Malignant pleural mesothelioma (MPM) is an aggressive cancer that is typically diagnosed at advanced stages, where prognosis is poor and survival short. Until recently, chemotherapy combination of cisplatin and pemetrexed has been standard of care. However, in the phase III MAPS trial, the addition of the angiogenesis inhibitor bevacizumab to standard chemotherapy demonstrated significant overall survival (OS) benefit. These data indicate that targeting angiogenesis may be an important treatment approach in mesothelioma. The tyrosine kinase inhibitor (TKI) nintedanib is known to target both angiogenesis and other pathways associated with poor prognosis in MPM, making it a rational candidate for MPM treatment.
In the randomized, double-blind, phase II LUME-Meso study (N = 87), nintedanib (200 mg twice daily) plus pemetrexed and cisplatin was compared to placebo plus pemetrexed and cisplatin in patients with previously untreated advanced MPM.
The addition of nintedanib to chemotherapy resulted in a 3.7-month improvement in progression-free survival (PFS) compared to chemotherapy alone (9.4 months vs 5.7 months; HR 0.54, P = .010). PFS improvement with nintedanib was most evident in patients with epithelioid histology (9.7 months vs 5.7 months; HR 0.49, P = .006). Preliminary OS analysis showed a nonsignificant trend favoring nintedanib (18.3 months vs 14.2 months; HR 0.77, P = .319). In patients with epithelioid histology, OS improvement was 5.4 months (20.6 months vs 15.2 months; HR 0.7, P = .197). The overall response rate (ORR) was higher in patients receiving nintedanib plus chemotherapy compared to chemotherapy alone (56.8% vs 44.2%).
The addition of nintedanib to chemotherapy was associated with higher rates of grade ≥3 adverse events (AEs) compared to chemotherapy alone (79.5% vs 53.7%). The most frequently reported AEs associated with nintedanib were diarrhea and neutropenia, though rates of febrile neutropenia were low. Rates of AEs typically associated with angiogenesis inhibitors, including bleeding, gastrointestinal perforation, and thromboembolism, were not increased in patients receiving nintedanib.
The investigators concluded that the addition of nintedanib to standard chemotherapy in treatment-naïve patients with MPM led to clinically meaningful improvements in efficacy with manageable toxicity. In particular, the median OS of 20.6 months in patients with epithelioid histology is the longest reported in a randomized phase II trial and provides sufficient rationale to proceed with a phase III trial in this population.