Teaching pack: Mesothelioma

Malignant pleural mesothelioma arises from the lining of the lung, almost always decades after asbestos exposure, and is rising in countries that banned asbestos late or not at all. It grows along surfaces rather than as a mass, is hard to image and stage, and resists most systemic therapy. Histology is the dominant biological variable: epithelioid tumours are slower and chemosensitive; sarcomatoid and biphasic tumours are aggressive, chemoresistant, and paradoxically more immunotherapy-responsive.

For 16 years after pemetrexed-cisplatin (2004) nothing improved survival except, modestly, adding bevacizumab (MAPS, 2016). Immunotherapy then changed the first line twice: nivolumab-ipilimumab (CheckMate 743, approved 2020) and pembrolizumab with chemotherapy (IND.227/KEYNOTE-483, approved September 2024). Tumour treating fields hold a device approval on single-arm data. Radical surgery, long assumed beneficial, was shown by MARS 2 (2024) to shorten survival and worsen quality of life, and is now largely confined to trials.

• IO doublet first line.
• Two immunotherapy-based first-line standards (nivolumab-ipilimumab; pembrolizumab-chemotherapy), chosen by histology.
• Radical surgery removed from routine care after MARS 2 showed harm.
• Five-year survival with nivolumab-ipilimumab 14% vs 6% with chemotherapy: a small but real tail of long-term survivors.
• MTAP deletion and BAP1 loss are routine diagnostic markers and emerging therapeutic handles.
• Mesothelin CAR-T delivered regionally has produced long survivors in phase 1.

1. 1960Wagner links mesothelioma to asbestos in South African miners
2. 1989US EPA asbestos ban partly overturned (1991); many countries ban asbestos over the following decades
3. 2003EMPHACIS: pemetrexed-cisplatin improves survival
4. 2004Pemetrexed-cisplatin approved
5. 2004Pemetrexed approved: first mesothelioma drug
6. 2011MARS 1: extrapleural pneumonectomy shows harm; practice shifts to lung-sparing surgery
7. 2016MAPS: bevacizumab adds ~3 months
8. 2019TTFields device approval (HDE) on STELLAR
9. 2019LUME-Meso fails; nintedanib abandoned in mesothelioma
10. 2020Nivolumab-ipilimumab first line

• Synthetic lethality approaches (technology)
• EB-MF-CAR-NK-01 (treatment)
• Anetumab ravtansine (treatment)
• Antibody-drug conjugates for mesothelioma: why they have failed so far and how they could work (idea)
• Anetumab ravtansine versus vinorelbine in relapsed mesothelin-positive pleural mesothelioma (trial)
• Pembrolizumab with or without anetumab ravtansine in mesothelin-positive pleural mesothelioma (NCI) (trial)
• Hemithoracic irradiation with proton therapy in malignant pleural mesothelioma (UCL) (trial)
• Proton therapy (technology)
• PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma (idea)
• Regionally delivered mesothelin CAR-T with PD-1 blockade (idea)
• CAR-T cell therapy (technology)
• Armoured, logic-gated & next-gen CARs (technology)

• IND.227 / KEYNOTE-483 (phase 2/3, n=440): Overall survival: 17.3 months vs 16.1 months, HR 0.79
• BEAT-meso (ETOP 13-18) (phase 3, n=400): Overall survival: 20.5 months vs 18.1 months, HR 0.84
• CheckMate 743 (phase 3, n=605): Overall survival: 18.1 months vs 14.1 months, HR 0.74
• MAPS (phase 2/3, n=448): Overall survival: 18.8 months vs 16.1 months, HR 0.77
• STELLAR (phase 2, n=82): Overall survival (single arm vs historical): 18.2 months vs 12.1 months
• MARS 2 (phase 3, n=335): Overall survival: 19.3 months vs 24.8 months, HR 1.28

• Sarcomatoid subtype.
• No early detection despite known exposure.
• Even the best first-line regimens give a median survival under two years; the tail of long survivors on immunotherapy is what to build on.
• Epithelioid disease gains little from immunotherapy over chemotherapy; no predictive biomarker beyond histology.
• No approved targeted therapy despite recurrent BAP1, CDKN2A/MTAP, and NF2 alterations.
• Once immunotherapy has been used first line, the second-line options are platinum-pemetrexed rechallenge, gemcitabine or vinorelbine, none with a randomised survival trial behind it in that sequence; mesothelin CAR-T, mesothelin ADCs and engagers, and PRMT5 inhibitors for MTAP-deleted tumours are the trials addressing it.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What was the first approval in nearly thirty years specific to locally advanced pancreatic cancer?
   Answer

   Optune Pax (tumour treating fields) with gemcitabine/nab-paclitaxel, approved Q1 2026 on PANOVA-3.
3. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
4. What are the main side effects of checkpoint inhibitors and how are they handled?
   Answer

   Immune-related adverse events such as colitis, thyroid problems, rash, hepatitis, and pneumonitis, most common with CTLA-4 plus PD-1 combinations; treated with steroids and sometimes other immunosuppressants, some endocrine effects are permanent.
5. What is CAR-T and which cancers is it approved for?
   Answer

   A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
6. What were the first checkpoint inhibitor and the first ADC ever approved?
   Answer

   Ipilimumab (2011) was the first checkpoint inhibitor; gemtuzumab ozogamicin (Mylotarg, 2000) was the first ADC, withdrawn in 2010 and re-approved in 2017.

• NCI PDQ: malignant mesothelioma treatment: https://www.cancer.gov/types/mesothelioma/hp/mesothelioma-treatment-pdq
• NICE NG12: suspected cancer, recommendations by site (lung and pleural cancers 1.1.1 to 1.1.6): https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer
• Wikipedia: https://en.wikipedia.org/wiki/Mesothelioma
• Guideline: https://www.nccn.org/guidelines/category_1