Study: Phase III FLAURA2; 1L EGFR ex19/L858R metastatic NSCLC; osimertinib + chemo vs osimertinib alone.

Key data: Median OS 47.5 vs 37.6 months, HR 0.77 (95% CI 0.61–0.96; p=0.02). Grade ≥3 AEs 70% vs 34%; discontinuation of osimertinib 12% vs 7%. OS curves start separating ~16 months. 36-mo OS 63% vs 51%.

Why it matters: Confirms chemo-TKI as a valid 1L standard for fit patients prioritizing depth/duration of control and OS; sequencing remains an open question.

Clinical context & caveats: OS benefit was consistent across subgroups, though toxicity and infusion logistics are nontrivial; sequencing vs ‘TKI→chemo’ remains untested, and CNS data are descriptive, not powered.

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Study: Randomized phase III; post-TKI EGFR-mutant NSCLC; ADC vs physician’s-choice chemotherapy.

Key data: Median PFS 7.7 vs 4.0 months (HR 0.49; 95% CI 0.39–0.61; p < 0.001); ORR 32% vs 12%; disease-control rate 69% vs 42%; Grade ≥3 AEs 40% vs 29%. OS data immature.

Why it matters: Provides an ADC option after TKI±chemo where effective standards are limited; could shift post-TKI algorithms once OS and safety mature.

Clinical context & caveats: Entirely China-only population; current readout is PFS/ORR without OS yet. Post-progression treatments and testing access outside China may differ; expect HTA/guidelines to wait for survival and broader validation.

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Study: Long-term phase III follow-up of the pivotal ALEX trial in treatment-naïve ALK-positive advanced NSCLC (n = 303), comparing alectinib with crizotinib.

Key data: OS 94.4 vs 57.7 months (HR 0.56; 95% CI 0.42–0.73); 5-year OS rate 62.5% vs 45.5%; prior PFS HR 0.43. Median follow-up 74 months; CNS progression reduced by >50%.

Why it matters: Provides definitive proof of durable survival benefit with alectinib and one of the longest OS ever achieved in metastatic lung cancer, confirming CNS-active next-generation ALK TKIs as the enduring 1L standard.

Clinical context & caveats: Cross-trial comparisons with lorlatinib are methodologically unsound given differences in design and crossover, but this mature dataset sets the historical benchmark for 2nd-generation ALK inhibitors. Benefit was consistent across CNS and non-CNS subgroups, though Asian enrollment predominated (55%) and treatment crossover likely attenuated the true magnitude of OS gain.

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Study: Phase II CHRYSALIS-2 sub-analysis; EGFR-mutated advanced NSCLC with brain and/or leptomeningeal metastases after prior osimertinib ± chemotherapy.

Key data: Intracranial ORR 56%; median CNS-PFS 9.1 mo; manageable toxicity.

Why it matters: Strengthens the case for amivantamab-based combos in post-osimertinib CNS-progressors, a major unmet need.

Clinical context & caveats: The CNS/LM cohorts were small and non-randomized, with heterogeneous supportive therapy (steroids, intrathecal chemotherapy, radiation) and no comparator arm, so efficacy interpretation should remain exploratory. Median follow-up was short (~9 months), and most patients had previously responded to osimertinib, which may enrich for favorable biology. Larger randomized trials with standardized CNS assessment are needed to confirm these findings.

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Study: Phase III, squamous NSCLC; ivonescimab+chemo vs tislelizumab+chemo.

Key data: Median PFS 9.2 vs 6.8 months (HR 0.68; 95% CI 0.56–0.83; p < 0.001); ORR 66% vs 54%; Grade ≥ 3 AEs ≈ 51% both arms. OS data immature (approx 20% maturity at cut-off).

Why it matters: Signals that PD-1/VEGF-A bispecifics may incrementally outperform standard PD-1 combos in squamous disease; could alter China-first practice and inform global development.

Clinical context & caveats: China-only trial with major sex imbalance (female 4% and 11%), near-universal Han Chinese enrollment, and exclusion of active brain mets. Comparator isn’t global, and OS remains immature; global validation essential.

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Study: Phase III randomized trial using a 14-gene expression signature to identify “molecularly high-risk” stage I–IIA NSCLC for adjuvant platinum-based chemotherapy vs observation. n = 423.

Key data: 3-year DFS 93% vs 77% (HR 0.41; 95% CI 0.24–0.68; p < 0.001); Grade ≥ 3 AEs 28%; OS immature.

Why it matters: Validates genomics-guided selection for adjuvant therapy, shifting early-stage management from purely anatomical to biologically informed decisions.

