The American Society of Clinical Oncology (ASCO) recently released an update to their living guideline, Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations. This guideline update comes nearly two years after the last full guideline update, published in February 2024. In the 2026 update, ASCO updated the guideline based on its systematic review process, which included a review of randomized controlled trials spanning March through October of 2025.
The 2026 guideline, similar to the 2024 version, is largely split into first-line and second-line therapy recommendations. In the comparison table featured below, a notation row is added, differentiating the first-line section from the second-line section.
Key Elements of the 2026 ASCO NSCLC With Driver Alterations Update
The biomarker testing section was expanded, including recommendations for using both tissue- and blood-based testing, based on strong data that showed better overall survival and more cost-effective care through complete molecular profiling before starting first-line therapy.
Recommendation 1.1 was also updated to specify the inclusion of platinum-pemetrexed chemotherapy or amivantamab plus lazertinib to the use of osimertinib for typical EGFR mutation, based on the results of the phase 3 FLAURA2 and MARIPOSA trials.
Regarding recommendation 1.2 in the 2026 version, in consideration of the higher toxicity, longer infusion time, and increased treatment frequency, ASCO recommends that osimertinib monotherapy is a reasonable option for patients not interested in treatment intensification or for patients with poor performance status.
For second-line therapy, the EGFR section received some notable updates. Based on the phase 3 MARIPOSA-2 trial, ASCO recommends amivantamab plus chemotherapy after progression on osimertinib. For patients not candidates for the aforementioned combination, a new recommendation was added. This recommendation recommends platinum-based chemotherapy with or without continuation of osimertinib, and the continuation of osimertinib alongside chemotherapy was also recommended. Additional updates to the second-line EGFR recommendations, and more, are outlined in the following table.
The 2026 update identified the guideline published in 2024 as the last full version of the ASCO stage IV NSCLC with DA published before the current version. So we will compare the latest version to that version.
To view the complete living guideline, view the full-text version.
Comparison of Recommendations
| Item | 2024 Guideline (2023.3) | 2026 Guideline (2026.3.0) |
|---|---|---|
| First-Line Therapy | ||
| Biomarker Testing | Comprehensive genomic biomarker test results should be available and used to guide treatment. | Biomarker testing with a validated tissue and/or blood-based broad multigene panel and a validated tissue IHC assay for PD-L1, HER2, and MET protein expression should be universally accessible for all patients diagnosed with NSCLC. |
| EGFR | Clinicians should offer osimertinib. For other activating EGFR alterations, (G719X, L861Q, S768I), clinicians may offer afatinib or osimertinib or standard treatment following the non-driver alteration guideline. For any activating EGFR alteration, regardless of PD-L1 expression levels (including exon 20 insertions), single-agent immune checkpoint inhibitors should not be offered as first-line therapy. Clinicians may offer chemotherapy and amivantamab. If amivantamab is not available, clinicians should offer standard treatment following the non-driver alteration guideline. | Clinicians should offer osimertinib with platinum-pemetrexed chemotherapy or amivantamab plus lazertinib. Clinicians should offer osimertinib to patients not pursuing combination therapy. For other activating EGFR alterations (G719X, L861Q, S768I), clinicians may offer afatinib or osimertinib. Clinicians should offer chemotherapy plus amivantamab. For any activating EGFR alteration, regardless of PD-L1 expression levels, single-agent immune checkpoint inhibitors should not be offered as first-line therapy. |
| ALK | Clinicians should offer alectinib or brigatinib or lorlatinib. If alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. | Clinicians should offer alectinib or brigatinib or lorlatinib. If alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. |
| ROS1 | Clinicians may offer crizotinib or entrectinib. If crizotinib or entrectinib are not available or not tolerated, clinicians may offer ceritinib or lorlatinib. | Clinicians may offer crizotinib, entrectinib, repotrectinib, or taletrectinib. If crizotinib, entrectinib, repotrectinib, or taletrectinib are not available or tolerated, clinicians may offer ceritinib or lorlatinib. |
| BRAFV600E | Clinicians may offer dabrafenib and trametinib, or encorafenib and binimetinib. If dabrafenib and trametinib, or encorafenib and binimetinib are not available, clinicians may offer standard first-line therapy following the non-driver alteration guideline. | Clinicians may offer dabrafenib and trametinib, or encorafenib and binimetinib. |
| MET exon 14 skipping mutation | Clinicians may offer capmatinib or tepotinib. If capmatinib or tepotinib is not available, clinicians may offer standard first-line therapy following the non-driver alteration guidelines. | Clinicians may offer capmatinib or tepotinib. |
| RET rearrangement | Clinicians should offer selpercatinib. If selpercatinib is not available, clinicians may offer pralsetinib. If selpercatinib or pralsetinib are not available, clinicians may offer standard therapy following the non-driver alteration guideline. | Clinicians should offer selpercatinib. If selpercatinib is not available, clinicians may offer pralsetinib. |
| NTRK rearrangement | Clinicians may offer entrectinib or larotrectinib. If entrectinib or larotrectinib are not available, clinicians may offer standard therapy following the non-driver alteration guideline. | Clinicians may offer entrectinib or larotrectinib. |
