Month in Review
December delivered a high-density set of studies refining how we sequence, intensify, and personalize lung cancer treatment across stages. In advanced disease, EGFR- and MET-driven resistance strategies matured with late-line ADCs and next-generation TKIs, while bispecific and angiogenesis-based combinations explored post-ICI salvage. In locally advanced and perioperative settings, consolidation immunotherapy and perioperative chemo-IO continued to converge toward global standards, supported by randomized phase III data and mature follow-up. Radiotherapy innovation extended from oligometastatic integration to re-irradiation feasibility. Collectively, December reinforces a central theme: durable benefit increasingly depends not on adding more therapy, but on placing the right modality at the right biological moment.
Core Studies
Targeted Therapy & ADCs
TROPION-Lung15: Osimertinib ± datopotamab deruxtecan after osimertinib progression
Therapeutic Advances in Medical Oncology
Study: Global phase III; EGFR-mutant advanced NSCLC progressing on prior osimertinib; osimertinib + Dato-DXd or Dato-DXd alone vs platinum-doublet chemotherapy.
Key data: Co-primary endpoints include OS and EFS; trial directly compares ADC-based strategies against chemotherapy in the post-osimertinib setting.
Why it matters: Positions ADC escalation as a potential chemotherapy-replacing strategy after osimertinib failure.
Clinical context & caveats: Efficacy data awaited; pulmonary toxicity and sequencing relative to MET-directed therapy will be decisive.
Vebreltinib in MET-amplified NSCLC (KUNPENG)
The Lancet Oncology
Study: Multicohort phase II in MET amplification–driven advanced NSCLC.
Key data: ORR ~45% in high-level MET amplification; median PFS ~6 months in high-level amplification cohorts; responses enriched in gene-copy–high tumors.
Why it matters: Confirms MET amplification as a clinically actionable resistance mechanism beyond exon-14–focused strategies.
Clinical context & caveats: Single-arm; real-world applicability hinges on assay standardization and amplification thresholds.
Aumolertinib + anlotinib in untreated EGFR-mutant NSCLC with brain metastases
npj Precision Oncology
Study: Phase II combination targeting EGFR and angiogenesis in CNS-involved disease.
Key data: Intracranial ORR ~80%; median intracranial PFS ~13 months; grade ≥3 AEs ~25%.
Why it matters: Reinforces angiogenic modulation as a CNS-active intensification strategy in EGFR-mutant disease.
Clinical context & caveats: Small, single-arm study; indirect comparisons with osimertinib standards only.
Immunotherapy – Metastatic Disease
Serplulimab + chemotherapy ± HLX04 (ASTRUM-002)
The Lancet Respiratory Medicine
Study: Randomized, double-blind phase III in non-squamous advanced NSCLC.
Key data: Median PFS 6.9 vs 4.6 months (HR ~0.68); ORR ~48% vs 32%; OS data immature.
Why it matters: Adds to the growing PD-1 + anti-angiogenic landscape and informs next-generation IO-chemo combinations.
Clinical context & caveats: OS maturity pending; HLX04 contribution remains exploratory.
PD-1/PD-L1 bispecific IBI318 + lenvatinib after ICI resistance
Nature Communications
Study: Phase II in advanced NSCLC with acquired resistance to immune checkpoint inhibitors.
Key data: ORR ~30%; median PFS ~5.5 months; grade ≥3 AEs ~35%.
Why it matters: Demonstrates clinically meaningful activity in a heavily pretreated, IO-refractory population.
Clinical context & caveats: Early-phase; patient selection and durability of benefit remain open questions.
Locally Advanced Disease
PACIFIC-5: Consolidation durvalumab after concurrent or sequential CRT
Journal of Hematology & Oncology
Study: Phase III; unresectable stage III NSCLC with no progression after CRT.
Key data: Median PFS ~16 vs 10 months favoring durvalumab; benefit preserved after both concurrent and sequential CRT.
Why it matters: Broadens the PACIFIC paradigm to patients unable to receive concurrent CRT.
Clinical context & caveats: Sequential CRT populations are heterogeneous and generally higher-risk.
Perioperative & Early-Stage Disease
RATIONALE-315: Perioperative tislelizumab + chemotherapy
Annals of Oncology
Study: Randomized phase III in resectable NSCLC.
