Teaching pack: Pleural mesothelioma

Pleural mesothelioma is the commonest form of mesothelioma. It presents with pleural effusion, breathlessness and chest wall pain 20 to 50 years after asbestos exposure, and is diagnosed by thoracoscopic biopsy with immunohistochemistry (calretinin, WT1, D2-40) and loss of BAP1 or MTAP. Epithelioid histology, about two thirds of cases, carries a better outlook than biphasic or sarcomatoid disease. CheckMate 743 made nivolumab plus ipilimumab the first new first-line treatment in 16 years, and KEYNOTE-483 added pembrolizumab with platinum-pemetrexed; both are now standard, with histology guiding the choice. MARS 2 showed that extended pleurectomy and decortication harms rather than helps, so surgery is confined to diagnosis, pleurodesis and trials. Hemithoracic radiotherapy, tumour treating fields and mesothelin-directed therapies are the main lines of research.

• Immunotherapy doubled the share of patients alive at five years compared with chemotherapy alone, but most patients still die of the disease within two years.
• Randomised evidence has removed radical surgery from standard care, sparing patients a major operation with no benefit.
• Mesothelin is expressed on almost every tumour cell, and the next generation of antibody-drug conjugates and CAR-T cells is built on it.

1. 1960Wagner links pleural mesothelioma to asbestos
2. 2003Pemetrexed-cisplatin improves survival
3. 2020CheckMate 743: first immunotherapy survival gain
4. 2024MARS 2 ends radical surgery as standard
5. 2024Pembrolizumab with chemotherapy approved

• Antibody-drug conjugates for mesothelioma: why they have failed so far and how they could work (idea)

• IND.227 / KEYNOTE-483 (phase 2/3, n=440): Overall survival: 17.3 months vs 16.1 months, HR 0.79
• CheckMate 743 (phase 3, n=605): Overall survival: 18.1 months vs 14.1 months, HR 0.74
• AMPLE (phase 3, n=146): Total days in hospital to death or 12 months (median): 10 days vs 12 days
• TIME2 (phase 3, n=106): Mean breathlessness, 0-42 days (100 mm visual analogue scale): 24.7 vs 24.4
• MARS 2 (phase 3, n=335): Overall survival: 19.3 months vs 24.8 months, HR 1.28
• MEDI5752 in Combination With Carboplatin Plus Pemetrexed in Unresectable Pleural Mesothelioma (phase 3, n=863): result not yet recorded

• No curative treatment for the majority; median survival with the best regimens is about 18 months.
• Sarcomatoid disease responds poorly to everything except immunotherapy.
• No screening test for exposed workers, though BAP1 germline carriers and asbestos cohorts are being followed.

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 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%.
3. 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.
4. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.

• Wikipedia: https://en.wikipedia.org/wiki/Mesothelioma
• Mesothelioma UK: https://www.mesothelioma.uk.com/
• Wikipedia: https://en.wikipedia.org/wiki/Mesothelioma