ASCO Living Guide for Stage 4 Non-Mutational Non-Small Cell Lung Cancer
🌍 Lung cancer continues to be the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide.
🔍 Lung cancer is primarily classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
However, with the addition of genetic subtypes, more than 20 different types of lung cancer have now been defined.
📌 Unfortunately, over half of lung cancers are diagnosed at Stage IV.
🧬 A significant portion of Stage IV NSCLC patients have no actionable mutations and require a specific treatment approach.
"Living Guidelines" published by authoritative organizations like ASCO provide clinicians with up-to-date and practical guidance by keeping pace with rapid scientific developments.
📚 In this article, we will delve into ASCO’s updated 2025.1 version of the living guideline published on July 17, 2025, for Stage IV NSCLC patients without driver mutations, as well as the key clinical trials that shaped this update, including NIPPON, HARMONI-2, and DUBLIN-3.
We will also discuss how these new findings reflect in our treatment strategies and their potential impact on patient management.
1. 🕒 Evolution of the Treatment Paradigm: Timeline
- 2016: KEYNOTE-024: Pembrolizumab vs chemotherapy — showed superiority in PD-L1 positive patients.
- 2019: KEYNOTE-042: Pembrolizumab compared to chemotherapy in a broader PD-L1 positive NSCLC population.
- 2021: CheckMate 9LA: First triple regimen data: nivolumab + ipilimumab + 2 cycles of chemotherapy.
- 2022: ASCO Living Guidelines launched — separate roadmaps for Stage IV NSCLC with or without driver mutations.
- 2023: Guideline updates: versions 2022.2, 2022.3, 2023.1, and 2023.2 released.
- 2024: Guidelines updated with versions 2023.3 and 2024.1.
- June 2024: DUBLIN-3 study published.
- September 2024: NIPPON (JCOG2007) study concluded.
- April 10, 2024: Drafting date for the ASCO guideline article (Owen et al.).
- March 10, 2025: Literature review completion date.
- April 23, 2025: Approval by ASCO’s Evidence-Based Medicine Committee.
- March 2025: HARMONi-2 Phase III study published.
- June 10, 2025: ASCO guideline article accepted for publication.
- July 17, 2025: ASCO Living Guideline version 2025.1 (Owen et al.) published: updated treatment recommendations for Stage IV NSCLC without driver mutations.
2. First-Line Immunotherapy Comparison: What Does the NIPPON Study Say?
The NIPPON (JCOG2007) study is the first Phase III trial directly comparing two immunotherapy combinations in patients with Stage III–IV NSCLC without driver mutations.
💉 Compared Regimens
- Pembrolizumab arm: 4 cycles of carboplatin-based chemotherapy + pembrolizumab → followed by pembrolizumab maintenance (up to 2 years)
- Nivolumab + ipilimumab arm: 2 cycles of carboplatin-based chemotherapy + nivolumab (q3w) + ipilimumab (q6w) → followed by dual immunotherapy maintenance
📊 Efficacy Outcomes
| Outcome | Pembrolizumab | Nivo + Ipi | Comment |
|---|---|---|---|
| Overall survival (OS) | 20.5 months | 23.7 months | Not statistically significant (p = 0.46) |
| Progression-free survival (PFS) | 7.4 months | 6.0 months | Favors pembrolizumab |
| Objective response rate (ORR) | 65% | 55% | Favors pembrolizumab |
⚠️ Safety Findings
| Safety Metric | Nivo + Ipi | Pembrolizumab | Comment |
|---|---|---|---|
| Grade ≥3 non-hematologic adverse events | 60% | 41% | More toxic with Nivo + Ipi |
| Treatment-related death | 7% (11/148) | 2% (3/144) | Careful patient selection needed |
According to ASCO 2025.1 update: The combination of nivolumab + ipilimumab + chemotherapy is supported by only moderate-quality evidence.
3. Is a New Agent on the Horizon? The HARMONi-2 Trial and Ivonescimab
HARMONi-2 is a randomized, double-blind, Phase III first-line trial conducted in China. This study directly compared the standard treatment pembrolizumab with a new agent called ivonescimab in patients with advanced or metastatic NSCLC who were PD-L1 positive (≥1%) and EGFR/ALK wild-type.
- Number of participants: 398 patients
- Compared treatments: Ivonescimab (anti–PD-1 + anti–VEGF bispecific antibody) vs Pembrolizumab (anti–PD-1 monotherapy)
📈 Clinical Efficacy: Progression-Free Survival (PFS)
| Treatment Arm | Median PFS | HR (95% CI) |
|---|---|---|
| Ivonescimab | 11.1 months | 0.51 (0.38–0.69) |
| Pembrolizumab | 5.8 months | P < .0001 |
This significant improvement in PFS was maintained in subgroup analyses according to histologic subtypes and PD-L1 expression levels, consistently favoring ivonescimab.