Clinical context & caveats: The assay is proprietary and trial-specific; external validation and broader access are needed before routine use, especially since squamous histology and Western cohorts were under-represented.

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Study: Phase III randomized trial (n = 302 interim) comparing no mediastinal lymph-node dissection (MLND) vs systematic MLND in clinical T1N0 ground-glass opacity (GGO)–dominant invasive adenocarcinoma.

Key data: 0% nodal metastasis in both arms at interim analysis; median operative time reduced by ~45 minutes and blood loss halved in the no-MLND arm; no early recurrence observed.

Why it matters: Validates that omitting mediastinal dissection is safe in truly GGO-dominant cases; a paradigm shift toward minimally invasive, function-preserving surgery.

Clinical context & caveats: Strict GGO-dominant definition and expert radiology/surgery are prerequisites; early interim read (0% nodal disease in either arm so far) favors de-escalation but long-term oncologic endpoints are still maturing; copy-paste to “solid-predominant” would be unsafe.

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Study: Global, two-part phase II; 12 mg/kg Q3W expansion is the decision dose.

Key data: ORR 48% (95% CI 39.6–56.9); median PFS 4.9 mo; median OS 10.3 mo; grade ≥3 AEs 36%; ILD 12% (grade ≥3 4%).

Why it matters: Clinically meaningful activity in a space with thin options; supports ongoing phase III and positions B7-H3 as a tractable SCLC target.

Clinical context & caveats: ILD risk (12%) mandates early recognition and steroid protocols; efficacy strongest in 2L, where sequencing vs tarlatamab or lurbinectedin will matter most.

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Study: Prospective, multi-institutional phase II trial (n = 95) evaluating upfront stereotactic radiosurgery (SRS) for patients with 1–10 brain metastases from small-cell lung cancer.

Key data: 12-month neurologic death rate 11%; median overall survival 8.5 months; 12-month distant brain failure 52%; local control 94%; grade ≥ 3 neurotoxicity 0%.

Why it matters: Prospective evidence that SRS can be a rational first CNS therapy for selected SCLC, challenging historical default to up-front WBRT.

Clinical context & caveats: Outcomes hinge on rigorous MRI surveillance and early salvage; centres without tight imaging pathways may not replicate CNS control.

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Study: Retrospective multi-dataset biomarker analyses interrogating LRP1B status vs ICI outcomes.

Key data: Across datasets, LRP1B-mutant tumors showed improved PFS (pooled HR ≈ 0.86) and OS trend favoring ICI benefit, but associations weakened after adjusting for tumor mutational burden (TMB) and smoking signature.

Why it matters: Suggests LRP1B mutation correlates with an immunogenic phenotype but is not an independent predictive biomarker once TMB and other genomic covariates are considered.

Clinical context & caveats: Retrospective datasets with variable sequencing and definitions; signal likely reflects TMB enrichment. Routine testing premature pending harmonized prospective validation.

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Study: Phase III Japanese trial protocol comparing anatomic segmentectomy vs lobectomy in solid-predominant small tumours.

Key data: Designed as a non-inferiority trial; radiologic criteria require consolidation-to-tumor ratio ≥ 0.5; intraoperative frozen section confirmation and surgical margin ≥ 2 cm or ≥ tumor size.

Why it matters: Aims to determine whether segmentectomy can safely replace lobectomy in solid-predominant tumors; potentially expanding sublobar surgery beyond current GGO-dominant indications.

Clinical context & caveats: Conducted exclusively in Japan, where surgical and radiologic quality control are exceptional; replication elsewhere will require rigorous QA to ensure margin adequacy and reproducibility of “solid-predominant” classification. Long-term oncologic outcomes remain years away.

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EGFR therapy now spans from intensified 1L (OS benefit FLAURA2) to ADC salvage (NEJM tirumotecan).

SCLC sees its first post-IO progress: Ifinatamab Deruxtecan achieves 48% ORR, validating ADC therapy beyond DLL3.

Precision surgery and genomic risk are shifting early-stage practice toward individualized extent and adjuvant choice.

CNS management in both NSCLC and SCLC increasingly favors targeted and focal approaches over WBRT.

Region-locked trials: Several readouts are China-only; confirm in multi-regional RCTs before changing global standards (HARMONi-6, sacituzumab tirumotecan).

Population skews: Marked sex imbalance in HARMONi-6 (female 4% vs 11%); CNS-active disease often excluded; both can inflate apparent benefit in practice.

Imaging/ops dependency: SRS in SCLC works when MRI surveillance/salvage are tight; be realistic about system capacity before replacing up-front WBRT.