Julia Rotow, MD

Julia Rotow, MD, and Jyoti Malhotra, MD, MPH, discuss the rationale for evaluating IB6 as a target in non–small cell lung cancer.

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 emerging therapies like patritumab (a HER3-directed antibody-drug conjugate [ADC]), datopotamab (a TROP2 ADC), and ivonescimab (a PD-1/VEGF bispecific) show distinct toxicity profiles compared with existing treatments, potentially influencing earlier use. Balancing efficacy gains against toxicity risks remains critical in optimizing EGFR-mutated non–small cell lung cancer (NSCLC) treatment.

Panelists discuss how various strategies have been developed to enhance the tolerability of intravenous amivantamab, including premedication, step-up dosing, and infusion rate adjustments. Adoption into clinical practice varies, with many institutions integrating these approaches to mitigate infusion-related reactions and improve patient outcomes.

Panelists discuss how, if the MARIPOSA trial shows an overall survival advantage exceeding 1 year, the amivantamab-lazertinib combination may see increased frontline use. Subsequent therapy options could include chemotherapy, targeted therapies based on resistance mechanisms, or clinical trials for emerging treatments.

Panelists discuss how medical professionals consider continuing osimertinib with second-line and subsequent therapies based on disease progression, resistance mechanisms, and patient response. It may be combined with other agents or switched depending on clinical trials, biomarkers, and overall treatment goals to optimize outcomes.

Panelists discuss how medical professionals balance maximizing progression-free survival with preserving future treatment options by considering disease biology, resistance mechanisms, and patient factors. At first progression, the NCCN recommends continuing current therapy or switching to amivantamab with a platinum doublet, based on mutation status, prior response, toxicity, and patient preferences.

Panelists discuss how medical professionals use shared decision-making by aligning treatment options with patient values, discussing benefits, risks, and preferences. Patients often prioritize longest progression-free survival (PFS), lowest toxicity, and shortest infusion time. Collaborative discussions ensure personalized, evidence-based care.

Panelists discuss how disease-related factors like central nervous system (CNS) involvement or specific metastatic sites can guide treatment selection, favoring agents with CNS penetration or targeted efficacy. Mutational factors, such as TP53 comutations, may impact therapy response. Patient-related aspects, including age and comorbidities, influence tolerability and regimen choice.

Panelists discuss how, when discussing frontline regimens for EGFR-mutated non–small cell lung cancer (NSCLC), the NCCN-recommended options include osimertinib monotherapy for its targeted approach with lower toxicity; amivantamab/lazertinib combination for potentially deeper responses in specific mutations; and osimertinib with platinum-doublet chemotherapy for more aggressive disease requiring enhanced tumor control.

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.