What are the treatment options for stage IVa M1a lung adenocarcinoma?

Treatment Options for Stage IVa M1a Lung Adenocarcinoma

For stage IVa M1a lung adenocarcinoma, treatment selection must be driven by molecular testing results and PD-L1 expression status, with targeted therapy prioritized for driver alterations and immunotherapy-based combinations for driver-negative disease. 1

Essential First Step: Comprehensive Molecular Testing

Biomarker testing with tissue and/or blood-based broad multi-gene panel and PD-L1 immunohistochemistry should be performed universally before initiating treatment. 1

• Test for actionable driver alterations: EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, MET exon 14 skipping mutations, RET rearrangements, NTRK rearrangements, and HER2 alterations 1
• Combination of blood and tissue testing maximizes detection of molecular alterations, though tissue testing allows histologic assessment and should be attempted when feasible 1
• PD-L1 expression by immunohistochemistry guides immunotherapy selection 1

Treatment Algorithm Based on Molecular Profile

For Driver Alteration-Positive Disease

Targeted therapy with tyrosine kinase inhibitors should be offered as first-line treatment for patients with identified driver alterations, as these provide superior outcomes compared to chemotherapy. 1

EGFR Exon 19 Deletion or L858R Mutations:

• Osimertinib is the preferred first-line agent 1
• Alternative options include amivantamab plus lazertinib, or osimertinib plus chemotherapy, though these combinations increase toxicity (75% and 64% grade ≥3 toxicities respectively versus 43% and 27% with osimertinib alone) 1
• Balance efficacy with toxicity when discussing combination therapies, incorporating patient goals, preferences, and comorbidities 1

ALK Rearrangements:

• Offer ALK tyrosine kinase inhibitors as first-line therapy 1
• Crizotinib is an established option 1

ROS1 Rearrangements:

• Crizotinib should be offered 1

BRAF V600E Mutations:

• Offer dabrafenib and trametinib, or encorafenib and binimetinib 1
• If unavailable, follow standard first-line therapy for non-driver alteration disease 1

MET Exon 14 Skipping Mutations:

• Offer capmatinib or tepotinib 1
• If unavailable, follow standard first-line therapy guidelines 1

RET Rearrangements:

• Selpercatinib should be offered as first-line therapy 1
• If unavailable, pralsetinib may be offered 1

NTRK Rearrangements:

• Offer entrectinib or larotrectinib 1

For Driver Alteration-Negative Disease

Treatment selection depends on PD-L1 tumor proportion score (TPS) and performance status, with immunotherapy-based regimens preferred for most patients. 1

PD-L1 TPS ≥50%:

• Single-agent pembrolizumab, cemiplimab, or atezolizumab should be offered 1
• Alternative options include pembrolizumab plus carboplatin plus pemetrexed, or cemiplimab plus carboplatin plus pemetrexed 1
• Atezolizumab plus carboplatin plus nab-paclitaxel with or without bevacizumab may be offered (in absence of bevacizumab contraindications) 1
• Nivolumab plus ipilimumab, or nivolumab plus ipilimumab plus two cycles of platinum-based chemotherapy may be offered 1
• Durvalumab plus tremelimumab plus platinum-based chemotherapy may be offered 1

PD-L1 TPS 1-49%:

• Pembrolizumab plus carboplatin plus pemetrexed, or cemiplimab plus carboplatin plus pemetrexed should be offered 1
• Alternative options include atezolizumab plus carboplatin plus (nab)-paclitaxel ± bevacizumab 1
• Nivolumab plus ipilimumab, nivolumab plus ipilimumab plus two cycles of platinum-based chemotherapy, or durvalumab plus tremelimumab plus platinum-based chemotherapy may be offered 1
• For patients ineligible for or declining combination doublet platinum with anti-PD-(L)1, single-agent anti-PD-1 may be offered 1

PD-L1 TPS <1% or Unknown:

• Pembrolizumab plus carboplatin plus pemetrexed, or cemiplimab plus carboplatin plus pemetrexed may be offered 1
• Alternative options include atezolizumab plus carboplatin plus (nab)-paclitaxel ± bevacizumab, nivolumab plus ipilimumab, nivolumab plus ipilimumab plus two cycles of platinum-based chemotherapy, or durvalumab plus tremelimumab plus platinum-based chemotherapy 1

Bevacizumab Addition:

• Adding bevacizumab to carboplatin plus paclitaxel is recommended for nonsquamous histology if no contraindications exist (excluding brain metastases, hemoptysis, therapeutic anticoagulation, significant cardiovascular disease, or uncontrolled hypertension) 1
• For patients with treated, stable brain metastases who are otherwise candidates, bevacizumab addition to first-line platinum-based chemotherapy is safe 1

Performance Status Considerations

For patients with ECOG performance status 2, combination or single-agent chemotherapy or palliative care alone may be used. 1

• Chemotherapy decisions should not be based on age alone 1
• For elderly patients (age 70-79 years) with good performance status and limited comorbidities, monthly carboplatin plus weekly paclitaxel is recommended 1

Treatment Duration and Maintenance

First-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients with nonresponsive stable disease. 1

• For patients with stable disease or response after four cycles of pemetrexed-containing regimen, pemetrexed continuation maintenance may be used 1
• If initial regimen does not contain pemetrexed, switch maintenance chemotherapy may be used, or a break from chemotherapy until disease progression may be recommended 1
• Switch maintenance pemetrexed is suggested for nonsquamous NSCLC patients not experiencing disease progression after four cycles of platinum-based therapy (not including pemetrexed) 1
• Maintenance erlotinib is suggested for patients not experiencing disease progression after four cycles of platinum-based double agent chemotherapy 1

Essential Concurrent Care

Patients with advanced lung cancer should be referred to interdisciplinary palliative care teams that provide outpatient and inpatient care early in the course of disease, alongside active treatment of their cancer. 1, 2

• Palliative care improves quality of life, mood, and potentially survival 2
• Early palliative care consultation is a strong recommendation with high-quality evidence 1

Common Pitfalls to Avoid

• Never use PD-L1 immunohistochemistry alone to guide treatment decisions 1
• Do not add anti-PD-(L)1 agents with or without platinum chemotherapy for patients with EGFR mutations who progress on EGFR TKI, as multiple phase III trials showed no benefit 1
• Avoid three-drug cytotoxic chemotherapy combinations, as they provide no survival benefit and may be harmful 1
• Do not use switch maintenance chemotherapy agents other than pemetrexed, as they have not demonstrated overall survival improvement 1
• Ensure molecular testing is complete before initiating therapy, as the false negative rate of liquid biopsy must be considered 1

Special Considerations for M1a Disease

Stage IVa M1a disease includes separate tumor nodules in a contralateral lobe, or tumor with pleural or pericardial nodules or malignant effusion 1

• Malignant pleural or pericardial effusion requires pathologic confirmation through thoracentesis or pericardiocentesis 1
• In absence of nonmalignant causes, exudate or sanguinous effusion is considered malignant regardless of cytologic examination results 1
• Local therapy for effusions (ambulatory small catheter drainage, pleurodesis, pericardial window) should be considered alongside systemic therapy 1