Nivolumab/ipilimumab continues to provide survival benefit in unresectable MPM

In the 3-year update from CheckMate743, nivolumab/ipilimumab continued to be superior to chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). Exploratory analyses suggest a high inflammatory gene signature score to be predictive for survival benefit with nivolumab/ipilimumab in these patients.

In the randomised, phase 3 CheckMate743 trial (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) over chemotherapy in patients with unresectable MPM (18.1 vs 14.1 months; HR 0.74; P=0.0020) [1]. This regimen is now approved in EU & USA, amongst others, as first-line treatment for (adult) patients with unresectable MPM. However, no long-term outcomes of immunotherapy in MPM had been reported. Prof. Solange Peters (Lausanne University Hospital, Switzerland) presented the 3-year update of efficacy and safety results from CheckMate743 as well as results from exploratory biomarker analyses.

The study enrolled 606 patients with untreated MPM, stratified by histology (epithelioid vs non-epithelioid) and sex. Patients were randomised 1:1 to nivolumab (3 mg/kg every 2 weeks)/ipilimumab (1 mg/kg every 6 weeks) up to a maximum of 2 years or to chemotherapy (every 3 weeks, 6 cycles). The primary endpoint was OS, safety and biomarker assessments were prespecified exploratory endpoints. OS association with a 4-gene inflammatory gene expression signature (CD8A, PD-L1, STAT-1, LAG-3) was estimated by RNA sequencing and categorised as high versus low relative to median score.

With a minimum follow-up of 35.5 months, nivolumab/ipilimumab continued to provide OS benefit versus chemotherapy (HR 0.73). OS rates were 41% versus 27% at 24 months and 23% versus 15% at 36 months. Progression-free survival (PFS) rates at 36 months were 14% versus 1%. Of note, treatment with nivolumab/ipilimumab stopped at a maximum of 24 months. OS rates in the nivolumab/ipilimumab-treated population were irrespective of histology. Median duration of response was 11.6 months for nivolumab/ipilimumab versus 6.7 months for chemotherapy. In a post hoc analysis, discontinuation of nivolumab/ipilimumab due to treatment-related adverse events did not have a negative impact on the long-term benefits seen in all randomised patients.

Exploratory biomarker analyses showed that median OS was longer for patients with high inflammatory gene signature score (21.8 months vs 16.8 months for low inflammatory gene signature score) in the nivolumab/ipilimumab-treated population. At 3 years, 35% of nivolumab/ipilimumab-treated patients with a high inflammatory gene signature score were still alive versus 15% of patients with a low score. The inflammatory gene signature score was not associated with prolonged OS for chemotherapy (see Figure).

Figure: OS by 4-gene inflammatory signature score [2]



“These updated data further reinforce previously published findings and support the benefit of giving patients immunotherapy instead of chemotherapy,” concluded Prof. Peters.

1. Baas P, et al. Lancet 2021;397:375-386.


2. Peters S, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate743. Abstract LBA65, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 2021