Combination therapy with nintedanib plus pirfenidone appears well tolerated in IPF

Key takeaways:

• Nintedanib plus pirfenidone led to a comparable rate of adverse events as monotherapy.
• Combination therapy may lead to less decline in FVC compared with monotherapy.

HONOLULU — Treatment with nintedanib plus pirfenidone resulted in a similar frequency of adverse events as monotherapy among patients with idiopathic pulmonary fibrosis, according to a systemic review presented at the CHEST Annual Meeting.

However, use of nintedanib (Ofev, Boehringer Ingelheim) and pirfenidone together, both antifibrotic medications with different pharmacodynamics, increased the rate of treatment discontinuation due to an adverse event, according to researchers. In two studies, the combination also appeared to improve efficacy, although these studies were small with few patients.

“Combination therapy and monotherapy appear to have very similar profiles in terms of adverse events,” Tanmay Gandhi, MD, third-year internal medicine resident at University of Arkansas for Medical Science, said during his presentation. “However, patients on the combination therapy were more likely to experience an adverse event that led to discontinuation from combination to the monotherapy.”

Using PubMed, Embase and Web of Science, Gandhi and colleagues reviewed and assessed seven studies including 238 patients (mean age, 68.2 years; 79% men) with IPF receiving a combination of nintedanib (200 mg to 300 mg per day) and pirfenidone (600 mg to 2,400 mg per day) to determine the prevalence of adverse events and how effective this combination therapy is in this patient population.

The designs of the studies varied, with three retrospective observational cohort studies, two open-label randomized controlled trials (RCTs), one open-label single arm clinical trial and one double-blind RCT. Three of the seven included studies directly compared combination therapy with monotherapy.

The studies had an average follow-up of 7.5 months (range, 1-14), and patients received the combined therapy for an average of 4.5 months (range, 0.75-6).

Among the total cohort, mean FVC was 71.3% predicted (95% CI, 64.1%-78.5%), and mean diffusing capacity of the lungs for carbon monoxide was 48.2% predicted (95% CI, 45.2%-51.2%), according to researchers.

Adverse events related to treatment occurred in most patients (79%; 95% CI, 70%-88%) taking nintedanib and pirfenidone together. Diarrhea was the most frequent event, reported in 41% of patients, followed by nausea (35%), vomiting (22%), loss of appetite (19%), fatigue (15%), elevated liver enzymes (8%) and photosensitivity (7%).

Researchers further found that adverse events led to treatment discontinuation in 24% of patients, with 3% of patients experiencing a serious adverse event.

Notably, when researchers used data from only the three studies that compared combination therapy with monotherapy, they found a comparable rate of adverse events between the two groups (79%; 95% CI, 56%-91% vs. 81%; 95% CI, 58%-92%).

Researchers also found a comparable rate of serious adverse events among patients treated with combination therapy and patients treated with monotherapy (5%; 95% CI, 2%-14% vs. 9%; 95% CI, 4%-18%).

However, the percentage of patients who had an adverse event that resulted in treatment discontinuation was greater among those receiving combination therapy at 35% (95% CI, 21%-52%) vs. those receiving monotherapy at 11% (95% CI, 5%-24%).

In terms of efficacy, Gandhi said, “combination therapy appears to be more efficacious [than monotherapy].” Specifically, two studies showed a significantly lower rate of FVC decline with combination therapy vs. monotherapy (120.5 mL/year vs. 310 mL/year; P = .013; 0.12% predicted/month vs. 0.41% predicted/month; P = .045).

Importantly, Gandi mentioned that these two studies had a small number of patients, with 19 patients in the first study and 16 patients in the second.

“The preliminary data that we have so far does suggest a possible benefit of using combination therapy to slow the decline of FVC amongst patients as compared to the monotherapy with anti-fibrotic agents,” Gandhi said during his presentation.

“However, there are several limitations to the systematic review, and one of them is the high degree of heterogeneity amongst the studies that were included,” he said, again noting the small numbers of patients in some of the studies.