Recommended Reading from the Loyola University Medical Center Pulmonary and Critical Care Medicine Fellows; Bradford C. Bemiss, M.D., Faculty Advisor

The use of the medications nintedanib and pirfenidone has become routine for management of idiopathic pulmonary fibrosis (IPF). However, their use in non-IPF lung disease, including other interstitial lung diseases (ILDs) and pulmonary malignancies, is still being investigated. We provide a review of uses of pirfenidone and nintedanib for pulmonary diseases other than IPF.

In the first review, the INBUILD (Efficacy and Safety of Nintedanib in Patients with Progressive Fibrosing Interstitial Lung Disease [PF-ILD]) trial by Flaherty and colleagues has provided rationale for the use of nintedanib in progressive fibrosing ILDs besides nintedanib, resulting in approval from the U.S. Food and Drug Administration for this purpose. The second review shows some promise for the use of pirfenidone in unclassifiable ILDs, necessitating further study. The final study reviewed examined the use of nintedanib as an adjunctive antiangiogenic agent in malignant mesothelioma but unfortunately demonstrated no survival benefits.

Flaherty KR, et al; INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med (1)

Reviewed by Krishnan Warrior

The antifibrotic agents pirfenidone and nintedanib have shown efficacy in slowing progression in IPF (2–4). However, there remain few effective treatment options for patients with other ILDs with progressive phenotypes and similarly poor prognoses, termed progressive fibrosing ILD (PF-ILD) (5–8). The INBUILD trial sought to examine the efficacy of nintedanib in slowing the rate of decline in FVC in patients with PF-ILD (1).

The INBUILD trial was a multinational, double-blind, randomized controlled trial. Enrolled patients were adults with PF-ILD other than IPF, with fibrosis affecting greater than 10% of lung volume on high-resolution computed tomography chest and progression defined as decline in FVC of at least 10% predicted, a decline in FVC of 5–10% with worsening respiratory symptoms or increased fibrosis on imaging, or worsening respiratory symptoms and fibrosis on imaging. A total of 663 patients were included in this study, randomized to treatment with nintedanib or placebo. Notably, patients on immunosuppression before randomization were excluded from this trial. The primary endpoint was annual rate of decline in FVC.

The baseline characteristics of the nintedanib group and the placebo group were similar in demographics, proportion of patients with radiographic usual interstitial pneumonitis pattern, and baseline FVC. Chronic hypersensitivity pneumonitis and autoimmune ILD were the most common diagnoses. The 52-week rate of decline in FVC was −80.8 ml per year in the nintedanib group and −187.8 ml per year in the placebo group, a difference of 107.0 ml (P < 0.001). There was no significant difference between groups in symptom burden, time until exacerbation, or mortality. Adverse events were more common in the treatment group, with 66.9% of patients developing diarrhea compared with 23.9% in the placebo group, leading to 19.6% of patients in the nintedanib group discontinuing treatment compared with only 10.3% in the placebo group.

In the INBUILD trial, patients in the nintedanib group had slower decline in FVC, demonstrating delayed progression of fibrosis. However, there was no significant difference in patient-centered outcomes like mortality or symptom burden. Furthermore, exclusion of patients on immunosuppressants limits generalizability, as many patients with autoimmune PF-ILD will be on concomitant immunosuppressive agents. Despite these limitations, the U.S. Food and Drug Administration has approved nintedanib for treatment of PF-ILD based on this trial. More investigations regarding use of antifibrotic agents in PF-ILD are surely forthcoming and will help demonstrate their utility in these diseases (5, 6).

Maher TM, et al. Pirfenidone in Patients with Unclassifiable Progressive Fibrosing Interstitial Lung Disease: A Double-Blind, Randomised, Placebo-controlled, Phase 2 Trial. Lancet Respir Med (9)

Reviewed by Paul A. Chung

The diagnosis of specific ILDs is important for management strategy and prognosis (9–11). However, up to 10% of ILDs remain unclassifiable (uILD), with some having a progressive fibrosing phenotype similar to IPF (9–12). Pirfenidone and nintedanib have been shown to slow disease progression in IPF (3, 13, 14). As there are no currently approved treatments available for uILD, this study aimed to assess the efficacy and safety of pirfenidone in progressive fibrosing uILD (PF-uILD).

