ASCO Living Guideline for Stage 4 Non-Small Cell Lung Cancer Without Mutations

1. 🕒 Evolution of the Treatment Paradigm: Timeline

• 2016: KEYNOTE-024: Pembrolizumab vs chemotherapy—superiority over chemotherapy demonstrated in PD-L1-positive patients.
• 2019: KEYNOTE-042: Pembrolizumab compared with chemotherapy in a broader PD-L1-positive NSCLC population.
• 2021: CheckMate 9LA: Initial triplet-regimen data presented for nivolumab + ipilimumab + 2 chemotherapy cycles.
• 2022: ASCO living guidelines launched —two separate roadmaps for Stage IV NSCLC according to driver mutation status.
• 2023: Guideline updates: Versions 2022.2, 2022.3, 2023.1 and 2023.2 published.
• 2024: Guidelines updated with versions 2023.3 and 2024.1.
  • June 2024: DUBLIN-3 published.
  • September 2024: NIPPON (JCOG2007) completed.
• April 10, 2024: Writing date for the ASCO guideline article (Owen et al.).
• March 10, 2025: Literature search completed.
• April 23, 2025: ASCO Evidence-Based Medicine Committee approval granted.
• March 2025: HARMONi-2 Phase III trial published.
• June 10, 2025: ASCO guideline article accepted.
• July 17, 2025: ASCO Living Guideline version 2025.1 (Owen et al.) published, presenting updated treatment recommendations for stage IV NSCLC without driver mutations.

2. Comparing First-Line Immunotherapies: What Does NIPPON Show?

NIPPON (JCOG2007) is the first Phase III study directly comparing two immunotherapy combinations in Stage III–IV NSCLC without driver mutations among these patients.

💉 Compared Regimens

• Pembrolizumab arm: 4 cycles of carboplatin-based chemotherapy + pembrolizumab → then pembrolizumab maintenance alone (up to 2 years)
• Nivolumab + ipilimumab arm: 2 cycles of carboplatin-based chemotherapy + nivolumab (q3w) + ipilimumab (q6w) → then dual immunotherapy maintenance

📊 Efficacy Results

⚠️ Safety Findings

According to the ASCO 2025.1 update: Nivolumab + ipilimumab + chemotherapy has only moderate-quality evidence

3. A New Agent on the Horizon? HARMONi-2 and Ivonescimab

HARMONi-2is a randomized, double-blind Phase III first-line trial conducted in China. It directly compared the standard treatment PD-L1-positive (≥1%), EGFR- or ALK-mutation-negativeadvanced or metastatic NSCLC patients receive, pembrolizumab with ivonescimab , a novel agent.

• Participant number: 398 patients
• Compared treatments: Ivonescimab (anti-PD-1 + anti-VEGF bispecific antibody) vs Pembrolizumab (anti-PD-1 monotherapy)

📈 Clinical Efficacy: Progression-Free Survival (PFS)

This substantial PFS improvementwas also maintained across histological subtype and PD-L1 subgroup analyses, favoring ivonescimab throughout.

⚠️ Side-Effect Profile

The ASCO 2025.1 guidelinedoes not yet recommend ivonescimab for routine clinical use. The main reasons include a nonglobal patient population, immature OS data and shorter-than-expected PFS in the pembrolizumab arm of the study.

4. A New Second-Line Option? DUBLIN-3 and Plinabulin

DUBLIN-3is a Phase III, single-blind randomized trial involving patients progressing after first-line platinum chemotherapy, with EGFR wild-type NSCLC and comparing docetaxel + plinabulin with docetaxel + placebo in this setting.

Plinabulinis an experimental agent with antitumor and immunomodulatory effects, described as a tubulin polymerization inhibitor . It aims to enhance immune responses by increasing dendritic cell activity during treatment.

• Total patient number: 559

📊 Clinical Efficacy: Overall Survival (OS)

Although overall survival in the plinabulin arm increased by approximately 1.1 months in absolute terms, statistical significance was borderline in the analysis.

⚠️ Safety Data and Study Limitations

According to the ASCO guideline, although DUBLIN-3 shows promise for plinabulin, the vast majority of participants had not received immunotherapy and therefore generalizability to today’s second-line patient population is limited. Consequently, the recommendation level for plinabulin was not changed.

5. New Targets, Clear Messages: Other Guideline Highlights and Future Perspectives

The ASCO 2025.1 living guidelinesummarizes first- and second-line advances in NSCLC without driver mutations, also highlighting specific subgroups and future research areas.

🎯 The Importance of Subgroups: HER2 Overexpression

In NSCLC with high HER2 protein expression, trastuzumab deruxtecanhas emerged as a second-line option with a ‘weak recommendation’ level.

This shows that even in patients thought to have no driver mutation , identifying molecular subgroups can affect treatment decisions.

📌 However, this option was not comprehensively included in the 2025.1 updateand is mentioned here for reference only.

💡 Other Key Messages in Practice Guidance

• Palliative care: Supportive approaches integrated into patient care should begin early and remain an inseparable part of treatment.
• Patients unsuitable for immunotherapy: Platinum-based chemotherapy regimens remain valid, effective first-line options.

🔬 What Is Missing? Which Questions Remain Unanswered?

Future research is expected to focus particularly on two areas:

• Direct comparisons between immunotherapy regimens
• Testing next-generation molecules in resistant or progressing patient subgroups

🔍 Access to clinical trialsis a fundamental priority for treatment equity. Every patient’s right to participate in these trials is specifically emphasized.

📌 Overall Assessment and Conclusion

The ASCO 2025.1 updateis our most current scientific guide for managing Stage IV NSCLC without driver mutations.

• NIPPON: Immunotherapy combinations were directly compared for the first time. However, increased mortality with the nivolumab–ipilimumab regimenhighlighted the need for careful patient selection.
• HARMONi-2: Ivonescimabsignificantly improved progression-free survival, but the lack of global data and insufficient OS data prevented a guideline recommendation.
• DUBLIN-3: Plinabulin showed an OS advantage, but because the study population largely predates immunotherapy as a treatment era, generalizability is limited.

🧬 The living guideline modelfacilitates access to current, reliable information in rapidly changing oncology practice, strengthening patient-centered decision-making in clinical care.