Nintedanib (Ofev) for Mesothelioma

Nintedanib, marketed as Ofev (and Vargatef in some regions), is a triple angiokinase inhibitor that was investigated as a treatment for malignant pleural mesothelioma in the LUME-Meso clinical trial program. Nintedanib works by blocking three families of receptors involved in tumor blood vessel formation (angiogenesis): VEGF receptors, FGF receptors, and PDGF receptors. By simultaneously inhibiting all three pathways, nintedanib aims to cut off the blood supply that mesothelioma tumors depend on for growth and survival.¹

The LUME-Meso trial was a randomized phase II/III study that evaluated nintedanib combined with standard pemetrexed/cisplatin chemotherapy versus placebo plus chemotherapy as first-line treatment for unresectable malignant pleural mesothelioma. The phase II portion showed encouraging results: patients receiving nintedanib plus chemotherapy had improved progression-free survival (9.4 months vs. 5.7 months) compared to chemotherapy alone, particularly in patients with epithelioid histology.²

However, the phase III portion of the LUME-Meso trial, which enrolled a larger patient population, did not confirm the progression-free survival benefit seen in phase II. The trial was discontinued in 2019 after a pre-planned interim analysis determined that it was unlikely to meet its primary endpoint. This disappointing result was a significant setback for the anti-angiogenic approach in mesothelioma, though the drug's activity in the phase II cohort suggests that certain patient subgroups may still benefit.³

Nintedanib remains FDA-approved for idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease, making it relevant for mesothelioma patients who may also have asbestos-related pulmonary fibrosis (asbestosis). The drug's oral formulation and manageable side effect profile make it an attractive candidate for further study in mesothelioma, potentially in combination with immunotherapy or in biomarker-selected populations.¹

Nintedanib has been studied as an addition to standard first-line chemotherapy for mesothelioma:²

LUME-Meso Trial Protocol

• Design — Randomized, double-blind, placebo-controlled phase II/III trial
• Treatment arm — Nintedanib 200 mg orally twice daily on Days 2–21 + pemetrexed 500 mg/m² + cisplatin 75 mg/m² on Day 1 of each 21-day cycle for up to 6 cycles, followed by nintedanib maintenance
• Control arm — Placebo + pemetrexed + cisplatin, followed by placebo maintenance

Phase II Results (Encouraging)

The phase II portion demonstrated promising activity:²

• Median PFS (all patients) — 9.4 months (nintedanib) vs. 5.7 months (placebo); HR 0.54
• Median PFS (epithelioid only) — 9.7 months vs. 5.7 months; HR 0.49
• Objective response rate — 57% vs. 44%
• Disease control rate — 93% vs. 85%

Phase III Results (Did Not Confirm)

The confirmatory phase III trial was stopped after interim analysis:³

• Primary endpoint (PFS) — Not met; the addition of nintedanib did not significantly improve PFS over placebo + chemotherapy in the larger phase III population
• Discontinuation — The independent data monitoring committee recommended stopping the trial in 2019
• Possible explanations — Phase III enrolled a broader patient population; differences in regional treatment practices; potential biomarker-defined subgroup benefits not captured in the unselected population

Despite the negative phase III results, the LUME-Meso data provides important insights into anti-angiogenic therapy in mesothelioma:²

• Phase II signal — The 9.4-month PFS with nintedanib + chemo (vs. 5.7 months with placebo + chemo) in the phase II cohort represented a substantial improvement
• Epithelioid subtype — Patients with epithelioid histology showed the strongest benefit signal, consistent with the pattern seen with bevacizumab in the MAPS trial
• Anti-angiogenic context — The MAPS trial showed that bevacizumab added to pemetrexed/cisplatin improved survival (18.8 vs. 16.1 months), validating the anti-angiogenic approach in mesothelioma even though nintedanib specifically did not confirm benefit in phase III
• Ongoing research — Identifying biomarkers to select patients most likely to benefit from anti-angiogenic therapy remains an active research priority

Nintedanib's side effects reflect its anti-angiogenic mechanism and oral administration route:¹

• Diarrhea — The most common side effect, affecting 60–70% of patients (grade 3–4 in approximately 10%). Managed with loperamide, dietary modifications (avoiding fatty foods), and dose reduction if necessary. Patients should have loperamide available from the first day of treatment
• Nausea and vomiting — Occurs in 20–30% of patients. Taking nintedanib with food reduces gastrointestinal symptoms. Anti-emetics may be used as needed
• Liver enzyme elevation — ALT/AST elevations occur in 10–15% of patients. Liver function tests are monitored monthly during the first 3 months and periodically thereafter
• Appetite loss and weight loss — Reported in 15–25% of patients. Nutritional counseling and small, frequent meals can help maintain caloric intake
• Bleeding risk — Anti-angiogenic agents increase bleeding risk. Patients should report any unusual bleeding, and nintedanib should be withheld before surgical procedures
• Wound healing — Impaired wound healing is a class effect of anti-angiogenic drugs. Nintedanib should be stopped before and after any surgical procedure