Researchers reported phase II findings from the LUME-Meso phase II/III trial, an ongoing study evaluating nintedanib in combination with chemotherapy for the first-line treatment of unresectable malignant pleural mesothelioma (MPM). The phase II portion met its primary endpoint, moving nintedanib to phase III, but experts caution against over interpretation of results. Results were reported at the ESMO 2017 Congress (Abstract 1618PD).
MPM is a rare, aggressive disease with a poor overall prognosis and limited treatment options; the only first-line treatment available to patients with unresectable MPM is cisplatin plus pemetrexed. Nintedanib, an oral tyrosine kinase inhibitor, is being evaluated as an agent to be used in combination with cisplatin plus pemetrexed. Currently, nintedanib is FDA-approved for idiopathic pulmonary fibrosis.
Clinical Trial Details
The phase II trial randomized 87 participants with unresectable MPM who had not received systemic chemotherapy to the combination or placebo arm. Those in the combination arm received nintedanib plus pemetrexed and cisplatin, and those in the placebo arm received pemetrexed and cisplatin, the standard of care. Patients whose disease did not progress during the combination therapy phase continued on either nintedanib or placebo monotherapy.
Participants were selected based on MPM histology, which can be divided into epithelioid, sarcomatoid, and biphasic (mixture of epithelioid and sarcomatoid). Participants had either epithelioid or biphasic histology; those with sarcomatoid histology were excluded.
Participant characteristics, including histology, were generally equal between both arms. Most patients were male (79% of participants), had prior exposure to asbestos (70% of participants), and epithelioid histology (89% of participants).
The study met its primary endpoint, which was progression-free survival (PFS). Participants in the combination arm had a statistically significant longer median PFS (HR=0.54; 95% CI: 0.33-0.87; P=0.010; median PFS 9.4 vs. 5.7 months), and the extent was greatest for participants with epithelioid histology (HR=0.49; 95% CI: 0.30-0.82; P=0.006; median PFS 9.7 vs. 5.7 months).
“I think it's sufficient data to examine a further study,” said Alain Borczuk, MD, mesothelioma expert at Weill Cornell Medicine and NewYork-Presbyterian. Borczuk explained that MPM can behave differently depending on the histological subtype and that the epithelioid subtype, which was found to have a better response in the study, generally has the best prognosis of the three subtypes. He suggested that the study researchers should focus on the epithelioid subtype specifically for future work.
“In such an intractable disease, seeing any statistically significant benefit does warrant moving it to the next level,” he said.
Nintedanib may have a greater clinical activity in the epithelioid subtype for a few possible reasons, Borczuk explained. He said that, to begin with, the epithelioid subtype is generally more responsive to chemotherapy. Another reason is nintedanib targets multiple signaling pathways. By targeting multiple pathways of activation, nintedanib could be targeting a tumor type that has these multiple pathways of activation simultaneously on, he said.
The study was less successful at meeting its secondary endpoints, in particular median overall survival (OS). The combination arm had a longer median OS than the placebo arm, but the difference was not statistically significant (HR=0.77; 95% CI: 0.46-1.29; P=0.3193; median OS 18.3 vs. 14.2 months). When analyzing only participants with epithelioid histology, the findings were similar; the intervention had a longer median OS than the placebo arm, but the difference again lacked statistical significance (HR=0.70; 95% CI: 0.40-1.21; P=0.1965; median OS 20.6 vs. 15.2 months).
Forced vital capacity (FVC), a measure of pulmonary function and quality of life, was also an endpoint; higher FVC correlates with improved pulmonary function and quality of life. The study suggested favorability for the combination arm over the placebo arm at cycle 8 (mean treatment difference: 7.2% [SE: 4.5]) and for those with epithelioid histology (mean treatment difference 9.9% [SE: 4.5])
The authors concluded that adding nintedanib to chemotherapy showed “a trend” towards improvement of OS and pulmonary function. Borczuk disagreed with these conclusions.
“An endpoint of what's described as ‘a trend’ certainly is an overstatement. The only [statistically] significant outcome was the progression-free survival,” he said. “They saw an improvement in progression-free survival with the addition of the nintedanib. They did not see a significant association with overall survival or with changes in pulmonary function.”
The safety profile for nintedanib plus chemotherapy was described as manageable by the study authors. The percentage of patients who discontinued treatment as a result of adverse events was lower in the combination arm than placebo (6.8% vs. 17.1%), and the rate of grade 3 or higher adverse events was greater in the nintedanib arm than the placebo arm (79.5% vs. 53.7%).
Borczuk said that, although toxicity was higher for the combination arm, the level of toxicity was not clinically concerning. “This is a disease that is associated with a very high mortality on its own, so the risk-benefit in these patients is a strong consideration.”
Borczuk cautioned against overinterpreting the study. He said it is a small group of patients with a mixed set of histological subtypes, and histology can affect clinical outcomes. “I think a study of that size would not be sufficient to start recommending use of an agent,” he said.
David Sugarbaker, MD, Professor and Chief in the Division of General Thoracic Surgery and Director of the Lung Institute at Baylor College of Medicine, Houston, described the study as “interesting” but added caution, too. “I don't think we necessarily have enough data with enough impact to let us conclude that nintedanib should be used in combination off label with conventional chemotherapy.”
“People talk about theoretical reasons why an agent that seems promising in a phase II setting is not promising in a phase III setting; there are many reasons for that,” Borczuk said. “One of the realities is, in a disease as rare as malignant mesothelioma, the studies of this size are critical to be performed, but they also need to be confirmed.
“[MPM] is a disease that has some heterogeneity within it. In a small group, such heterogeneity can lead to false conclusions, so at that point you do need to either do a larger study or at least a confirmatory study,” he continued. “The accruing of about 80 patients is already a quite great accomplishment, so I don't want to be overly critical of the small sample.”
Christina Bennett is a contributing writer.