Mesothelioma Second-Line Treatment Options

When First-Line Treatment Stops Working

Most mesothelioma patients begin treatment with cisplatin and pemetrexed chemotherapy. When the disease progresses, meaning tumors grow or new lesions appear, doctors recommend second-line treatment. Second-line options have expanded significantly, with immunotherapy combinations and clinical trials offering new hope.

Second-Line Treatment Options

Gemcitabine Chemotherapy

Gemcitabine is an established second-line chemotherapy option when platinum-based treatment fails. What the research shows:

• Effective for late-stage mesothelioma
• Can be given alone or in combination
• Generally well-tolerated RAMES trial findings:
• Studied gemcitabine with or without ramucirumab (a VEGF inhibitor)
• Combination showed potential benefits in progression-free survival
• Results varied by patient performance status

Immunotherapy Combinations

After First-Line Chemotherapy

For patients who received chemotherapy first, immunotherapy options include:

• Opdivo (nivolumab) + Yervoy (ipilimumab)
• Keytruda (pembrolizumab): alone or with other agents CheckMate-743 trial results:
• Nivolumab + ipilimumab: 18.1 months median survival
• Chemotherapy alone: 14.1 months median survival
• 22% reduction in death risk with immunotherapy

After First-Line Immunotherapy (PEMMELA Trial)

For patients who received nivolumab + ipilimumab first-line and progressed, the PEMMELA cohort 2 trial tested pembrolizumab + lenvatinib. Key findings (Lancet Oncology, 2025):

• 60% objective response rate (12 of 20 patients)
• Median follow-up: 11.9 months
• Published by Netherlands Cancer Institute (NCT04287829) Toxicity considerations:
• 70% experienced grade 3–4 adverse events
• Most common: hypertension (25%), fatigue (20%)
• 45% required dose reductions
• 10% discontinued due to toxicity
• No treatment-related deaths

Survival Outcomes by Treatment Approach

Treatment Approach	Median Survival
Chemotherapy alone	12–14 months
Chemotherapy (optimal candidates)	Up to 21 months
Nivolumab + ipilimumab (first-line)	18.1 months
Keytruda + chemotherapy	17.3 months
Multimodal (surgery + chemo + radiation)	>5 years (select patients)

Cell Type and Second-Line Response

Sarcomatoid and Biphasic Mesothelioma

Patients with aggressive cell types showed particularly strong responses to immunotherapy:

• With immunotherapy: 18.1 months average survival
• With chemotherapy alone: 8.8 months average survival This represents a significant advancement for historically treatment-resistant disease.

Epithelioid Mesothelioma

Responds well to both chemotherapy and immunotherapy, with treatment selection based on:

• Prior treatment history
• Performance status
• Patient preference and goals

Clinical Trials for Progression

Active and recently completed trials for second-line treatment include:

Trial	Treatment	Status
PEMMELA (NCT04287829)	Pembrolizumab + lenvatinib	Completed
RAMES	Gemcitabine + ramucirumab	Published
TEADES	ODM-212 (pan-TEAD inhibitor)	Phase 2 (2026)
Various	Opdivo/Yervoy + surgery	Ongoing
Various	Radiation + Keytruda	Ongoing

How to Find Clinical Trials

• ClinicalTrials.gov: Search “mesothelioma second-line”
• National Cancer Institute: cancer.gov/about-cancer/treatment/clinical-trials
• Your oncologist: Can identify trials you qualify for
• Mesothelioma specialty centers: Often have exclusive trial access

Treatment Sequencing Strategies

After First-Line Chemotherapy

Options:

1. Immunotherapy (Opdivo + Yervoy or Keytruda)
2. Gemcitabine (with or without ramucirumab)
3. Clinical trial enrollment

After First-Line Immunotherapy

Options:

1. Pembrolizumab + lenvatinib (PEMMELA approach)
2. Chemotherapy if not previously received
3. Clinical trial enrollment

Multimodal Approaches

When disease allows, combining second-line systemic therapy with:

• Surgery (if tumor becomes resectable)
• Radiation (for symptom control or consolidation)

Making Treatment Decisions

Factors to Consider

Performance status:

• ECOG 0–1 generally required for aggressive second-line treatment
• Poorer performance status may favor supportive care or less intensive options Prior treatment response:
• Duration of response to first-line therapy
• Type and severity of side effects experienced Goals of care:
• Life extension vs. quality of life
• Willingness to accept treatment toxicity
• Access to clinical trials

Questions for Your Oncologist

1. What second-line options am I eligible for?
2. Based on my response to first-line treatment, what would you recommend?
3. Are there clinical trials I should consider?
4. What are the expected side effects of each option?
5. How will you monitor for treatment response?
6. When would we consider third-line treatment or palliative care?

Toxicity Management

Common Second-Line Side Effects

Treatment	Common Side Effects
Gemcitabine	Fatigue, low blood counts, flu-like symptoms
Immunotherapy	Fatigue, skin rash, colitis, pneumonitis
Pembrolizumab + lenvatinib	Hypertension, fatigue, diarrhea

Monitoring Requirements

• Regular blood tests
• Blood pressure monitoring (especially with lenvatinib)
• Imaging to assess response
• Symptom assessment at each visit

When to Consider Palliative Care

Palliative care can be integrated alongside second-line treatment to:

• Manage symptoms
• Improve quality of life
• Support treatment tolerance If second-line treatment is not appropriate or fails, transitioning to comfort-focused care remains an important option.

Key Takeaways

• Second-line options have expanded significantly with immunotherapy combinations
• Gemcitabine remains a standard second-line chemotherapy option
• PEMMELA trial showed promising results for post-immunotherapy progression
• Cell type matters: sarcomatoid patients may particularly benefit from immunotherapy
• Clinical trials offer access to emerging treatments
• Toxicity is significant: discuss risks and monitoring with your doctor