| General Approaches | For patients with a poor PS, tyrosine kinase inhibitor may be offered based on drug access and toxicity profile. Patients with advanced lung cancer should be referred to interdisciplinary palliative care teams (consultation) that provide inpatient and outpatient care early in the course of disease, alongside active treatment of their cancer. | For patients with a PS >2, tyrosine kinase inhibitor may be offered based on drug access and toxicity profile and based on clinician evaluations that the benefit outweighs the risk. Patients with advanced lung cancer should be referred to interdisciplinary palliative care teams (consultation) that provide inpatient and outpatient care early in the course of disease, alongside active treatment of their cancer. |
| Second-Line Therapy | ||
| EGFR | For patients that develop EGFR T790M resistance alterations in tumor after first- or second-generation EGFR TKIs, clinicians should offer osimertinib. For patients who have progressed on osimertinib or other EGFR TKIs without emergent T790M or other targetable alterations, clinicians should offer platinum-based chemotherapy following the non-driver alteration guideline. For patients with an exon 20 insertion alteration who have received prior treatment with platinum chemotherapy, clinicians may offer treatment with amivantamab. | For patients whose cancer develops EGFR T790M resistance alterations in tumor after first- or second-generation EGFR TKIs, clinicians should offer osimertinib. For patients who have progressive disease on osimertinib (or other third-generation TKI), clinicians may offer platinum-based chemotherapy with amivantamab. For patients who are not candidates for Recommendation 2.2, platinum-based chemotherapy may be offered with or without osimertinib. For patients who have progressive disease on EGFR TKI, anti–PD-(L)1 agents with or without platinum chemotherapy are not recommended. For patients whose disease has progressed on osimertinib and platinum chemotherapy, clinicians may offer datopotamab deruxtecan. For patients who have progressive disease on EGFR TKI with acquired MET amplification, clinicians may offer osimertinib in combination with tepotinib or savolitinib. For patients with an exon 20 insertion alteration who have received prior treatment with platinum chemotherapy, clinicians may offer treatment with amivantamab or sunvozertinib. For patients with an exon 20 insertion alteration who have received prior treatment with platinum chemotherapy and amivantamab, clinicians may offer treatment with sunvozertinib. |
| ALK | For patients who have previously received crizotinib, clinicians should offer alectinib, brigatinib, or ceritinib and may offer lorlatinib. For patients who have previously received other ALK inhibitors including alectinib or brigatinib, clinicians may offer lorlatinib. | For patients who have previously received crizotinib, clinicians should offer alectinib, brigatinib, lorlatinib, or ceritinib. For patients who have previously received other ALK inhibitors including alectinib or brigatinib, clinicians may offer lorlatinib. |
| ROS1 | For patients who have previously received crizotinib or entrectinib or ceritinib, clinicians may offer lorlatinib. Clinicians should offer platinum-based chemotherapy following the non-driver alteration guideline. | For patients who have previously received crizotinib, entrectinib, lorlatinib, or ceritinib, clinicians may offer repotrectinib or taletrectinib. |
| BRAFV600E | For patients who have not received BRAF therapy, clinicians may offer dabrafenib and trametinib or encorafenib and binimetinib. For patients who have previously received BRAF or MEK targeted therapy, clinicians should offer standard first-line therapy following the non-driver alteration guideline. For BRAF alterations other than BRAF V600E alterations, clinicians should offer standard therapy following the non-driver alteration guideline. | For patients who have not received BRAF therapy, clinicians may offer dabrafenib and trametinib, or encorafenib and binimetinib. For BRAF alterations other than BRAFV600E alterations, clinicians should offer standard therapy following the nondriver alteration guideline. |
| MET exon 14 skipping mutation | For patients who have not received MET-targeted therapy, clinicians may offer capmatinib or tepotinib. For patients previously treated with MET-targeted therapy, clinicians should offer standard therapy following the non-driver alteration guideline. | For patients who have not received MET-targeted therapy, clinicians may offer capmatinib or tepotinib. |
| RET rearrangement | For patients who have not received a RET inhibitor, clinicians should offer selpercatinib or pralsetinib. If selpercatinib or pralsetinib is not available, clinicians may offer treatment following the non-driver alteration guideline. | For patients who have not received a RET inhibitor, clinicians should offer selpercatinib or pralsetinib. |
| NTRK rearrangement | For patients who have not received an NTRK inhibitor, clinicians should offer entrectinib or larotrectinib. If entrectinib or larotrectinib is not available, clinicians may offer standard therapy following the non-driver alteration guideline. | For patients who have not received an NTRK inhibitor, clinicians should offer entrectinib or larotrectinib. |
| HER2 exon 20 mutations | Clinicians may offer treatment with trastuzumab deruxtecan. | Clinicians may offer treatment with trastuzumab deruxtecan or zongertinib or sevabertinib. For patients who have previously received trastuzumab deruxtecan, clinicians may offer sevabertinib or zongertinib. |
| KRAS G12C | Clinicians may offer treatment with sotorasib. Clinicians may offer treatment with adagrasib. | Clinicians may offer treatment with sotorasib or adagrasib. |
| NRG1 fusion | N/A | Clinicians may offer treatment with zenocutuzumab. |
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