The treatment of advanced stage IV non-small-cell lung cancer (NSCLC) has evolved dramatically in the past decade. In order to keep pace with advancing therapies, the American Society of Clinical Oncology (ASCO) has published a Living Guidelines series for NSCLC to ensure timely clinical practice updates. These guidelines, launched in 2022, are updated regularly by a standing expert panel that systematically reviews the health literature on a continuing basis.
Building upon the original 2020 recommendations, this article summarizes key changes in the ASCO Living Guidelines (2022-2025) regarding systemic therapy for stage IV NSCLC patients without driver alterations. The progression of evidenced-based treatments tailored for select cancer subtypes over time are highlighted here. Pharmacological interventions include chemotherapy, immunotherapy and other therapies used alone or in combination.
Guidelines Referenced
- Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3
- Publication: February 27, 2025
- Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3 | Journal of Clinical Oncology
- Publication: February 28, 2024
- Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.1 | Journal of Clinical Oncology
- Publication: April 6, 2023
- Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline
- Publication: July 11, 2022
- Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update
- Publication: January 28, 2020
Snapshot of Changes and Newly Added Recommendations from the ASCO January 2020 Guideline
| 2022 Recommendation Updates | 2023 Recommendation Updates | Takeaways | |
|---|---|---|---|
| Patients with high PD-L1 expression (TPS ≥ 50%), nonsquamous cell carcinoma (non-SCC) and PS (0-1): | - Clinicians may offer the single-agent atezolizumab (1.5). - Clinicians may offer single-agent cemiplimab (1.6). - Clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (1.7). | - no update | -The January 2020 guideline offered no treatment recommendation for patients with high PD-L1 expression and non-SCC, due to lack of data regarding the first-line use of immune checkpoint inhibitors (other than pembrolizumab) as single agents, combined, or with chemotherapy. - Based on supporting evidence, the July 2022 guideline expanded treatment recommendations for the use of checkpoint inhibitors by adding atezolizumab as a treatment option. - The July 2022 guideline broadened treatment recommendations even further by adding cemiplimab for use as a single agent, and the use of nivolumab and ipilimumab (CTLA-4 inhibitor) as standalone treatments or in combination with traditional chemotherapy. |
| Patients with negative (TPS 0%) and low positive (TPS 1% to 49%) PD-L1 expression, non-SCC and PS 0-1: | - Clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (2.7). | - Clinicians may offer cemiplimab plus chemotherapy (2.8). - Clinicians may offer combination durvalumab and tremelimumab plus platinum-based chemotherapy (2.9). | - Both the July 2022 and April 2023 guidelines added new treatment recommendations to the original January 2020 guideline for patients with negative (TPS 0%) and low positive (TPS 1% to 49%) PD-L1 expression with non-SCC. - The July 2022 treatment recommendations for this patient population added nivolumab and ipilimumab used either alone or combined together with traditional chemotherapy. - The April 2023 guideline built on this list of treatment options with the addition of cemiplimab combined with traditional chemotherapy. A new treatment regimen was also added, combining traditional chemotherapy with the checkpoint inhibitor durvalumab and the CTLA-4 inhibitor tremelimumab. |
| Patients with high PD-L1 expression (TPS ≥ 50%), squamous cell carcinoma (SCC), and PS 0-1: | - Clinicians may offer single-agent atezolizumab (3.3). - Clinicians may offer single-agent cemiplimab (3.4). - Clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (3.5). | - no update | - The January 2020 guideline offered no treatment recommendation for patients with high PD-L1 expression and non-SCC, due to lack of data regarding the first-line use of immune checkpoint inhibitors (other than pembrolizumab) as single agents, combined, or with chemotherapy. - Based on supporting evidence, the July 2022 guideline expanded treatment recommendations for the use of checkpoint inhibitors by adding atezolizumab as a treatment option for this patient population. - The July 2022 guideline also added cemiplimab to the list of treatment options, as well as nivolumab and ipilimumab for use as single agents or combined together with traditional chemotherapy. |
| Patients with negative (TPS 0%) and low positive (TPS 1%-49%) PD-L1 expression, SCC, and PS 0-1: | - Clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy (4.5). | - Clinicians may offer cemiplimab plus chemotherapy (4.6). | - Both the July 2022 and April 2023 guidelines broadened treatment recommendations from the original January 2020 guideline for patients with negative (TPS 0%) and low positive (TPS 1% to 49%) PD-L1 expression with SCC. - The July 2022 treatment recommendation for this patient population added nivolumab and ipilimumab used either alone or combined together with traditional chemotherapy, while the April 2023 guideline expanded the list of treatment options with the addition of cemiplimab plus chemotherapy. |
Newly Added Recommendation From 2024 to 2025
- Patients with good performance status, previously treated with chemotherapy and immune checkpoint therapy:
- Clinicians may offer trastuzumab deruxtecan for patients with human epidermal growth factor receptor 2 (HER2)–overexpressing NSCLC defined as HER2 (IHC) 3+ gastric scoring (5.3).
- Takeaways:
- The February 2025 guideline built upon the February 2024 guideline by recommending a novel HER2-targeted antibody-drug conjugate for patients with HER2 receptor overexpression. This new treatment regimen combines trastuzumab (a monoclonal antibody targeting HER2 receptors) and deruxtecan (a newer generation chemotherapeutic agent).
The treatment of Stage IV NSCLC without driver alterations has evolved rapidly over time and continues to advance with new therapeutic options. While there is no cure for stage IV NSCLC without driver alterations, newly added treatments from 2020 to 2025 have greatly increased the number of targeted treatment options for these patients. We expect that these and future therapies will improve patient outcomes by increasing precision, reducing toxicity, controlling disease progression, and enhancing survival.
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