CTLA-4 blockade in mesothelioma: ineffective or reason for optimism?

Our plain-English summary of CTLA-4 blockade in mesothelioma: ineffective or reason for optimism?, by A. Thomas, R. Hassan (The Lancet. Oncology, 2017).

The study

• Authors: A. Thomas, R. Hassan
• Journal: The Lancet. Oncology
• Published: 2017;18(9):1150-1151
• Type of article: Comment
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

In this comment, the authors discussed the DETERMINE trial, reported by Maio and colleagues in The Lancet Oncology. DETERMINE was a phase 2b, randomised, double-blind, placebo-controlled study of the anti-CTLA-4 antibody tremelimumab in patients with advanced unresectable pleural or peritoneal mesothelioma that had progressed after first-line or second-line therapy. The authors noted that pemetrexed plus cisplatin was the only approved therapy for unresectable malignant pleural mesothelioma and that no therapy was approved after progression. In DETERMINE, 571 of 658 enrolled patients were randomly assigned (2:1) to tremelimumab (n=382) or placebo (n=189). Most had pleural mesothelioma (95%) and epithelial histology (83%). Median overall survival, the primary endpoint, was 7·7 months with tremelimumab and 7·3 months with placebo, showing no difference. Grade 3 or worse diarrhoea (15% vs <1%) and colitis (7% vs none) were more common with tremelimumab. The authors described ongoing approaches. One was combined checkpoint blockade: the phase 3 CheckMate743 trial of ipilimumab plus nivolumab, and a reported randomised trial of 108 patients with objective responses in 17% receiving nivolumab and 27% receiving nivolumab plus ipilimumab. Another was checkpoint inhibition combined with chemotherapy. The authors concluded that the results, though disappointing, would inform future development of immune checkpoint inhibitors for mesothelioma. They said that identifying biomarker-defined patient populations likely to benefit would become imperative.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This article is a short commentary, not a new study. The authors discussed the DETERMINE trial, reported separately by Maio and colleagues. That trial compared the drug tremelimumab with placebo in patients with advanced pleural or peritoneal mesothelioma that had progressed after earlier treatment. As described here, 571 patients were randomly assigned, 382 to tremelimumab and 189 to placebo, and 545 of the 571 had pleural mesothelioma. The trial found no difference in overall survival: median 7.7 months (95% CI 6.8 to 8.9) with tremelimumab and 7.3 months (5.9 to 8.7) with placebo. Grade 3 or worse diarrhoea occurred in 58 (15%) tremelimumab patients versus one (less than 1%) placebo patient, and colitis in 26 (7%) versus none. The authors also described another trial in which 17% (nine of 54) of patients given nivolumab and 27% (14 of 54) given nivolumab plus ipilimumab had objective responses. Asbestos exposure was not discussed. The authors concluded that, although disappointing, the DETERMINE results will inform future development of immune checkpoint inhibitors for mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Commentary on another group's randomised trial (DETERMINE, a phase 2b, randomised, double-blind, placebo-controlled study reported by Maio and colleagues); not original research by these authors
• Who was studied: As described in the commentary, the DETERMINE trial enrolled 658 patients with advanced unresectable pleural or peritoneal mesothelioma. Of these, 571 were randomly assigned: 382 to tremelimumab and 189 to placebo. Of the 571, 545 (95%) had pleural mesothelioma, 475 (83%) had epithelial histology, and all had ECOG performance status 0 or 1.
• Exposure: No asbestos exposure was discussed. The treatment discussed was the anti-CTLA-4 antibody tremelimumab (10 mg/kg), compared with placebo, given every 4 weeks for seven doses and then every 12 weeks.
• Main results:
  • DETERMINE trial (reported by others): no difference in overall survival. Median overall survival was 7.7 months (95% CI 6.8 to 8.9) in the tremelimumab group and 7.3 months (5.9 to 8.7) in the placebo group.
  • DETERMINE trial: more adverse events with tremelimumab. Grade 3 or worse diarrhoea occurred in 58 (15%) tremelimumab patients versus one (less than 1%) placebo patient, and colitis in 26 (7%) versus none.
  • A separate randomised trial (reported by others) of 108 eligible patients treated as second-line or third-line therapy: objective responses in 17% (nine of 54) with nivolumab and 27% (14 of 54) with nivolumab plus ipilimumab, with slightly more adverse events in the combination group.
• The authors' conclusion: The authors concluded that, although disappointing, the DETERMINE results will inform ongoing and future development of immune checkpoint inhibitors for mesothelioma. They also wrote that understanding which biomarker-defined patient groups might benefit most will become imperative.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: CTLA-4, Mesothelioma, Tremelimumab, Unresectable, Peritoneal Mesothelioma, Second-Line Therapy, Pemetrexed (Alimta), Cisplatin.

Related studies

• CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy? — L. Calabrò, G.L. Ceresoli, et al. (2015)
• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor — S. Roncella, S. Laurent, et al. (2016)
• Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity — W.J. Lesterhuis, J. Salmons, et al. (2013)
• CTLA4 blockade in patients with malignant mesothelioma — B.M. Burt (2015)
• Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications — L. Calabrò, R. Danielli, et al. (2010)

Browse more research in The Lancet. Oncology, or return to medical research.