Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study

Background: MM is an asbestos-induced cancer with increasing global incidence. 1st-line treatment is pemetrexed + platinum; there are no approved 2nd-line therapies. CTLA-4 is a co-inhibitory receptor expressed on activated T cells. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4 that promotes T-cell activation. Single-arm Phase 2 trials of T using 2 different doses and schedules achieved responses and durable disease control in MM pts.1,2 DETERMINE (NCT01843374) evaluated T vs placebo (P) in pts with unresectable pleural or peritoneal MM. Methods: Eligible pts who progressed after 1–2 lines of prior therapy were randomized 2:1 to receive T (10 mg/kg q4w for 7 doses, then q12w) or P, and stratified by EORTC status, line of therapy and anatomic site. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival, objective response rate and duration, durable disease control rate and safety. Results: From May 2013 to December 2014, 571 pts were randomized (382 to T, 189 to P; median age 66 yrs [range 28–87]; male 76%; EORTC status low/high risk: 58%/42%; pleural 95%; epithelioid histology 83%; 2nd/3rd line: 63%/37%). 380 received T, 189 P (median 3.0 [range 1–13] doses for both arms). 81% have died. There was no statistically significant difference in OS, T vs P (median 7.7 vs 7.3 mos; HR = 0.92, 95% CI: 0.76–1.12, p = 0.408). Subsequent anticancer treatment was low (T 24%, P 31%). Most frequent Grade ≥ 3 treatment-emergent AEs (T 65%/P 48%): dyspnea (9%/14%), diarrhea (15%/1%) and colitis (7%/0%). Most frequent AEs (any grade) included: diarrhea (47%/19%), dyspnea (32%/37%), decreased appetite (29%/24%), fatigue (24%/32%), nausea (28%/20%), constipation (17%/28%), pruritus (27%/8%) and rash (21%/7%). Conclusions: T monotherapy did not demonstrate superiority to P for the primary endpoint OS in 2nd/3rd-line MM. Preliminary safety data are consistent with the known safety profile of T. Other endpoint data will be presented. An ongoing Phase 2 study (NIBIT-MESO-1) evaluates T in combination with durvalumab in 1st/2nd-line MM. 1. Calabrò et al. Lancet Resp Med 2015; 2. Calabrò et al. Lancet Oncol 2013 Clinical trial information: NCT01843374.