First-Line Nivolumab–Ipilimumab Boosts Unresectable Mesothelioma Overall Survival

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: The CheckMate 743 trial has achieved an overall survival (OS) gain with first-line nivolumab plus ipilimumab versus chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM).

Median OS was 18.1 months with up to 2 years of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks versus 14.1 months with six cycles of cisplatin or carboplatin plus pemetrexed, giving a significant hazard ratio (HR) for death of 0.74, reported Paul Baas, from the Netherlands Cancer Institute in Amsterdam.

“This is the first positive randomized trial of dual immunotherapy in first line treatment of patients with unresectable MPM and therefore [nivolumab plus ipilimumab] should be considered as a new standard of care”, he commented at the 2020 Virtual Presidential Symposium of the World Congress on Lung Cancer.

The 303 patients given nivolumab plus ipilimumab and the 302 patients given chemotherapy were followed-up for a median of 29.7 months (minimum 22.1 months), during which time a corresponding 44% and 41% went onto receive another systemic therapy.

As previously found for MPM, patients with epithelioid histology did significantly better with chemotherapy than those with non-epithelioid histology, with a median OS of 16.5 versus 8.8 months.

The corresponding median OS values for nivolumab plus ipilimumab in these groups were a more comparable 18.7 and 18.1 months, so that the HR for death favoured the immunotherapy combination for both epithelioid and non-epithelioid subgroups, at a nonsignificant 0.86 and a significant 0.46, respectively.

Among participants with a PD-L1 score of less than 1%, median OS did not significantly differ between the nivolumab plus ipilimumab and chemotherapy treatment arms, whereas median OS was significantly longer with the immunotherapy regimen among patients with a score of 1% or higher (18.0 vs 13.3 months, HR=0.69).

Progression-free survival (PFS) did not significantly differ between the nivolumab plus ipilimumab and chemotherapy arms (median 6.8 vs 7.2 months). However, although the chemotherapy arm initially did better, over time the PFS curves crossed and then separated, so that by 2 years 16% of the patients in the immunotherapy arm were alive and free from progression versus just 7% of controls.

The immunotherapy and chemotherapy arms had similar objective response rates (40 vs 43%) but median duration of response was longer with nivolumab plus ipilimumab, at 11.0 versus 6.7 months; 32% of responders had an ongoing response at 2 years after immunotherapy versus 8% of those who responded to chemotherapy.

Median treatment duration was 5.6 months for nivolumab plus ipilimumab and 3.5 months for chemotherapy. Grade 3–4 treatment-related adverse events (TRAEs) were comparable in the two arms (30 vs 32%) but the immunotherapy group had higher rates of grade 3–4 TRAEs leading to discontinuation (15 vs 7%) and serious TRAEs (15 vs 6%), with three and one treatment-related deaths reported, respectively.

Nivolumab and ipilimumab were most commonly associated with diarrhoea and pruritus, while chemotherapy was linked to nausea, decreased appetite, fatigue, asthenia and haematological AEs, said Paul Baas.

Immunological TRAEs in the nivolumab plus ipilimumab group were most commonly grade 1–2 skin, gastrointestinal, endocrine and hypersensitivity or infusion reactions.

“The safety profile of [nivolumab plus ipilimumab] was consistent with that previously seen at this dose and schedule”, the presenter commented.

Session discussant Dean Fennell, from the University of Leicester in the UK, highlighted the enriched epithelial–mesenchymal transition in nonepithelioid histology MPM which “may account for the drug resistance that we see in the CheckMate 743 with chemotherapy” but “does not appear to impact in any way the efficacy of the immunotherapy.”

He noted that the ATOMIC trial is now underway to attempt targeting of chemotherapy in nonepithelioid mesothelioma using arginine deprivation and hypothesized that this strategy could be used alongside nivolumab plus ipilimumab.

Concluding that the CheckMate 743 study “heralds a new standard of care in this setting”, Dean Fennell awaits results from ongoing studies investigating pembrolizumab or nivolumab, or atezolizumab in combination with bevacizumab and chemotherapy in the MPM population.

Reference

Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. WCLC Virtual Presidential Symposium 2020.