This was a multicenter, double-blind, randomized, placebo-controlled phase 2 trial. Included patients had ILD that could not be classified based on multidisciplinary discussion, fibrosis with an FVC greater than 45% predicted, and greater than 10% fibrosis on chest computed tomography, and progression based on >5% change in FVC or worsening of symptoms within the past 6 months. Two hundred fifty-three patients with PF-uILD were randomized to receive 2,403 mg of pirfenidone daily or placebo. The primary endpoint was mean change in FVC from baseline over 24 weeks measured by daily home spirometry. Important secondary endpoints included change in FVC measured by clinic-based spirometry, proportion of patients with absolute decline in FVC ≥5% or ≥10%, and change in 6-minute-walk distance from baseline.

The primary endpoint could not be analyzed because of recorded home spirometry values that were physiologically implausible and unreliable. However, there was a lower mean decline in FVC for the pirfenidone group compared with the placebo group using clinic-based spirometry, with a between-group difference of 95.3 ml (95% confidence interval, 35.9–154.6; P = 0.002). There was also a lower proportion of patients with decline in FVC >5% or >10% and a lower mean decline in 6-minute-walk distance from baseline in the pirfenidone group than in the placebo group.

There were more treatment-related adverse events, especially gastrointestinal side effects, in the pirfenidone group than in the placebo group, although serious adverse events were similar between the groups. Treatment discontinuation due to adverse events was higher in the pirfenidone group.

Although the primary endpoint could not be analyzed, the secondary endpoints show that pirfenidone is a promising treatment for PF-uILD. Furthermore, the safety profile from this study was consistent with other trials evaluating pirfenidone in IPF (15). Some limitations of this study include the absence of centralized review of imaging to confirm that the disease was unclassifiable and an unreliable primary endpoint. Further trials with a more reproducible primary endpoint like clinic-based spirometry are needed to evaluate long-term benefits.

Scagliotti GV, et al. Nintedanib in Combination with Pemetrexed and Cisplatin for Chemotherapy-Naive Patients with Advanced Malignant Pleural Mesothelioma (LUME-Meso): A Double-Blind, Randomised, Placebo-controlled Phase 3 Trial. Lancet Respir Med (15)

Reviewed by Michal Reid

Malignant pleural mesothelioma (MPM) is an aggressive disease. First-line therapy with pemetrexed and cisplatin (PC) in unresectable cases is associated with a median survival of approximately 1 year (16, 17). Angiogenesis contributes to the pathogenesis of MPM; therefore, VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor), and FGF (fibroblast growth factor) are potential therapeutic targets for MPM, all of which are also inhibited by nintedanib (18–23). The LUME-Meso trial was conceived to study the effect of the addition of nintedanib to usual treatment for MPM. Phase 2 of the LUME-Meso study showed prolonged progression-free survival in the nintedanib and PC group compared with placebo and PC. Progression-free survival was also improved in a subgroup analysis of patients with only epithelioid histology (24). Therefore, the trial was amended and a confirmatory phase 3 trial was created.

This was a double-blind, randomized, placebo-controlled trial done at 120 sites in 27 countries. Patients with unresectable MPM with biopsy-confirmed epithelioid histology that had not previously received systemic chemotherapy and with life expectancy of more than 3 months were included. Patients were randomized 1:1 to PC and either nintedanib or placebo. The primary endpoint was progression-free survival, and the main secondary endpoint was overall survival. In total, 458 patients were randomized, 229 to each group. There was no difference in progression-free survival between the groups with a median of 6.8 months (95% confidence interval, 6.1–7.0) in the nintedanib group versus 7.0 months (6.7–7.2) in the placebo group. Additionally, there was no difference between groups in objective response, disease control, and serious adverse events.

The reason for the disparate results between the phase 2 and phase 3 trials is unclear as the methodology and baseline characteristics were similar, aside from the limitation to only patients with epithelioid histology in phase 3. The double-blind design, large sample size, and geographically diverse population are strengths of the study, and limitations such as the lack of a central pathological review to confirm histology and the inability for patients to switch to carboplatin from cisplatin are unlikely to have affected the primary endpoint. Unfortunately, this trial did not show improvement in progression-free survival with the addition of nintedanib to PC. Other phase 2 and 3 trials targeting angiogenesis have also shown mixed results, raising questions surrounding the utility of angiogenesis as a therapeutic target (23, 25–27). Ongoing research is needed to improve outcomes in patients with unresectable MPM.