We thank Dr. T. Narra for the insightful comments about our article reporting results from the Combi-PF study [1], a long-term retrospective multicentre study of nintedanib combined with pirfenidone in patients with idiopathic pulmonary fibrosis or progressive pulmonary fibrosis.

We agree that the optimal management strategy for patients who experience continued progression of pulmonary fibrosis despite antifibrotic therapy remains undefined. Available options include continuation of the current antifibrotic agent as monotherapy, switching to the alternative antifibrotic drug, combining approved antifibrotic therapies, enrollment in a clinical trial, and referral for lung transplantation in eligible patients.

We further agree that safety and tolerability—which constituted the primary objective of our study—represent the principal contribution of real-world investigations. In the Combi-PF study, we evaluated the tolerability of the combination of nintedanib and pirfenidone and observed that adverse drug reactions occurred in the majority of patients, with 28.9% classified as severe, predominantly gastrointestinal in nature. Poor tolerability, particularly weight loss, emerged as the main challenge associated with this combination therapy.

Although our findings suggest a potential benefit of combination therapy in slowing the decline in lung function compared with continued antifibrotic monotherapy, these efficacy results should be interpreted with caution given the retrospective design of the study. Nevertheless, these observational data complement those from the three available clinical trials [2–4], including one randomized study.

The PROGRESSION-IPF clinical trial (ClinicalTrials.gov identifier: NCT03939520), which is currently enrolling patients with idiopathic pulmonary fibrosis who experience disease progression despite first-line antifibrotic therapy and randomizing them to one of three strategies (continuation of antifibrotic monotherapy, switching to an alternative antifibrotic agent, or combination antifibrotic therapy), is expected to provide important evidence to guide clinical decision-making.

In the future, combination antifibrotic therapy will likely consist of pirfenidone or nintedanib administered with a next-generation antifibrotic agent, such as nerandomilast (or potentially inhaled treprostinil, admilparant, or other investigational compounds), ideally offering an improved tolerability profile.

Nevertheless, the combination of nintedanib and pirfenidone may represent a reasonable therapeutic option in selected patients, particularly as a bridge to lung transplantation, especially when newer agents such as nerandomilast are not available and the patient is ineligible for participation in clinical trials.