Nivolumab prolongs survival and delays disease progression in patients with relapsed malignant mesothelioma
Results of the phase III CONFIRM trial demonstrate that the immune checkpoint inhibitor nivolumab significantly prolongs the survival and delays the disease progression compared to placebo in patients with relapsed malignant mesothelioma. This clinical benefit was observed irrespective of the PD-L1 expression, but seemed to be limited to patients with an epithelioid histology.
Patients with relapsed mesothelioma represent an important unmet need. Recently, 3 phase II trials demonstrated clinical potential of the PD-1 inhibitor nivolumab in this setting, resulting in a licensing of nivolumab for relapsed mesothelioma in Japan. The results of these phase II trials formed the basis for the phase III CONFIRM trial, comparing nivolumab to placebo in patients with relapsed mesothelioma. In total, 332 patients with relapsed mesothelioma, who had progressed on at least 1 prior line of therapy, were randomised (2:1) to receive nivolumab (240 mg day 1 per 14-day cycle), or placebo, until progression, unacceptable toxicity, study withdrawal for a maximum of 12 months. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS).
Nivolumab associated with a median overall survival benefit of 9.2 months
The median age of participants in this study was 70 years, approximately three quarters were male and 20% of participants in both treatment arms had an ECOG PS of 0. Furthermore, 37% of patients receiving nivolumab had PD-L1 expression ≥1%, compared to 27% in the placebo arm. In both arms, 88% of patients had epithelioid histology, whilst 56% of patients receiving nivolumab and 59% of placebo patients had progressed on third-line treatment. The median duration of treatment in this study was 84 days for the nivolumab arm, and 43 days for patients receiving placebo. Nivolumab significantly prolonged the median PFS (3.0 months vs. 1.8 months), with a 12-month PFS rate of 14.5% and 4.9%, for nivolumab and placebo, respectively (HR[95%CI]: 0.61[0.48-0.77], p< 0.001). Data for OS were still immature, but also in terms of this endpoint nivolumab significantly outperformed placebo with a median OS of 9.2 and 6.6 months, respectively (HR[95%CI]: 0.72[0.55-0.94], p= 0.018). The level of PD-L1 expression did not predict survival outcomes. In the nivolumab and placebo arms, patients with PD-L1 expression ≥1% were found to have a median OS of 8.0 vs. 8.7 months, respectively (HR[95%CI]: 0.95[0.51-1.76], p= 0.864). Conversely, patients with a PD-L1 expression <1% were found to have a median OS of 9.0 months vs. 6.4 months (HR[95%CI]: 0.74[0.51-1.08], p= 0.115). Interestingly, when zooming in on the impact of histology, it became clear that the clinical benefit of nivolumab was mainly driven by the effect in patients with an epithelioid histology. In this subgroup, nivolumab induced a significant OS benefit with a median OS 9.4 months as compared to 6.6 months with placebo (HR[95%CI]: 0.71[0.53-0.95], p= 0.021). In the non-epithelioid subgroup, no OS benefit of nivolumab was seen with a median OS 5.9 and 6.7 months for nivolumab and placebo, respectively (HR[95%CI]: 0.79[0.35-1.79], p= 0.572).
Grade ≥3 adverse events (AEs) occurred in 45% and 42% of nivolumab and placebo patients, including 36% and 39% of serious AEs, respectively. In total, 3.6% of deaths were thought to be related to serious AEs in the nivolumab arm, whilst 5.3% were thought to be related to serious AEs in the placebo arm.
In the phase III CONFIRM trial, nivolumab monotherapy provided a statistically significant survival benefit in patients with relapsed mesothelioma patients. The study found PD-L1 expression status not to be predictive of clinical benefit. In contrast, the survival benefit did seem to be restricted to patients with an epithelioid histology. In light of these results, the researchers concluded that nivolumab monotherapy should be considered in a relapsed mesothelioma setting.
Fennell D et al., Nivolumab Versus Placebo in Relapsed Malignant Mesothelioma: Preliminary results from the CONFIRM Phase 3 Trial. Presented at WCLC 2020; Abstract PS01.011