Tremelimumab as Second, Third-Line Tx in Relapsed Malignant Mesothelioma



Title: Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial

Maio, M et al.


 

What You Need to Know:

Tremelimumab, a cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody, did not significantly prolong overall survival in patients with previously treated malignant mesothelioma when compared to placebo.

Trial Design:

  • Double-blind, placebo-controlled, phase 2b study (DETERMINE) assessed the effect of tremelimumab “in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease”
  • 571 patients were randomized (2:1) to receive tremelimumab (n=382) or placebo (n=189); stratified by the European Organization for Research and Treatment of Cancer status, second vs third line therapy, as well as anatomic site
  • Dosing of tremelimumab: 10 mg/kg administered intravenously every 4 weeks for 7 doses, then every 12 weeks until criterion for treatment discontinuation was met
  • Primary endpoint: overall survival; analyzed using the intention-to-treat population
  • Safety: analysis included all patients who received 1 dose of study medication

Key Outcomes:

  • 569 patients received treatment; 2 tremelimumab patients were excluded from the safety assessment since they did not receive treatment
  • 80% of tremelimumab patients (307/382) and 81% of placebo patients (154/189) had died by the data cutoff date
  • Median overall survival: 7.7 months for patients receiving tremelimumab (95% CI: 6.8, 8.9) vs 7.3 months for patients receiving placebo (95% CI: 5.9, 8.7) (HR: 0.92; 95% CI: 0.76, 1.12; P=0.41)
  • Treatment-emergent adverse events grade 3 or higher: experienced by 65% of patients in the tremelimumab group (246/380) vs 48% of patients in the placebo group (91/189)
  • Most common treatment-emergent adverse events grade 3 or higher: dyspnea (experienced by 9% of tremelimumab patients vs 14% of placebo patients), diarrhea (15% vs <1%), and colitis (7% vs 0%)
  • Most common serious adverse events: diarrhea (experienced by 18% of tremelimumab patients vs <1% of placebo patients), dyspnea (8% vs 13%), and colitis (6% vs 0%)
  • 9% of tremelimumab patients (36/380) experienced a treatment-emergent event that led to death compared to 6% of placebo patients (12/189)
  • Treatment-emergent events leading to the death of >1 patient: mesothelioma (3 patients in the tremelimumab group vs 2 patients in the placebo group), dyspnea (3 vs 2), respiratory failure (1 vs 3), myocardial infarction (3 vs 0), lung infection (3 vs 0), cardiac failure (1 vs 1), and colitis (2 vs 0)
  • 1% of tremelimumab patients (5/380) experienced a treatment-related adverse event that led to death compared to zero patients in the placebo group; causes of death were lung infection (n=1), intestinal perforation and small intestinal obstruction (n=1) colitis (n=2), and neuritis and skin ulcer (n=1)