Therapy for Stage IV Non-Small Cell Lung Cancer (NSCLC) With Driver Alterations
A living guideline by ASCO.
These guideline summaries are shared for educational purposes only and are not intended to direct patient care. For detail on the specific recommendations and information about the evidence considered by the guideline developer, we encourage you to go to the original guideline statement cited below.
First-line Treatment Based on Driver Alteration
Biomarker testing with a validated tissue and/or blood-based broad multi-gene panel and a validated tissue immunohistochemistry (IHC) assay for PD-L1, HER2, and MET protein expression should be universally accessible for all patients diagnosed with NSCLC.
Clinicians should offer osimertinib with platinum-pemetrexed chemotherapy or amivantamab plus lazertinib.
Clinicians should offer osimertinib to patients not pursuing combination therapy.
For patients unable to access osimertinib, lazertinib monotherapy may be offered as an alternative treatment option if available.
For other activating EGFR alterations (G719X, L861Q, S768I), clinicians may offer afatinib.
For other activating EGFR alterations (G719X, L861Q, S768I), clinicians may offer amivantamab plus lazertinib.
For other activating EGFR alterations (G719X, L861Q, S768I), clinicians may offer osimertinib.
Clinicians should offer sunvozertinib monotherapy, or combination treatment with platinum doublet 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.
Clinicians should offer lorlatinib.
Clinicians should offer alectinib, brigatinib, or ensartinib when lorlatinib is unsuitable because of anticipated toxicity, comorbidities, patient preferences, or access limitations, or when treatment-emergent toxicity remains unacceptable despite appropriate management, including dose modification when clinically appropriate.
If alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib.
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.
Clinicians may offer dabrafenib and trametinib, or encorafenib and binimetinib.
Clinicians may offer capmatinib or tepotinib.
Clinicians should offer selpercatinib.
If selpercatinib is not available, clinicians may offer pralsetinib.
Clinicians may offer entrectinib, larotrectinib, or repotrectinib.
Clinicians may offer zongertinib.
For patients with a performance status (PS) >2, tyrosine kinase inhibitor (TKI) 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 and Subsequent Treatment Based on Driver Alteration
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 the above recommendation, platinum-based chemotherapy may be offered with or without osimertinib.
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, anti-PD-(L)1 agents with or without platinum chemotherapy are not recommended.
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 whose cancer develops EGFR T790M resistance alterations in tumor after first- or second-generation EGFR TKIs, clinicians should offer osimertinib.
For patients who have received prior treatment with platinum chemotherapy, clinicians may offer treatment with amivantamab or sunvozertinib.
For patients who have received prior treatment with platinum chemotherapy and amivantamab, clinicians may offer treatment with sunvozertinib.
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.
For patients who have previously received crizotinib, entrectinib, lorlatinib, or ceritinib, clinicians may offer repotrectinib or taletrectinib.
For patients who have not received BRAF therapy, clinicians may offer dabrafenib and trametinib, or encorafenib and binimetinib.
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 MET-targeted therapy, clinicians may offer capmatinib or tepotinib.
For patients who have not received a RET inhibitor, clinicians should offer selpercatinib or pralsetinib.
For patients who have not received an NTRK inhibitor, clinicians should offer entrectinib, larotrectinib, or repotrectinib.
For patients that have received a prior NTRK inhibitor, clinicians may offer repotrectinib.
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.
Clinicians may offer treatment with sotorasib or adagrasib.
Clinicians may offer treatment with zenocutuzumab.