Study: Open-label randomized phase III trial comparing first-line aumolertinib plus platinum–pemetrexed chemotherapy versus aumolertinib alone in treatment-naïve locally advanced or metastatic NSCLC with EGFR exon 19 deletion or L858R mutations.

Key data: N=624. Median PFS was 28.9 vs 18.9 months; HR 0.47. Median follow-up was 23.4 months. OS immature at 21.6% maturity, with no detrimental survival trend. Grade 3–4 neutrophil count decrease occurred in 55% vs 1%, white blood cell count decrease in 34% vs <1%, and platelet count decrease in 20% vs 1%. Serious AEs occurred in 36% vs 17%.

Why it matters: Adds another randomized phase III dataset supporting first-line EGFR-TKI plus chemotherapy as a higher-intensity option for EGFR-mutated advanced NSCLC.

Clinical context & caveats: Conducted in China and open-label. The PFS benefit is large, but toxicity is substantially higher and OS remains immature. Best fit may be patients with higher-risk disease features rather than routine use for all.

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Study: Randomized double-blind phase III trial of ivonescimab, a PD-1/VEGF bispecific antibody, plus pemetrexed–carboplatin versus placebo plus chemotherapy in EGFR-variant nonsquamous NSCLC after EGFR-TKI progression.

Key data: N=322. Median OS 16.8 vs 14.1 months; HR 0.74. Absolute median OS gain was 2.7 months. Estimated 30-month OS was 29.1% vs 18.4%. Grade ≥3 TEAEs occurred in 67.1% vs 54.7%; grade ≥3 TRAEs in 59.6% vs 44.7%. Treatment discontinuation due to TEAEs occurred in 11.8% vs 8.1%.

Why it matters: Provides one of the clearest OS-positive phase III signals after EGFR-TKI progression, a setting where IO-based regimens have historically struggled.

Clinical context & caveats: Median OS gain is modest, but later survival separation appears clinically relevant. China-only trial; access and generalizability will matter.

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Study: Open-label randomized phase III trial testing adjuvant nivolumab for up to 1 year versus observation after complete resection and planned standard adjuvant therapy in NSCLC without sensitizing EGFR or ALK alterations.

Key data: N=935. Median follow-up 72.6 months. Median DFS 71.3 vs 68.8 months; HR 0.97, 95% CI 0.81–1.17; 1-sided p=0.39. In PD-L1 ≥50%, median DFS 89.8 vs 78.5 months; HR 0.86, 95% CI 0.59–1.25; 1-sided p=0.22. Trial stopped for futility.

Why it matters: Shows that adjuvant nivolumab alone after surgery and standard adjuvant therapy does not improve DFS.

Clinical context & caveats: Important negative study in a treatment landscape now shaped by neoadjuvant and perioperative IO. The result argues against assuming that IO benefit transfers across timing strategies.

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Study: Prespecified secondary analysis of the international double-blind phase III ASTRUM-005 trial evaluating first-line serplulimab plus carboplatin–etoposide versus placebo plus chemotherapy in extensive-stage SCLC.

Key data: N=585. Median follow-up 42.4 months. Median OS 15.8 vs 11.1 months; HR 0.60. Four-year OS 21.9% vs 7.2%. Median PFS 5.8 vs 4.3 months; HR 0.47. Confirmed ORR 68.9% vs 58.7%. Grade ≥3 serplulimab-related or placebo-related TEAEs occurred in 35.0% vs 29.1%.

Why it matters: Confirms durable survival benefit for serplulimab plus chemotherapy in ES-SCLC, with a notable long-term OS tail.

Clinical context & caveats: Strong randomized data, but regimen availability differs by region. The magnitude and durability compare favorably with earlier chemo-IO SCLC benchmarks.

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Study: Final survival analysis of randomized double-blind phase III ASTRUM-002 in treatment-naïve locally advanced or metastatic nonsquamous NSCLC without EGFR, ALK, or ROS1 alterations.

Key data: N=636. Median OS was 23.7 months with serplulimab + HLX04 + chemotherapy, 26.8 months with serplulimab + chemotherapy, and 20.3 months with chemotherapy. Serplulimab + chemotherapy improved OS versus chemotherapy; HR 0.66. No OS benefit was seen from adding HLX04 to serplulimab + chemotherapy; HR 1.12, 95% CI 0.88–1.42; p=0.363.

Why it matters: Confirms OS benefit for serplulimab plus chemotherapy, while failing to support routine addition of a bevacizumab biosimilar to that backbone.

Clinical context & caveats: First-line chemo-IO is already established. The practical contribution is the negative HLX04 increment, consistent with uncertainty around additive anti-VEGF benefit in unselected nonsquamous NSCLC.

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Study: Updated phase II TRAILBLAZER analysis of induction retlirafusp alfa, an anti-PD-L1/TGF-β bifunctional agent, with or without chemotherapy followed by MDT-directed surgery or radiotherapy and consolidation retlirafusp alfa in initially unresectable stage III NSCLC.

Key data: N=107. Median follow-up 39.4 months. Three-year EFS was 50.5% in retlirafusp alfa + chemotherapy arms and 77.1% in the high PD-L1 monotherapy arm. Three-year OS was 68.3% and 87.5%, respectively. Among 27 patients who underwent surgery, 3-year EFS and OS were 69.5% and 84.9%, compared with 50.8% and 70.4% in radiotherapy-treated patients. No new safety signals were reported.

