Joshua K. Sabari, MD

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. 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.

Joshua K. Sabari, MD, discusses the complexities of managing SCLC across both academic and community settings.

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. 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. 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. 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. 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.

Experts discuss the potential of amivantamab and velertinib in early-stage lung cancer treatment, emphasizing the need for careful patient management.

Subcutaneous amivantamab offers significant advantages over IV administration, including reduced infusion reactions and quicker patient turnover in clinics.

Subcutaneous amivantamab offers significant advantages over IV administration, including reduced infusion reactions and quicker patient turnover in clinics.

Explore the impact of CNS metastasis on prognosis in EGFR mutant lung cancer and the promising results from the MARIPOSA trial.

The FDA-approved combination of amivantamab and lazertinib transforms frontline treatment for EGFR-mutated lung cancer, enhancing patient outcomes and convenience.

The FDA approval of amivantamab and lazertinib transforms frontline treatment for EGFR-mutated lung cancer, enhancing patient outcomes and convenience.

Experts explore the evolving standards of care for EGFR-mutated advanced NSCLC, highlighting therapy selection and innovative combination strategies.

Joshua K. Sabari, MD, discusses the significance of the FDA approval of subcutaneous amivantamab for the treatment of patients with EGFR-mutant NSCLC.

Panelists discuss clinical pearls for community oncologists, emphasizing that comprehensive testing is essential since zongertinib offers dramatic improvements with 75% response rates and progression-free survival exceeding 12 months in HER2 exon 20 mutations, while noting that HER2 immunohistochemistry testing shouldn’t be neglected for identifying patients who may benefit from trastuzumab deruxtecan, requiring a multilayered molecular profiling approach encompassing DNA, RNA, and protein analysis to provide new hope for patients with HER2-mutant disease.

Panelists discuss how combination therapies represent the future of HER2 mutation treatment, drawing parallels to successful EGFR combination strategies, with particular interest in anti-VEGF agents and potentially anti-PD-1/PD-L1 therapies, while noting that zongertinib’s favorable tolerability profile makes it an ideal candidate for combination approaches compared with more toxic agents like trastuzumab deruxtecan or sevabertinib, though current trial designs should incorporate 3-armed studies to evaluate up-front combination strategies rather than sequential monotherapy comparisons.

Panelists discuss how shared decision-making between zongertinib and trastuzumab deruxtecan (T-DXd) in second-line treatment involves presenting key differences to patients, including that T-DXd requires intravenous (IV) infusion with chemotherapy-like toxicities and closer monitoring (including cardiac function), while zongertinib is an oral, once-daily targeted therapy with better patient-reported outcomes and functional status improvements, fewer clinic visits after initial monitoring, and superior tolerability, leading to a preference for zongertinib first followed by T-DXd sequencing.

Panelists discuss how treatment sequencing for HER2-mutation non–small cell lung cancer (NSCLC) prioritizes zongertinib over trastuzumab deruxtecan in the second-line setting due to superior efficacy and tolerability, while noting that special populations like patients with baseline lung dysfunction (favoring zongertinib to avoid interstitial lung disease risk) or CNS (central nervous system) metastases (where zongertinib shows promising brain activity but may require concurrent radiation for larger lesions) require individualized, case-by-case management with close monitoring and early imaging follow-up.

Joshua K. Sabari, MD, discusses the significance of the FDA approval of first-line maintenance therapy with lurbinectedin plus atezolizumab for ES-SCLC.

Panelists discuss a clinical scenario involving a 73-year-old Asian woman with stage 4 lung adenocarcinoma harboring a HER2 exon 20 insertion mutation (A775-G776 YVMA) who initially responded to carboplatin, pemetrexed, and pembrolizumab for 4 cycles followed by maintenance therapy, but now presents with progressive cough and shortness of breath suggesting clinical progression, requiring decisions about next-step management in this fit patient with good performance status.

Panelists discuss how emerging second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC) include sevabertinib (a dual HER2/EGFR exon 20 inhibitor with higher gastrointestinal toxicity but similar efficacy to zongertinib) and other brain-penetrant tyrosine-kinase inhibitors (TKIs) in development, while noting that multiple ongoing phase 3 trials are studying frontline comparisons of these targeted therapies vs chemotherapy plus immunotherapy, creating a complex treatment landscape where the principle of using the best therapy first must consider efficacy, tolerability, and quality-of-life factors.

Panelists discuss how the Beamion LUNG-1 trial demonstrated zongertinib’s impressive efficacy in second-line treatment of HER2–mutant non–small cell lung cancer (NSCLC)with a 75% response rate and 14.1-month duration of response in previously treated patients, while showing a favorable safety profile as a true targeted therapy with mainly low-grade diarrhea and minimal toxicities compared with chemotherapy-like side effects, and maintaining activity even after prior trastuzumab deruxtecan treatment with a 50% response rate.

Panelists discuss how second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC), particularly trastuzumab deruxtecan (T-DXd), require careful management of significant adverse effects, including interstitial lung disease/pneumonitis (especially concerning after prior immunotherapy due to the antibody’s immune-active properties), topoisomerase inhibitor–related gastrointestinal toxicity requiring strong antiemetic protocols, and cytopenias leading to fatigue and infection risk, making it more complex to manage than traditional precision medicine targeted therapies.