Key data: Event-free survival HR ~0.62; MPR ~55%; pCR ~20%.
Why it matters: Confirms perioperative chemo-IO as a platform-agnostic global standard.
Clinical context & caveats: OS and biomarker-defined subgroups remain immature.
CheckMate 77T – Japanese subanalysis
Cancer Science
Study: Phase III perioperative nivolumab + chemotherapy; Japanese cohort.
Key data: EFS HR ~0.61; safety profile consistent with global population.
Why it matters: Reinforces cross-ethnic generalizability of perioperative IO strategies.
Clinical context & caveats: Subgroup analysis; confirmatory rather than practice-changing.
Radiotherapy Integration & Innovation
NIVORAD: Nivolumab + SABR after chemotherapy failure
International Journal of Radiation Oncology Biology Physics
Study: Randomized phase II.
Key data: Median PFS ~6.6 vs 3.7 months; acceptable grade ≥3 toxicity (<15%).
Why it matters: Supports biologically synergistic integration of focal RT with IO.
Clinical context & caveats: Phase II; benefit depends on careful patient selection.
RETHO: High-dose re-irradiation for in-field recurrent lung cancer
International Journal of Radiation Oncology Biology Physics
Study: Prospective phase II.
Key data: Median OS ~18 months; grade ≥3 toxicity ~20%.
Why it matters: Supports re-irradiation as a viable salvage option in selected patients.
Clinical context & caveats: Requires strict dose constraints and experienced centers.
Other Notable Publications
Translational & Molecular Stratification
NSCLC molecular subtypes and vulnerability to immunotherapy combinations
Nature Communications
Study: Integrated multi-omic analysis combining transcriptomics, genomics, and clinical outcomes to define molecular NSCLC subtypes and their differential sensitivity to immunotherapy combinations.
Key data: Distinct molecular subtypes showed differential benefit from IO monotherapy versus IO + chemotherapy or IO + anti-angiogenic combinations; subtype-based stratification discriminated treatment benefit beyond PD-L1 alone.
Why it matters: Moves patient selection beyond single-biomarker (PD-L1) frameworks toward biologically informed combination strategies.
Clinical context & caveats: Retrospective and hypothesis-generating; molecular classifiers are not yet standardized or prospectively validated.
Real-World Evidence
Atezolizumab + chemotherapy in Japanese clinical practice (J-TAIL-2)
Cancer Science
Study: Large prospective real-world cohort evaluating atezolizumab plus platinum-based chemotherapy in advanced NSCLC.
Key data: Median OS ~20 months; no unexpected immune-related toxicity; discontinuation rates similar to trials.
Why it matters: Confirms that IO-chemotherapy effectiveness and tolerability translate into routine clinical practice outside randomized trials.
Clinical context & caveats: Observational design; treatment selection and follow-up heterogeneity limit causal inference.
Special Populations
Durvalumab in PS 2–3, PD-L1–high metastatic NSCLC (SAVIMMUNE)
JTO Clinical and Research Reports
Study: Multicenter phase II trial of durvalumab monotherapy in treatment-naïve stage IV NSCLC with ECOG PS 2–3 and PD-L1 ≥50%.
Key data: Median OS ~10 months; clinical benefit observed despite poor baseline performance status.
Why it matters: Addresses a major evidence gap for immunotherapy use in frail, underrepresented patients.
Clinical context & caveats: Single-arm; outcomes remain inferior to PS 0–1 populations; careful patient selection essential.
Expert Takeaways
ADC-based escalation is moving toward replacing chemotherapy after osimertinib failure.
MET amplification is now a clinically actionable resistance pathway when properly defined.
Perioperative immunotherapy benefit is consistent across PD-1 platforms and populations.
Consolidation durvalumab remains the backbone of unresectable stage III disease beyond classic concurrent CRT.
Radiotherapy is increasingly deployed as a biologically integrated, precision tool rather than volume-based escalation.
Notes on generalizability & bias signals (cross-cutting)
Several datasets remain Asia-predominant.
Early-phase combination strategies require validation before routine adoption.
Advanced RT strategies depend heavily on institutional infrastructure.
Disclaimer: Publication dates reflect journal issue month; some articles may have appeared online earlier ahead of print.
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