We read with great interest the editorial by Luppi and Spagnolo [1] and the recent Combi-PF study by Meersseman et al. [2], which together highlight the growing interest in combination antifibrotic therapy for pulmonary fibrosis. The rationale for targeting multiple pathogenic pathways is compelling, and emerging data suggest that combination approaches may be feasible in selected patients. For more than a decade, treatment options for idiopathic pulmonary fibrosis (IPF) were limited to pirfenidone and nintedanib. More recently, agents such as nerandomilast and inhaled treprostinil have demonstrated efficacy in reducing FVC decline, thus further expanding the therapeutic landscape (Table 1). However, we believe that the central question has evolved beyond whether combination therapy is feasible. A more fundamental challenge is emerging as therapeutic options continue to increase: what is the optimal therapeutic strategy for patients with IPF?

Which therapy should be selected first? Should treatment selection be guided by clinical characteristics, disease behavior, comorbidities, patient preferences, or molecular phenotypes? When disease progression occurs, is switching therapy preferable to escalation through combination treatment or the addition of novel agents? These questions are becoming increasingly relevant as the number of available therapeutic options continues to grow.

Current evidence does not provide definitive answers regarding the optimal therapeutic strategy in IPF. Neither the recent TETON-2 [3] and FIBRONEER-IPF [4] trials nor the observational Combi-PF [2] study was designed to compare therapeutic strategies. Although these studies provide valuable information regarding efficacy, safety, and feasibility, they cannot determine which therapeutic strategy is superior, including monotherapy, treatment switching, combination approaches, or other escalation strategies. In clinical trials, randomization was performed for the investigational drug rather than for the treatment strategy itself. Consequently, subgroup analyses according to background antifibrotic use should be interpreted cautiously because they remain susceptible to confounding by indication and other baseline differences. Similarly, observational studies such as Combi-PF are inherently vulnerable to treatment-selection bias, because add-on or combination approaches are often prescribed to patients with more advanced disease or ongoing progression despite treatment. Equally important will be the identification of clinical, biological, and genetic phenotypes—such as telomere-related abnormalities or the MUC5B promoter variant—that may predict treatment response and guide precision medicine approaches in IPF.

Future studies should move beyond evaluating individual drugs and focus on therapeutic strategies. Although conventional head-to-head randomized trials may be challenging in a relatively rare disease, such as IPF, innovative designs—including factorial, adaptive, and pragmatic strategy-based trials—could help compare monotherapy, treatment switching, escalation, and combination approaches [5]. High-quality observational studies using methods such as propensity score adjustment may also provide valuable complementary evidence. Whenever possible, these studies should incorporate stratification by clinical phenotype and biomarkers associated with disease behavior or treatment response. The challenge is no longer to simply develop new therapies but to determine how available and emerging treatments should be optimally combined, sequenced, and personalized.