Updated CheckMate 743 data support dual checkpoint blockade in mesothelioma
medwireNews: Extended follow-up of the phase 3 CheckMate 743 trial shows the continued overall survival (OS) benefit of first-line treatment with nivolumab plus ipilimumab over chemotherapy in patients with unresectable malignant pleural mesothelioma.
This benefit was observed even though patients had been off therapy for a year, presenting author Solange Peters, from Lausanne University Hospital in Switzerland, told delegates of the ESMO Congress 2021.
She reported on an analysis conducted at a minimum follow-up of 35.5 months, which showed that the risk for death was a significant 27% lower for the 303 patients who were randomly assigned to receive nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks for up to 2 years than for the 302 patients who instead received six cycles of cisplatin or carboplatin plus pemetrexed every 3 weeks.
The median OS times were 18.1 months in the dual checkpoint blockade group and 14.1 months in the chemotherapy group, with 3-year OS rates of 23.2% and 15.4%, respectively. The corresponding median progression-free survival (PFS) times were a comparable 6.8 and 7.2 months, while the 3-year PFS rates were 13.6% and 0.8%.
The objective response rate was lower in the nivolumab plus ipilimumab than chemotherapy arm, at 39.6% versus 44.0%, but the median duration of response was longer, at 11.6 versus 6.7 months, and the 3-year duration of response rates were 28.0% and 0.0%.
The current findings follow on from an interim analysis of the trial – conducted at a median follow-up of 29.7 months – which demonstrated a 26% reduction in the risk for death with nivolumab–ipilimumab relative to chemotherapy and led to the approval of the immunotherapy combination in the USA and European Union.
Peters also presented exploratory biomarker analyses that showed a significantly longer median OS among immunotherapy-treated patients with an inflammatory gene signature score (based on levels of CD8A, CD274, STAT1, and LAG3) above versus below the median, at 21.8 and 16.8 months, respectively (hazard ratio=0.57).
By contrast, there was no such association between OS and the signature among those who received chemotherapy.
The incidence of treatment-related adverse events (TRAEs) of grade 3 or 4 was comparable in the nivolumab–ipilimumab and chemotherapy groups, at 31% and 32%, respectively, but a higher proportion of immunotherapy-treated patients discontinued any (15 vs 7%) or all (13 vs 5%) components of the treatment regimens due to TRAEs of these grades.
There were three treatment-related deaths in the nivolumab–ipilimumab arm – one case each of pneumonitis, encephalitis, and acute heart failure – and one in the chemotherapy arm due to myelosuppression.
Peters highlighted that TRAE-related discontinuation of the checkpoint inhibitors “did not have a negative impact on the long-term benefits seen in all randomized patients.”
Specifically, a post-hoc analysis of the 52 patients who discontinued all components showed a median OS time of 25.4 months and a 3-year survival rate of 37%. And 34% of these patients had an ongoing response for at least 3 years.
In conclusion, the presenter said that the CheckMate 743 data cement the combination of nivolumab and ipilimumab “as a standard of care” for treatment-naïve patients with inoperable malignant pleural mesothelioma.
Pilar Garrido López (Hospital Universitario Ramón y Cajal, Madrid, Spain), who discussed the presentation, highlighted the “critical need” to establish predictive biomarkers in this patient population, not only to identify patients likely to progress early but also to characterize long-term responders.
She believes that “better characterization of predictive biomarkers is crucial” to improve the outcomes of patients.
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