Why it matters: Suggests induction immunotherapy with response-adapted local therapy may be feasible in selected initially unresectable stage III NSCLC.

Clinical context & caveats: Phase II, nonstandard treatment pathway, and strong selection effects for surgery. This is hypothesis-generating, not a replacement for CRT followed by durvalumab.

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Study: Single-arm phase II trial evaluating subablative radiotherapy plus ipilimumab/nivolumab in metastatic NSCLC with low or negative PD-L1 expression after progression on first-line anti-PD-1 therapy.

Key data: N=31. ORR in non-irradiated lesions was 7% at 6 weeks and 10% at 12 weeks; best overall response reached 29%. DCR was 58% and 39% at 6 and 12 weeks. Median OS was 10.1 months overall and differed by best response: 3.1 months with progression, 13.5 months with stable disease, and 22.5 months with partial/complete response. Grade 3 TRAEs occurred in 26%; no grade 4–5 treatment-related AEs were reported.

Why it matters: Suggests a subset of immunotherapy-refractory NSCLC patients may still respond to combined RT and dual checkpoint blockade.

Clinical context & caveats: Small single-arm study without a control arm. Early ORR was modest; the 29% best response rate reflects delayed activity and should not be overinterpreted.

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Study: Multicenter single-arm phase II trial evaluating first-line cadonilimab, a PD-1/CTLA-4 bispecific antibody, plus platinum-based chemotherapy in PD-L1-negative advanced NSCLC.

Key data: N=50 treated; 47 in full analysis set. Twelve-month PFS rate 42.1%, meeting the prespecified threshold. Median PFS 9.7 months; median OS not reached. ORR 66.0%; DCR 100.0%; median DoR 9.5 months. Grade ≥3 TRAEs occurred in 52.0%; no TRAE-related deaths. cfDNA methylation response preceded radiographic response by approximately 5 cycles; baseline molecular low-risk patients had longer median PFS than high-risk patients, 11.4 vs 6.9 months.

Why it matters: Adds prospective signal for PD-1/CTLA-4 bispecific therapy in PD-L1-negative NSCLC, a subgroup with limited benefit from standard IO.

Clinical context & caveats: Single-arm China-based phase II study. Efficacy appears encouraging, particularly in squamous disease, but randomized confirmation is essential.

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Study: Retrospective multicenter study developing and validating SCENT, a CT-based deep learning model to predict PD-L1 status and immunotherapy outcomes in metastatic NSCLC.

Key data: MD Anderson cohort N=972; SCENT developed and validated in 640 patients with paired CT and PD-L1 IHC, with additional validation in MD Anderson CT-only patients, Mayo Clinic N=72, and LONESTAR N=116. SCENT predicted PD-L1 ≥50% with AUC 0.84 internally, and external AUC 0.80 in Mayo and 0.78 in LONESTAR. SCENT-derived PD-L1 stratified PFS (HR 1.49, p<0.001) and OS (HR 1.40, p=0.009). Longitudinal use remained exploratory and was not statistically significant after correction.

Why it matters: Supports the concept of CT-based “virtual biopsy” as a noninvasive adjunct to tissue PD-L1 assessment.

Clinical context & caveats: Retrospective and not practice-changing. Manual tumor ROI annotation, scanner variability, tissue/imaging discordance, and prospective validation remain major hurdles.

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EGFR-mutated NSCLC continues to move toward risk-adapted first-line intensification, with AENEAS2 adding another phase III PFS-positive EGFR-TKI plus chemotherapy dataset.

HARMONi-A is clinically important because OS-positive post-EGFR-TKI trials are uncommon, even if the median OS gain is modest.

Adjuvant IO remains context-dependent. The study shows that nivolumab after surgery and completed standard adjuvant therapy does not replicate perioperative IO benefit.

SCLC chemo-IO benefit can be durable. ASTRUM-005 shows a meaningful 4-year OS tail with serplulimab plus chemotherapy.

Anti-VEGF addition remains unsettled. ASTRUM-002 supports serplulimab plus chemotherapy, but not routine addition of HLX04.

Rescue strategies after IO failure remain exploratory. RECLAIM is interesting, but still far from practice-changing.

AI biomarkers are maturing technically, but clinical deployment still requires prospective validation and operational clarity.

Several major positive trials were conducted exclusively or predominantly in China, including AENEAS2, HARMONi-A, ASTRUM-002, cadonilimab, and TRAILBLAZER.

AENEAS2 shows a large PFS benefit, but toxicity is substantial and OS remains immature.

HARMONi-A demonstrates OS benefit, but the absolute median OS gain is modest and access to ivonescimab varies by region.

EA5142 was designed before the current perioperative IO era, but its negative result remains important for treatment timing.

TRAILBLAZER and RECLAIM are phase II and heavily selection-dependent; neither should change routine practice.

Cadonilimab and RECLAIM are single-arm studies and should be interpreted as hypothesis-generating.

SCENT is promising but retrospective; longitudinal PD-L1 inference from CT remains exploratory.