Nivolumab Shows Promise in Mesothelioma

Paul Baas, MD, PhD

Treatment with the PD-1 inhibitor nivolumab (Opdivo) showed promising results in patients with recurrent malignant pleural mesothelioma (MPM), according to findings from the phase II Nivo-Mes trial presented at the 17th World Lung Cancer Conference in Vienna.

“The Nivo-Mes trial demonstrated that immune-oncology in MPM with nivolumab is feasible, with limited toxicity, and can result in long-term responses lasting more than a year,” said lead author Paul Baas, MD, PhD, thoracic oncologist in the Division of Medical Oncology of the Netherlands Cancer Institute in Amsterdam, The Netherlands.

Recurrent MPM is the most common form of mesothelioma and has few treatment options beyond surgery. There is a paucity of reported survival benefits in MPM, which attacks the protective lining of the lung, known as the pleura. Although pleural mesothelioma is related to inhaling asbestos fibers, only a fraction of individuals exposed to asbestos develop mesothelioma, leading investigators to explore genetic components that may play a contributing role.

“No studies have reported a survival benefit in recurrent malignant pleural mesothelioma,” said Baas. Currently, there is no standard recommendation for induction therapy for MPM, leading Baas and colleagues to test an induction schedule of nivolumab in MPM.

Nivo-Mes is a single-center, phase II study that tested nivolumab at 3 mg/kg every 2 weeks in 38 patients with MPM. The patients’ mean age was 66 years (range, 51-81), and 28 of 38 patients were male. The histology was epithelial in 28 patients, mixed in 4 patients, and non-epithelial in 2 patients.

All patients had progressive disease and 33 patients had paired biopsies that had been taken at week 1 prior to treatment and at week 6 during treatment. The biopsy tissue was used to determine antitumor activity and for PD-L1 expression and other biomarker analysis.

The study’s primary endpoint was an improvement in disease control rate of 20% to 40% after 12 weeks of nivolumab, as compared with historic controls.

“Nivolumab in second or later lines in recurrent malignant pleural mesothelioma met the primary endpoint,” said Baas.

After the 12 weeks of treatment with nivolumab, the disease control rate was 50%, including a confirmed partial response in 5 patients. Stable disease was achieved by 12 patients. Progressive disease was reported for 17 patients and 3 patients showed pseudoprogression of disease.

Of the responders, 13 patients had epithelioid histology, including 4 patients achieving partial response and 9 with stable disease.

No treatment-related deaths occurred. The investigators noted “mild toxicity.” Treatment discontinuation due to grade 3 toxicity was reported in 8 patients.

“We observed long-lasting results and there was some correlation between PD-L1 expression and response,” said Baas. PD-L1 was expressed in the tumor at levels ≥1% in 9 of 32 evaluable patients. Of these, 2 of the 9 patients showed a confirmed partial response at 12 weeks.

He noted that his team is planning further studies to improve treatment options in malignant pleural mesothelioma.

Nivolumab is an IgG4 monoclonal antibody targeting tithe PD-1 receptor, that acts as an immune checkpoint inhibitor that results in enhanced T-cell antitumor activity that has been shown to have greater benefit in patients expressing PD-L1.

Other anti—PD-1/PD-L1 agents are also being explored in mesothelioma. Another abstract presented at the World Lung Conference provided data for the PD-1 inhibitor pembrolizumab (Keytruda) from the MPM arm of the KEYNOTE-028 trial.

Among 25 patients, the overall response rate was 20% (n = 5; 95% CI, 6.8-40.7), comprising all partial responses. Thirteen patients had stable disease. The median duration of response was 12 months (range, 3.7-20.5+). A decrease in tumor size was observed in 60.9% of evaluable patients.

The median progression-free survival (PFS) was 5.4 months (95% CI, 3.4-7.5). The 6- and 12-month PFS rates were 45.8% and 20.8%, respectively. The median overall survival (OS) was 18 months (95% CI, 9.4-NR), with 6- and 12-month OS rates of 83.5% and 62.6%, respectively.

Earlier in the year, in a phase Ib study presented at the 2016 ASCO Annual Meeting, the PD-L1 inhibitor avelumab demonstrated clinical activity in patients with advanced or unresectable mesothelioma (J Clin Oncol. 2016;34[suppl; abstr 8503]).

In the multicohort, dose-expansion trial, 5 of 53 patients had partial responses, and 25 others had stable disease, resulting in a disease control rate of 56.6%. Evaluation of response by a tumor’s PD-L1 status showed an overall response rate of 14.3% for patients with tumors exhibiting ≥5% cell staining for PD-L1, versus 8.1% for patients with PD-L1—negative tumors.