Tremelimumab Fails To Improve Relapsed Malignant Mesothelioma Patient Survival

Tremelimumab does not offer improved overall survival for patients with relapsed and unresectable malignant mesothelioma

medwireNews: The DETERMINE trial rules out a role for tremelimumab monotherapy in patients with relapsed malignant mesothelioma, finding no clinical benefit with the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor over placebo. 

The phase IIb study recruited 571 patients from 19 countries in under a year, all of whom had received one or two prior systemic therapies for unresectable pleural or peritoneal disease, the investigators report in The Lancet Oncology. 

Overall survival (OS) was a median of 7.7 months for the 382 patients who were randomly assigned to receive tremelimumab 10 mg/kg every 4 weeks for seven doses, with further treatment given at 12-week intervals thereafter. This did not significantly differ from the median OS of 7.3 months for the 189 patients who were given placebo on the same dosing schedule. 

The OS analysis had “high maturity”, the researchers note, with around 80% of patients dying by the time of data cutoff. Just 24% of tremelimumab-treated patients and 31% of controls received subsequent anticancer treatment and none received checkpoint inhibitor agents, prompting the authors to say there is “no evidence” of potential confounding on OS from later therapy. 

Nor were there “clinically meaningful” differences between the tremelimumab and placebo groups with regard to progression-free survival (median 2.8 vs 2.7 months), which also had high maturity by the time of data cutoff. An objective response was achieved by 4.5% and 1.1% of the groups, respectively, and lasted a median of 4.8 and 5.6 months, respectively. 

Michele Maio, from the University Hospital of Siena in Italy, and co-authors say the safety data were “consistent” with earlier reports for tremelimumab and other CTLA-4 inhibitors.  

Nevertheless, tremelimumab-treated patients had a higher rate of treatment-emergent grade 3 or more severe events than controls (65 vs 48%), with diarrhoea (15 vs <1%), dsypnoea (9 vs 14%) and colitis (7 vs 0%) the most commonly reported of these. 

Treatment-related events leading to death were reported for five (1%) patients given tremelimumab; namely single reports of lung infection, intestinal perforation and small intestinal obstruction, and neuritis and skin ulcer, as well as two colitis-related deaths. 

“The rapid accrual to the DETERMINE trial underscores the urgent and unmet need for new treatment options for patients with malignant mesothelioma and for further research to identify alternative therapeutic strategies”, the researchers comment. 

“Anti-PD-1 and anti-PD-L1 monotherapies have shown preliminary signs of clinical activity in malignant mesothelioma; thus, combining antibodies that target the PD-1/PD-L1 pathway and the CTLA-4 pathway could provide additional therapeutic benefit”, the investigators hypothesise. 

Tremelimumab is now being studied in combination with the anti-PD-L1 agent durvalumab in the phase II NIBIT-MESO-1 trial, they add. 

Reference 

Maio M, Scherpereel A, Calabrò L, et al. Tremelimumab as second-line or third-line treatment in relapsed malignant melanoma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol; Advance online publication 17 July 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30446-1 

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