⚠️ Adverse Event Profile
| Adverse Event | Ivonescimab | Pembrolizumab | Comment |
|---|---|---|---|
| Grade ≥3 adverse events | 29% | 16% | Ivonescimab more toxic |
| Immune-related AEs | 30% | 28% | Similar |
| Serious immune-related AEs | 6% | 11% | Lower with Ivonescimab |
According to the ASCO 2025.1 guideline, ivonescimab is not yet recommended for routine clinical use. Key reasons include the non-global patient population, immature OS data, and unexpectedly short PFS in the pembrolizumab arm.
4. A New Option in Second-Line Therapy? The DUBLIN-3 Trial and Plinabulin
The DUBLIN-3 trial is a Phase III, single-blind, randomized study comparing docetaxel + plinabulin vs docetaxel + placebo in patients with EGFR wild-type NSCLC who progressed after first-line platinum-based chemotherapy.
Plinabulin is an experimental agent described as a tubulin polymerization inhibitor with both anti-tumor and immunomodulatory effects, aiming to boost immune response through dendritic cell activation.
- Total number of patients: 559
📊 Clinical Efficacy: Overall Survival (OS)
| Treatment Arm | Median OS | HR (95% CI) |
|---|---|---|
| Docetaxel + Plinabulin | 10.5 months | 0.82 (0.68–0.99) |
| Docetaxel + Placebo | 9.4 months | Reference |
Although the plinabulin arm showed an absolute increase of approximately 1.1 months in OS, the statistical significance was borderline.
⚠️ Safety Data and Study Limitations
| Assessment | Plinabulin Arm | Placebo Arm | Comment |
|---|---|---|---|
| Grade ≥3 adverse events | 33.1% | 42% | Better tolerated with plinabulin |
| Pre-immunotherapy patient rate | 20% | Most patients had not received immunotherapy | |
According to the ASCO guideline, although the DUBLIN-3 trial shows promise for plinabulin, the limited generalizability of the findings to today’s second-line patient population—due to the low rate of prior immunotherapy—means routine recommendation has not been made for plinabulin.
5. New Targets, Clear Messages: Other Highlights and Future Perspectives
The ASCO 2025.1 Living Guideline not only summarizes the innovations in first- and second-line treatments for NSCLC without driver mutations, but also highlights certain subgroups and areas for future research.
🎯 Importance of Subgroups: HER2 Overexpression
In NSCLC patients with high HER2 protein expression, trastuzumab deruxtecan has emerged as a "weakly recommended" second-line treatment option.
This demonstrates that even in patients presumed to be without driver mutations, identifying molecular subgroups can influence treatment decisions.
📌 However, this treatment option is not comprehensively included in the 2025.1 update and is mentioned here for reference purposes only.
💡 Other Key Messages Highlighted in the Guideline
- Palliative care: Supportive approaches integrated into the patient’s treatment should begin early and be an integral part of the care process.
- Patients ineligible for immunotherapy: Platinum-based chemotherapy regimens remain a valid and effective first-line option.
🔬 What’s Missing? Which Questions Remain?
Future research is expected to focus particularly on the following areas:
- Head-to-head comparisons of different immunotherapy regimens
- Testing next-generation molecules in resistant or progressing patient subgroups
🔍 Access to clinical trials is a fundamental priority in achieving treatment equity. It is emphasized that every patient has the right to participate in such studies.
📌 Key Messages From the ASCO 2025.1 Living Guideline Update: What Should Shape Treatment Choices?
🧩 1. How Reasonable Is the Nivolumab + Ipilimumab Combination?
Finding: The NIPPON study showed that this triple regimen did not offer a clear advantage over pembrolizumab + chemotherapy and was associated with more severe adverse events.
What Does This Mean?
- ➡ This combination (nivolumab + ipilimumab + 2 cycles of chemotherapy) should be considered only in carefully selected patients.
- ➡ May be an option for young, low-comorbidity patients with potentially strong immune responses.
🔖 Guideline Status: Offered as a weak recommendation.
🧪 2. Is Ivonescimab Truly More Effective?
Finding: Ivonescimab significantly improved PFS (11.1 vs. 5.8 months), but results are based solely on data from China and OS data is not yet mature.
What Does This Mean?
- ➡ Promising results, but it is still too early for clinical adoption.
- ➡ While a new agent seems to be on the horizon, pembrolizumab remains the safer, guideline-approved choice for now.
💊 3. Can Plinabulin Be a Second-Line Alternative?
Finding: The DUBLIN-3 trial showed a modest OS benefit with plinabulin + docetaxel versus placebo.
What Does This Mean?
- ➡ Efficacy is limited and the study population was from the pre-immunotherapy era.
- ➡ Most second-line patients today have already received immunotherapy, so the data has limited relevance to current practice.
🔍 4. What Should Guide Treatment Selection?
Finding: Treatment decisions should always consider immunotherapy eligibility, PD-L1 expression level, histology, and comorbidities.
What Does This Mean?
- ➡ For patients with high PD-L1 expression, pembrolizumab monotherapy remains a strong option.
- ➡ In low or negative PD-L1 settings, chemoimmunotherapy combinations should be preferred.
- ➡ For immunotherapy-ineligible patients, platinum-doublet chemotherapy is still the most reliable approach.
Dwight H. Owen et al. Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1. JCO 0, JCO-25-01062 DOI:10.1200/JCO-25-01062
