What are the first, second, and third lines of systemic therapy for a patient with pleural mesothelioma?

Systemic Therapy for Pleural Mesothelioma

First-Line Therapy

For patients with newly diagnosed nonepithelioid mesothelioma (biphasic or sarcomatoid), ipilimumab plus nivolumab should be offered as first-line systemic therapy for up to 2 years in the absence of disease progression or intolerable toxicity. 1

For patients with newly diagnosed epithelioid mesothelioma, pembrolizumab combined with pemetrexed plus platinum-based chemotherapy may be offered as first-line therapy for up to 2 years. 1

Standard First-Line Options by Histology

Nonepithelioid histology (biphasic/sarcomatoid):

• Ipilimumab plus nivolumab is the preferred regimen, given up to 2 years regardless of PD-L1 status 1
• This represents a paradigm shift based on superior outcomes in this historically poor-prognosis subgroup 1

Epithelioid histology:

• Pembrolizumab with pemetrexed plus platinum (cisplatin or carboplatin) for up to 2 years 1
• Alternative: Nivolumab plus ipilimumab (also effective regardless of histology or PD-L1 status) 1
• Alternative: Pemetrexed plus cisplatin (Category 1 evidence, median OS 12.1 months) 1
• Alternative: Pemetrexed plus carboplatin (preferred for poor performance status or comorbidities, median OS 12.7-14 months) 1, 2
• Alternative: Bevacizumab plus cisplatin/pemetrexed (only for patients without bevacizumab contraindications) 1

Critical Implementation Details

All pemetrexed-based regimens require mandatory vitamin supplementation:

• Vitamin B12 1000 μg intramuscularly starting at least 1 week before first dose, then every 9 weeks 2, 3
• Folic acid 0.4-1.0 mg orally daily, starting at least 1 week before first dose and continuing throughout treatment 2, 3

Treatment duration:

• Administer 4-6 cycles of chemotherapy-based regimens 1, 2
• Immunotherapy can continue up to 2 years if no progression or intolerable toxicity 1

Special consideration for asymptomatic patients:

• Those with minimal pleural disease who are not surgical candidates may be offered close observation before initiating systemic therapy 1, 2
• Chemotherapy should be planned at time of symptomatic or radiographic progression 1

Second-Line Therapy

For patients previously treated with chemotherapy who are immunotherapy-naïve, single-agent nivolumab is superior to best supportive care and represents the standard second-line option. 1

Second-Line Options Based on Prior Treatment

If first-line was chemotherapy (immunotherapy-naïve):

• Single-agent nivolumab (superior to best supportive care) 1
• Single-agent pembrolizumab (similar outcomes to single-agent chemotherapy) 1
• Combination nivolumab-ipilimumab can be considered 1

If first-line was immunotherapy:

• Pemetrexed plus platinum-based chemotherapy can be reintroduced in patients with durable response (>6 months) to first-line pemetrexed-based therapy 1
• Single-agent pemetrexed has second-line activity in selected circumstances 1
• Single-agent gemcitabine or vinorelbine (limited activity, ORR-based evidence) 1
• Gemcitabine-ramucirumab combination shows encouraging activity 1

Retreatment with immunotherapy:

• May be offered to patients with initial disease control whose disease progressed after completing treatment 1
• Discontinue if severe immunotherapy-related toxicities occurred 1

Second-Line Clinical Outcomes

• Median PFS: 3.7 months 4
• Median OS: 7.2 months 4
• Disease control rate: 83% 4
• Patients who achieved PFS ≥6 months at first-line should be prioritized for second-line treatment 4

Third-Line Therapy

There is no evidence basis for routine third-line therapy in malignant pleural mesothelioma, and clinical trial participation should be strongly considered. 1

Limited Third-Line Options

For highly selected patients:

• Retreatment with pemetrexed-based chemotherapy may be considered if patient had prolonged response (>6 months) to prior pemetrexed therapy 4
• Patients who responded to first-line therapy and achieved PFS >6 months may benefit from third-line treatment 5
• Median OS in responders to first-line who received third-line: 28.9 months versus 17.8 months in non-responders 5

Critical caveat: The evidence for third-line therapy is extremely limited, derived primarily from retrospective analyses rather than prospective trials 1, 4, 5. Clinical trial enrollment remains the preferred approach at this stage.

Important Contraindications and Performance Status Considerations

Absolute contraindications:

• Severe renal impairment for pemetrexed-based regimens 2

Performance status considerations:

• PS 0-2: Eligible for standard combination regimens 1
• PS 2: Consider single-agent pemetrexed, vinorelbine, or gemcitabine (expect low response rates) 1
• PS 3-4: Best supportive care recommended; chemotherapy not recommended 1, 2

Maintenance therapy:

• Maintenance pemetrexed is NOT recommended after first-line platinum-pemetrexed 1
• Vinorelbine or gemcitabine switch maintenance may be offered in select cases 1
• Maintenance gemcitabine is not routinely recommended but may prolong PFS when benefits outweigh toxicities 1