Bruna Pellini, MD

The panel discusses the full multidisciplinary team required to optimize outcomes for patients with ROS1-positive advanced NSCLC: neuro-oncology for brain metastasis management, radiation oncology for CNS and bone disease, palliative care and symptom management specialists from diagnosis, physical therapy and nutrition, social work, and mental health services.

The panel addresses patients who received crizotinib or entrectinib in first line rather than lorlatinib, and who are now progressing.

The panel reinforces that oligo-progression management in ROS1-positive NSCLC requires careful distinction from strategies used in EGFR-mutated NSCLC.

For the patient with a G2032R resistance mutation and intracranial progression, the panel unanimously favors lorlatinib-based therapy in second line based on its known activity against solvent-front mutations and documented CNS penetrance, with median duration of response of approximately 7 to 8 months in this setting.

The second clinical case presents a patient with ROS1 fusion-positive advanced NSCLC who achieved partial response on frontline lorlatinib, maintained for 18 months, before symptomatic and radiographic progression: increasing primary tumor size, new contralateral pulmonary nodules, and brain MRI showing 3 new small intracranial lesions.

Given the patient's osseous disease, the panel discusses bone-directed therapy integration.

All panelists select lorlatinib at 600 mg for this patient based on response rates, duration of disease control, favorable tolerability, and its design intent to achieve superior CNS penetration compared to earlier-generation ROS1 inhibitors, which is particularly relevant given the patient's age, symptomatic disease burden, and risk of future CNS progression.

The first clinical case presents a 58-year-old female never-smoker with persistent cough, mild dyspnea, and new right-sided pleural effusion.

The panel addresses scenarios where patients arrive on treatments other than the panel's preferred agent.

Beyond efficacy, the panel identifies the key factors influencing agent selection: brain metastasis activity given the high prevalence of CNS involvement in younger ROS1-positive patients; toxicity profiles (earlier agents cause significant dizziness, taste changes, and neuropathic pain that are poorly tolerated chronically); frequency of clinic visits; and insurance access.

INSIGHT tests if NSCLC super-responders with pathologic complete response can skip adjuvant durvalumab, reducing toxicity without sacrificing survival.

The panel discusses first-line treatment selection once a ROS1 fusion is confirmed in a treatment-naive patient.

The panel discusses how patients with ROS1-positive advanced NSCLC arrive in clinic through in-system diagnosis, second opinions, or new patient referrals and the detective work required to ensure complete molecular testing is available before treatment decisions.

ROS1 gene fusions occur in approximately 1% to 2% of advanced NSCLC cases, a small but clinically meaningful subset predominantly found in younger patients, women, light or never smokers, and those with non-squamous histology, most commonly adenocarcinoma.

With 4 ROS1-directed TKIs now in the mix, community oncologists need a clear framework for sequencing and CNS considerations in this rare NSCLC subset.

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