evaluation. Dr Singhal describes how patient factors such as tumor location, disease burden, and the feasibility of obtaining a tissue sample guide this decision.

This segment focuses on how clinicians decide between tissue biopsy and blood based testing when planning initial genomic evaluation.

This opening segment introduces the goals of the OncLive Insights program and frames genomic testing as a core element of the modern lung cancer diagnostic pathway.

Panelists discuss how ASCO 2025 highlighted exciting advances in targeted therapy including neoadjuvant approaches, dynamic biomarkers like circulating tumor DNA, mixed results with HER3-directed antibody-drug conjugates (ADCs) in the EGFR space, but promising data with trastuzumab-based ADCs, emphasizing the critical importance of comprehensive biomarker testing to ensure no patients miss potentially life-changing targeted therapies.

Panelists discuss how real-world data becomes crucial for guiding treatment decisions in rare subsets like ROS1-positive patients where head-to-head trials are challenging, and how next-generation inhibitors like NVL-520 and taletrectinib aim to improve efficacy while reducing TRK-related toxicities through more selective targeting.

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.

This episode focuses on exploring additional therapeutic options for managing previously treated advanced or metastatic EGFR-mutated NSCLC, highlighting strategies to optimize patient survival across various stages of disease progression.

This episode discusses the desired outcomes from the HERTHENA-Lung02 trial that would justify using HER3-DXd before platinum and pemetrexed chemotherapy while also exploring the potential benefits of amivantamab, including its PFS advantage and the observed trend toward improved OS in this treatment setting.

This episode summarizes the HERTHENA-Lung02 trial and examines the average duration of response to platinum-based chemotherapy in patients with advanced EGFR-mutated NSCLC who have previously undergone multiple lines of EGFR TKI therapy, discusses strategies for community oncologists to tackle diverse resistance mechanisms to third-generation TKIs, and evaluates the importance of tolerability in sparing platinum-based chemotherapy compared with using ADCs in subsequent treatment lines.

This episode explores management strategies for hematologic toxicities arising within the first 3 weeks of treatment with HER3-DXd, discusses the potential integration of HER3-DXd into clinical practice upon approval, and identifies unmet needs and suitable patient populations for future clinical trials evaluating HER3-DXd based on insights from the HERTHENA-Lung01 trial results.

This episode reviews the response rates reported in the HERTHENA-Lung01 trial among patients with advanced NSCLC exhibiting various resistance mechanisms, evaluates the clinical significance of responses to HER3-DXd based on HER3 expression scores, discusses the relevance of the reported overall DOR, median PFS, and OS, and examines the CNS ORR among patients with baseline brain metastases in relation to the ORRs.

This episode addresses strategies for mitigating and managing adverse events associated with Dato-DXd in patients with advanced NSCLC, explores how the drug’s structure may help prevent acquired resistance mechanisms that are common with TKIs, and discusses the broader implications of integrating Dato-DXd and other ADCs into the treatment landscape for this patient population.

This episode discusses the impressive ORR of more than 40% from the phase 2 TROPION-Lung05 trial of Dato-DXd in patients with EGFR-mutated advanced NSCLC, its clinical impact on those treated with 3 or more prior therapies, and explores the potential of Dato-DXd as a practice-changing therapy, given the median DOR of 7 months and DCR of 79%.

This episode examines the management of ILD/pneumonitis associated with TROP2-directed ADCs in patients with advanced NSCLC and strategies for mitigating these risks, addresses hematologic toxicities related to docetaxel, and discusses the improved tolerability and lower incidence of severe treatment-emergent adverse events with Dato-DXd compared with docetaxel.

This episode covers current sequencing strategies for NSCLC after targeted therapies and platinum chemotherapy, discusses the COMPEL trial with osimertinib, reviews OS and PFS end points from the TROPION-Lung01 study, examines hypotheses behind differential PFS responses in nonsquamous vs squamous NSCLC, and addresses what constitutes a clinically meaningful, durable response in heavily pretreated patients with advanced NSCLC and actionable genomic alterations.

This episode discusses the urgent need for more effective and tolerable therapies for patients with EGFR-mutated NSCLC who have exhausted targeted treatments, comparing the clinical benefits of a targeted ADC approach vs chemotherapy, with a focus on the TROPION-Lung01 study of Dato-DXd vs docetaxel for heavily pretreated advanced/metastatic NSCLC with actionable genomic alterations.

This episode highlights the significance of third-generation EGFR TKIs in delaying subsequent therapies for resectable, stage IB to IIIA EGFR-mutated NSCLC, explores the risks of postresection treatments for disease progression, and discusses treatment considerations for patients across different stages, focusing on the ADAURA trial outcomes for stage IB to IIIA NSCLC.

Although the NCCN guidelines recommend osimertinib as an adjuvant therapy option, what is your position on its use for completely resected stage IB to IIIA NSCLC with less common EGFR activating mutations, such as exon 20 insertion?

This episode reviews the key takeaways from the ADAURA trial, discusses strategies for protecting the CNS in EGFR-mutated NSCLC, and examines the impact ADAURA had on recurrence rates in patients with completely resected EGFR-mutated NSCLC who were previously treated with adjuvant chemotherapy.

This episode delves into expert perspectives on the safety and tolerability of combining osimertinib with chemotherapy in untreated, advanced EGFR-mutated NSCLC, resistance to third-generation EGFR TKIs, the superiority of concurrent versus sequential therapy from the FLAURA2 study, the role of ctDNA in managing additional EGFR mutations, and decision-making in utilizing FLAURA2 for treatment selection.

This episode explores expert insights on the clinical use of osimertinib in the frontline setting for EGFR-mutated NSCLC, the impact of combining osimertinib with platinum-based chemotherapy on progression-free survival (PFS), and the significance of extending PFS by nearly 9 months in patients with advanced NSCLC who are not candidates for curative treatment.