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The European Medicines Agency has validated a Type II Variation for nivolumab in combination with ipilimumab as a frontline treatment for previously untreated patients with unresectable malignant pleural mesothelioma.
The European Medicines Agency (EMA) has validated a Type II Variation for nivolumab (Opdivo) in combination with ipilimumab (Yervoy) as a frontline treatment for previously untreated patients with unresectable malignant pleural mesothelioma, according to Bristol Meyers Squibb.1
The submission is based on data from the pivotal phase 3 CheckMate-743 trial, which showed that the combination resulted in a significant improvement of overall survival (OS) versus chemotherapy in the first-line treatment of this patient population, meeting the primary end point of the trial.
“Not only is malignant pleural mesothelioma a particularly aggressive cancer, it has also proven difficult to treat, with no new options approved in years that can meaningfully extend survival,” Sabine Maier, MD, vice president of Oncology Clinical Development at Bristol Myers Squibb, stated in a recent press release. “The CheckMate-743 trial has shown the potential for [nivolumab plus ipilimumab] to help address this significant unmet need.”
Results presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium showed that the median OS with was 18.1 months in those given nivolumab/ipilimumab (n = 303) compared with 14.1 months in those who received chemotherapy (n = 302; hazard ratio [HR], 0.74; 95% CI, 0.60-0.91; P =.0020).2 At 12 months, the OS rates in the experimental and control arms were 68% and 58%, respectively; these rates were 41% and 27%, respectively, at 24 months.
Notably, the significant OS benefit observed with nivolumab/ipilimumab also extended to key patient subgroups analyzed in the trial, such as those with epithelioid or non-epithelioid disease and those with PD-L1 expression of less than 1% or 1% or higher.
Paul Baas, MD, PhD, chief of the Department of Thoracic Oncology at the Netherlands Cancer Institute, had noted in a presentation on the CheckMate-743 data that this was the first positive randomized trial of dual immunotherapy in the frontline treatment of patients with malignant pleural mesothelioma. “Therefore, nivolumab and ipilimumab should be considered the new standard of care,” Baas said.
A total of 605 patients with unresectable pleural mesothelioma were enrolled on the randomized, open-label phase 3 trial. Participants had not received prior systemic therapy and they had an ECOG performance status ranging from 0 to 1. Patients were stratified based on histology, either epithelial or non-epithelial disease, as well as gender.
In the trial, patients were randomized in a 1:1 fashion to receive either nivolumab at 3 mg/kg once every 2 weeks in combination with ipilimumab at 1 mg/kg once every 6 weeks for up to 2 years or chemotherapy comprised of cisplatin or carboplatin plus pemetrexed every 3 weeks. Participants continued to receive treatment until either disease progression, intolerable toxicities, or up to 2 years for those on the immunotherapy arm.
The primary end point of the trial was OS, while secondary end points included objective response rate (ORR), disease control rate, and progression-free survival (PFS) as assessed by blinded independent central review (BICR), and PD-L1 expression as a predictive biomarker.
The analysis plan was to identify a HR of 0.72 with a power of 90% and a 5% type-I error, with a planned total of 600 randomized participants and 473 deaths. Notably, the primary end point of OS was met at the time of the prespecified interim analysis.3
Additional results demonstrated that those in the immunotherapy arm experienced a shorter median PFS versus those on the chemotherapy arm, at 6.8 months versus 7.2 months, respectively (HR, 1.00; 95% CI, 0.82-1.21). However, the combination did have a higher PFS rate at both 12 months and 24 months versus the chemotherapy arm, at 30% versus 16%, respectively, and 24% and 7%, respectively.
Moreover, the ORR per BICR was 40% with nivolumab/ipilimumab compared with 43% with chemotherapy. The partial response (PR) rate in the immunotherapy arm was 38%, while the complete response (CR) rate was 2%. In the chemotherapy arm, the PR rate was 43% and the CR rate was 0%. The median duration of response (DOR) was 5.6 months in the investigational arm versus 3.5 months in the control arm.
With regard to safety, treatment-related adverse effects (TRAEs) of any grade were reported in 80% of participants who received the immunotherapy combination and 30% of patients had toxicities that were grade 3 or 4. Eighty-two percent of patients in the chemotherapy arm experienced TRAEs; 32% reported grade 3 or 4 toxicities. Serious TRAEs were experienced by 21% of those on the immunotherapy arm versus 8% of those on the chemotherapy arm.
The most commonly experienced TRAEs in the nivolumab/ipilimumab arm were diarrhea and pruritus. In the chemotherapy arm, participants reported nausea, anemia, neutropenia, fatigue, decreased appetite, and asthenia.
“We look forward to working with urgency alongside the EMA toward the goal of bringing this dual immunotherapy combination to patients in Europe, which faces one of the highest incidences of mesothelioma in the world,” added Maier.