Nivolumab/Ipilimumab Approved in Europe for Frontline Unresectable Malignant Pleural Mesothelioma

The European Commission (EC) has approved the dual immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for use in the frontline treatment of adults with unresectable malignant pleural mesothelioma.¹

The regulatory decision was based on findings from the phase 3 CheckMate-743 trial (NCT02899299), which showed that the doublet resulted in a 26% reduction in the risk of death compared with platinum-based, standard-of-care chemotherapy (HR, 0.74; 96.6% CI, 0.60-0.91; P = .002). The median OS with the immunotherapy regimen was 18.1 months (95% CI, 16.8-21.4) vs 14.1 months (95% CI, 12.4-16.2) with chemotherapy, meeting the primary end point of the trial. The 2-year OS rates in the investigative and combination arms were 41% and 27%, respectively.²

This is the first positive phase 3 trial of an immunotherapy in the frontline treatment of malignant pleural mesothelioma, according to Bristol Myers Squibb.

“After many years of limited progress in the treatment of malignant mesothelioma, we saw an important clinical benefit for patients with nivolumab plus ipilimumab in the CheckMate-743 trial,” Paul Baas, MD, PhD, of the Department of Thoracic Oncology at the Netherlands Cancer Institute and the University of Leiden, stated in a press release. “With the EC approval of this dual immunotherapy combination, patients and doctors will now have a new treatment option that has shown significant improvements in survival to manage this resistant disease.”

In the open-label, multicenter phase 3 CheckMate-743 trial, investigators examined nivolumab plus ipilimumab vs chemotherapy, which was either pemetrexed and cisplatin or carboplatin, in 605 patients with previously untreated malignant pleural mesothelioma.

Notably, patients who had interstitial lung disease, active autoimmune disease, any conditions that required systemic immunosuppression, or active brain metastases, were not eligible for enrollment. Participants were stratified based on histology, epithelial vs non-epithelial disease, and gender.

Study participants were randomized to receive either nivolumab at 3 mg/kg biweekly plus ipilimumab at 1 mg/kg every 6 weeks (n = 303), or cisplatin at 75 mg/m² or carboplatin AUC 5 plus pemetrexed at 500 mg/m² in 21-day treatment cycles for 6 cycles. Patients continued to receive treatment until progressive disease or intolerable toxicity; if in the doublet immunotherapy arm, they received up until 24 months.

The primary end point of the trial was OS in all randomized patients, while other key end points included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per blinded independent central review and RECIST criteria. Other exploratory

end points comprised safety, pharmacokinetics, immunogenicity, and patient-reported outcomes.

Additional data from the trial showed that the median PFS with nivolumab plus ipilimumab was shorter than that observed with chemotherapy, at 6.8 months vs 7.2 months, respectively (HR, 1.00; 95% CI, 0.82-1.21). However, the 1-year PFS rates in the investigative and control arms were 30% and 16%, respectively, while the 2-year PFS rates were 24% and 7%, respectively.

The ORRs between the investigative and control arms were similar, at 40% (95% CI, 34.1%-45.4%) and 43% (95% CI, 37.1%-48.5%), respectively. Moreover, the median DOR achieved with the doublet was 11.0 months (95% CI, 8.1-16.5) vs 6.7 months with chemotherapy (95% CI, 5.3-7.1). Thirty-two percent of the responders who received the immunotherapy combination experienced a response that continued at 2 years vs just 8% who received the chemotherapy. The median time to response was 2.7 months with the doublet and 2.5 months with the chemotherapy.

Additional data presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium showed that the 1-year OS rate with nivolumab plus ipilimumab was 68% vs 58% with chemotherapy.³ The 2-year OS rates in the investigative and control arms were 41% and 27%, respectively.

Notably, the survival benefit of the dual immunotherapy regimen was observed across all prespecified subgroups, irrespective of epithelioid disease or PD-L1 expression.

Regarding safety, nivolumab plus ipilimumab was determined to be manageable using established adverse effect management protocols. The safety profile of the regimen also proved to be consistent with what has been shown in prior studies of the combination in other tumor types.

The most common adverse effects reported in 10% or more of patients who received the doublet included fatigue (43%), diarrhea (31%), rash (30%), musculoskeletal pain (27%), decreased appetite (24%), pruritis (21%), constipation (19%), and hypothyroidism (13%).

“The EC’s approval of [nivolumab] plus [ipilimumab] is a crucial step in addressing the unmet needs of patients with malignant pleural mesothelioma,” Abderrahim Oukessou, MD, vice president and thoracic development lead at Bristol Myers Squibb, added in the release. “We thank the patients and investigators involved in the CheckMate-743 trial, whose contributions were essential to bringing the first immunotherapy option to [patients with] mesothelioma throughout the European Union [EU].”

The regulatory decision allows for the use of the combination in the frontline treatment of patients with unresectable malignant pleural mesothelioma in the 27 member states of the EU, as well as Iceland, Liechtenstein, and Norway. To date, the combination has been approved in six countries beyond the EU, and additional regulatory applications are under review by global health authorities.

Reference

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) plus Yervoy (ipilimumab) as first-line treatment for unresectable malignant pleural mesothelioma. News release. June 2, 2021. Accessed June 2, 2021. https://bit.ly/3fIXyw7
2. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397(10272):P375-386. doi:10.1016/S0140-6736(20)32714-8
3. Baas P, Scherpereel A, Nowak A, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; virtual. Abstract 3.