Christine Bestvina, MD

In this segment, faculty discuss long-term safety considerations associated with lorlatinib treatment in ALK-positive NSCLC. The panel reviews adverse events reported during extended follow-up, including hyperlipidemia, weight gain, edema, and neurocognitive effects, and discusses approaches to monitoring and management in clinical practice. Faculty describe strategies for dose modifications, supportive care interventions, and patient education throughout treatment. The discussion also addresses the role of multidisciplinary care and caregiver involvement when evaluating cognitive and behavioral changes that may occur during therapy. In addition, panelists review factors that may influence decisions regarding treatment continuation and long-term management. The segment provides an overview of safety considerations associated with prolonged ALK inhibitor therapy.

Faculty review findings from the 7-year update of the CROWN trial and discuss how long-term efficacy data are informing the management of ALK-positive NSCLC. The panel examines outcomes related to progression-free survival, durability of response, and intracranial disease control, and considers how these findings contribute to current treatment discussions. The conversation explores patterns observed over extended follow-up and addresses how long-term data may help clinicians communicate treatment expectations with patients. Faculty also discuss differences in patient outcomes over time and consider factors that may influence long-term disease control. This segment focuses on the interpretation and application of mature clinical trial data within contemporary practice.

This segment focuses on treatment selection and disease monitoring for patients with ALK-positive NSCLC. Faculty discuss factors that influence frontline treatment decisions, including central nervous system involvement, disease burden, and patient-specific considerations. The panel reviews approaches to counseling patients prior to treatment initiation and examines how efficacy and tolerability factor into therapeutic decision-making. Discussion also addresses strategies for monitoring treatment response, evaluating disease progression, and incorporating tissue and liquid biopsy at progression. In addition, faculty review resistance mechanisms that may emerge during treatment and discuss how molecular findings can help guide subsequent management decisions. The conversation highlights considerations involved in the ongoing care of patients receiving ALK-directed therapies.

In this segment, faculty discuss the biology of ALK rearrangements and their role in driving tumor growth in non-small cell lung cancer (NSCLC). The panel reviews clinical and demographic characteristics commonly associated with ALK-positive disease and examines the rationale for broad molecular testing regardless of patient presentation. Discussion focuses on testing strategies used to identify ALK rearrangements, including next-generation sequencing and liquid biopsy approaches, as well as practical considerations related to tissue availability and turnaround time. The faculty also address how comprehensive molecular profiling supports treatment planning and helps identify patients who may be eligible for targeted therapies. Throughout the conversation, panelists share perspectives on integrating biomarker testing into routine clinical practice and ensuring timely identification of actionable alterations in advanced NSCLC.

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.

Panelists discuss how they currently utilize emerging ctDNA platforms for high-risk patients and explore whether these advancements will soon become standard practice in clinical decision-making.

Panelists discuss how the field aims to translate lessons learned from metastatic treatment into earlier-stage interventions for select patients, sharing their current practices and hopes for future advancements in care.

Panelists discuss how recent insights into delayed resistance mechanisms in EGFR-positive cancers, including the role of combination therapies and improved testing methods, are shaping strategies to better manage and overcome resistance.

Panelists discuss how advancements in targeted therapies and personalized medicine are crucial for addressing the pressing unanswered questions in the management of ALK-positive and BRAF-positive cancers.

Panelists discuss the role of immunotherapy in the treatment landscape for BRAF-positive NSCLC, considering factors influencing the choice between immunotherapy and targeted therapy, emerging therapies, ongoing clinical trials, and approaches to dosing, sequencing, and toxicity management for both ALK and BRAF inhibitors.

Panelists discuss recent data on progression-free survival (PFS) and duration of response (DOR) for BRAF-MEK inhibitor combinations, including encorafenib + binimetinib and dabrafenib + trametinib, while also addressing emerging safety signals, differences in response based on treatment lines, and considerations for dose modifications and sequencing strategies in clinical practice.

Panelists discuss their insights on current and emerging combination strategies in the treatment of BRAF-positive NSCLC, focusing on the integration of targeted therapies, immunotherapies, or both.

Panelists discuss the findings from the ALINA study on adjuvant alectinib vs chemotherapy in resected ALK-positive NSCLC, considering how these results may influence early-stage management, sequencing strategies for ALK inhibitors, and the role of resistance mechanisms in treatment decisions.

Panelists discuss the efficacy of ALK inhibitors in treating brain metastases, referencing data from the REMARK study, the CROWN trial, ALTA-3, and ALTA-1L/brigatinib, among others.

Panelists discuss the circumstances under which they would consider switching patients on different first-line treatments to lorlatinib and outline approaches for CNS surveillance and management in ALK-positive patients.

Panelists discuss how recent data influence treatment choices for ALK-positive NSCLC patients, highlighting specific patient factors that guide decisions and potential concerns regarding the use of lorlatinib as first-line therapy.

Panelists discuss the key findings from the latest data from the CROWN and BRIGHTSTAR studies, emphasizing efficacy end points and comparing the effectiveness of these regimens with that of others in the treatment landscape for ALK-positive NSCLC.

Panelists discuss the importance of molecular testing in NSCLC, particularly for ALK rearrangements, and explore how recent advancements and emerging technologies are shaping first-line treatment selection for ALK-positive patients.

Christine Bestvina, MD, discusses strategies for managing adverse effects associated with the ROS1 TKI repotrectinib in patients with ROS1-positive metastatic non–small cell lung cancer.

Christine Bestvina, MD, discusses the emerging role of neoadjuvant chemoimmunotherapy in lung cancer.