Ticiana A. Leal, MD

Dr. Leal addresses CNS disease management in EGFR-mutated NSCLC, noting that baseline brain metastases represent a high-risk feature associated with worse prognosis and shorter PFS. Potent EGFR tyrosine kinase inhibitors, particularly osimertinib and lazertinib, remain most valuable for CNS control and reducing CNS progression risk in patients without baseline brain involvement. Amivantamab, an EGFR-MET bispecific antibody, has also demonstrated CNS benefit in both MARIPOSA and MARIPOSA-2. Notably, datopotamab deruxtecan, an antibody-drug conjugate not traditionally expected to cross the blood-brain barrier effectively, also demonstrated CNS activity in the pooled TROPION-Lung01/05 analysis. She emphasizes the importance of investigating CNS efficacy early in drug development to inform sequencing strategies that control CNS disease, reduce progression risk, and delay whole brain radiation given its neurologic toxicity.

Dr. Leal compares amivantamab plus chemotherapy (MARIPOSA-2) with datopotamab deruxtecan (from the pooled TROPION-Lung01 and TROPION-Lung05 analysis) in the second-line setting for EGFR-mutated NSCLC. Datopotamab deruxtecan, now FDA-approved for previously treated patients, demonstrated promising median PFS, OS of approximately 15 months, and notable CNS activity with an intracranial response rate of approximately 40%. As a monotherapy administered intravenously once every 3 weeks, she describes it as straightforward to incorporate clinically. Distinct toxicities associated with this TROP2-directed antibody-drug conjugate with a topoisomerase 1 inhibitor payload include mucositis (managed with prophylactic dexamethasone mouthwash), interstitial lung disease requiring close symptom monitoring, and ocular toxicities, predominantly dry eyes, mitigated with prophylactic eye drops and baseline ophthalmologic evaluation.

Dr. Sands discusses geographic and practice setting variations, noting lurbinectedin presents no administration challenges anywhere, whereas tarlatamab's rollout has been slower, initially concentrated in academic centers with clinical trial experience managing T-cell engagers and cytokine release syndrome.

Dr. Leal outlines her approach to second-line treatment selection following progression on frontline osimertinib monotherapy in EGFR-mutated NSCLC. She recommends repeat molecular testing at progression, particularly liquid biopsy for rapid, noninvasive results, ideally complemented by tissue biopsy to characterize resistance mechanisms and exclude histologic transformation such as small cell transformation. Common resistance mechanisms include C797S mutations and MET alterations. Clinical factors informing second-line selection include performance status, organ function (particularly renal function given platinum-based chemotherapy considerations), burden and sites of progression (with consideration of localized radiation for limited progression, including CNS-limited disease), social support, and patient preference regarding treatment intensity.

Dr. Shields addresses choosing between atezolizumab-based (IMpower133) and durvalumab-based (CASPIAN) induction regimens, noting both demonstrate similar OS benefits (approximately 2.5-3 months) with real-world data showing general equipoise between agents.

Dr. Sands addresses the NCCN footnote stating lurbinectedin cannot be reused after relapse following maintenance use, comparing this to how progression on one PD-L1 inhibitor doesn't necessarily preclude using another.

Dr. Leal addresses time toxicity data from Dr. Florez and colleagues comparing the clinic and at-home time burden across EGFR-mutated NSCLC frontline regimens. Both intravenous and subcutaneous amivantamab-lazertinib combinations carried higher time toxicity than osimertinib-chemotherapy or osimertinib monotherapy, driven largely by the prophylactic regimens required for dermatologic prophylaxis education and anticoagulation for thromboembolic risk reduction. She notes that with subcutaneous amivantamab now available, infusion-related burden is substantially reduced, and she actively transitions eligible patients to the subcutaneous formulation to minimize both time burden and administration-related adverse events.

Dr. Shields discusses trilaciclib, an FDA-approved supportive care medication from 2021 that prevents myelosuppression across red cells, white cells, and platelets, plus neutropenia.

Dr. Leal outlines current decision-making, noting lurbinectedin plus atezolizumab represents the approved standard frontline maintenance strategy for patients tolerating induction well, achieving stable disease or response, and motivated for treatment intensification.

Dr. Leal describes her real-world experience managing toxicity across frontline combination regimens in EGFR-mutated NSCLC. With osimertinib plus chemotherapy (FLAURA2 regimen), most grade 3 or higher adverse events occur during the carboplatin-pemetrexed-osimertinib induction phase, with hematologic toxicities being the primary driver of dose reduction or interruption; her practice manages these toxicities with familiar protocols, achieving dose intensity consistent with trial data. During chronic pemetrexed-osimertinib maintenance, fatigue, anemia, edema, and gradually rising creatinine are the most encountered issues, raising an open clinical question about optimal pemetrexed duration; average time on pemetrexed in FLAURA2 was approximately 8 months, with patients then continuing osimertinib monotherapy for over 30 months.

Dr. Chiang addresses whether tarlatamab used in maintenance retains efficacy if used again after progression, acknowledging significant unknowns regarding resistance mechanisms for novel T-cell engager therapies compared to better-understood chemotherapy resistance.

Dr. Sands argues that successful second-line agents should move earlier in treatment sequencing, citing precedent from other oncology fields. With only 40% to 50% of patients with ES-SCLC receiving second-line therapy due to rapid disease progression, declining functional status, or brain metastases, moving effective agents like tarlatamab earlier addresses this attrition problem.

Dr. Leal discusses the clinical and molecular features most useful for identifying patients likely to benefit from frontline treatment intensification in EGFR-mutated NSCLC. Across FLAURA2 and MARIPOSA, patients with TP53 co-mutations, positive baseline circulating tumor DNA (ctDNA), baseline brain metastases, and EGFR L858R mutation status, which are all associated with worse prognosis on monotherapy, consistently derived benefit from combination strategies, reinforcing the relevance of these markers for treatment selection.

Dr. Shields addresses limitations of phase 1b single-arm studies, noting smaller patient numbers may introduce selection bias toward patients most likely to benefit from T-cell engager therapy targeting DLL3 and CD3. She emphasizes the importance of randomized phase 3 data for head-to-head comparisons, particularly given that DeLLphi-303's control arm involved immunotherapy alone, preventing cross-trial comparisons with IMforte's different control arm.

Dr. Ticiana Leal introduces the discussion on treatment selection and sequencing in EGFR-mutated advanced non-small cell lung cancer (NSCLC), emphasizing that biomarker testing results must be available before initiating any frontline treatment discussion. With osimertinib monotherapy, osimertinib plus chemotherapy, and amivantamab plus lazertinib all now guideline-recommended, she reviews the comparative efficacy data driving patient discussions.

Dr. Sands discusses tarlatamab's unique mechanism as a bispecific T-cell engager linking DLL3 on tumor cells to CD3 on T cells, creating an antigen-directed immune response distinct from other therapeutic approaches. He characterizes the second-line DeLLphi-304 trial as establishing an entirely new paradigm, representing the only example of one drug outperforming others in SCLC's second-line setting across PFS, OS, tolerability, and symptom improvement.

Dr. Leal discusses practical logistics of lurbinectedin plus atezolizumab, administered together every 21 days. She incorporates maintenance discussions into initial treatment planning, particularly important for patients traveling long distances with caregivers. Most patients with ports prefer intravenous administration despite subcutaneous atezolizumab being an option with comparable efficacy, safety, and drug levels but shorter infusion time.

Dr. Shields confirms that NCCN guidelines now recommend lurbinectedin plus atezolizumab as preferred maintenance therapy following 4 cycles of chemotherapy and immunotherapy, with the specific footnote limiting this to patients with ECOG performance status 0 to 1 and no history of brain metastases. She strictly follows the brain metastasis exclusion criteria for treatment-naive patients but notes this restriction wasn't applied in second or third-line relapse settings.

Dr. Joshua Sabari introduces the program on evolving maintenance and sequencing strategies in extensive-stage small cell lung cancer (ES-SCLC), joined by Dr. Anne Chiang from Yale, Dr. Jacob Sands from Dana-Farber, Dr. Misty Shields from Indiana University, and Dr. Ticiana Leal from Emory University's Winship Cancer Institute.

Dr. Wistuba emphasizes the critical need for reinforcing RNA testing alongside DNA testing for comprehensive NGS in lung cancer.

Dr. Leal outlines her approach to frontline treatment selection for newly diagnosed patients with ROS1-positive lung cancer.

Dr. Rodriguez outlines patient education strategies emphasizing partnership from treatment initiation, as clinical trials demonstrate over half of patients require dose adjustments.

Dr. Rodriguez reviews historical toxicity profiles from earlier ROS1 inhibitors, noting that crizotinib and entrectinib presented novel side effects including visual field changes preventing night driving due to floaters, along with liver function test (LFT) abnormalities requiring monitoring.

Dr. Wistuba explains that acquired resistance to ROS1-targeted therapies frequently involves on-target mutations, with G2032R representing the most frequently observed resistance mutation among 10 to 12 described mutations that affect the ATP binding site and reduce drug binding efficiency.

Martin F. Dietrich, MD, PhD, and Ticiana Leal, MD, discuss other potential treatment avenues to explore in HER2-mutant non–small cell lung cancer.

Martin F. Dietrich, MD, PhD, and Ticiana Leal, MD, discuss how the NCCN Guidelines can help supplement HER2-mutant non–small cell lung cancer management decisions.

Ticiana Leal, MD, discusses frontline zongertinib in HER2-mutant non-small cell lung cancer, including activity in patients with active brain metastases, based on data from the BeamionLUNG-1 study presented at ELCC 2026.

Dr. Wistuba addresses the complexity of NGS reports that may include multiple abnormalities beyond ROS1 fusions.

Dr. Wistuba confirms that fusion variant identification does not impact treatment selection, emphasizing that ROS1-positive versus ROS1-negative status represents the key clinical decision point.

Martin F. Dietrich, MD, PhD, and Ticiana Leal, MD, examine sequencing considerations between tyrosine kinase inhibitors and antibody-drug conjugates in HER2-mutant non–small cell lung cancer.