Pamufetinib Fails to Slow FVC Decline in Progressive Fibrosing ILD

Pamufetinib (TAS-115), an oral multikinase inhibitor, failed to slow FVC decline compared with continued nintedanib or pirfenidone in a phase 2b trial of patients with progressive chronic fibrosing interstitial lung disease (CF-ILD).¹

“The FVC decline in the pamufetinib 100 mg group was suppressed until week 10, which was consistent with the previous phase 2a study,” wrote investigator Ryo Okuda, from Kanagawa Cardiovascular and Respiratory Center in Japan, and colleagues.¹ “However, after week 16, the rate of FVC decline was reversed, resulting in an FVC that was lower in the pamufetinib 100 mg group than the control group.”

No therapy is currently recommended for CF-ILD with disease progression despite treatment with nintedanib or pirfenidone. The earlier phase 2a single-arm study of pamufetinib suggested a delay in disease progression among patients with FVC decline on standard antifibrotic therapy, using intrapatient slope change as a surrogate endpoint.² This phase 2b study tested whether the signal would translate into a dose-dependent benefit when pamufetinib replaced standard antifibrotic therapy outright.¹

Pamufetinib Efficacy in the Phase 2b Chronic Fibrosing ILD Trial

This double-blind, multicenter, active-controlled phase 2b trial enrolled patients at 41 sites in Japan between October 2021 and June 2024.¹ Eligible patients had CF-ILD with a progressive phenotype, defined as a relative %FVC decline of ≥ 5% per year despite nintedanib or pirfenidone, and an %FVC of ≥ 50%. Patients were randomized 1:1:1 to pamufetinib 100 mg, pamufetinib 50 mg, or control therapy consisting of continued nintedanib or pirfenidone, using a double-dummy design to preserve blinding across the differing dosage forms.

Pamufetinib was administered on a 5-day-on/2-day-off oral schedule for 26 weeks. Of 243 patients randomized and treated, 71.0% had IPF, and mean %FVC was approximately 74% across the 3 arms.¹

The primary endpoint, 26-week rate of decline in FVC, was -157.8 mL (95% CI, -208.8 to -106.9) with pamufetinib 100 mg, -96.0 mL (95% CI, -145.4 to -46.6) with pamufetinib 50 mg, and -63.6 mL (95% CI, -111.8 to -15.5) with control therapy. No dose-response relationship was observed, and the 100 mg arm showed a numerically greater decline than control. Investigators noted the 100 mg arm maintained early suppression of FVC decline through week 10 before the effect reversed between weeks 16 and 26.¹

Pamufetinib Safety Profile and Secondary Endpoints in CF-ILD

Absolute change in %DLco from baseline at 26 weeks was -5.2% with pamufetinib 100 mg, -3.4% with pamufetinib 50 mg, and -2.6% with control therapy.¹ Acute exacerbation occurred in 12.8% (10/78) of the pamufetinib 100 mg group, 9.6% (8/83) of the pamufetinib 50 mg group, and 3.8% (3/80) of the control group by week 26. Death occurred in 3.8%, 6.0%, and 2.5% of patients, respectively, though the 26-week trial was not designed to detect survival differences.¹

Rash was the most frequent adverse event in both pamufetinib arms, reported in 29.1% of the 100 mg group and 14.3% of the 50 mg group versus 10.0% of the control group. Most cases were mild to moderate in severity.¹

Adverse events coded as ILD, encompassing both acute exacerbations and newly diagnosed disease, occurred in 10.1% of the 100 mg group, 9.5% of the 50 mg group, and 3.8% of the control group. The study reported serious adverse events in 27.8%, 20.2%, and 15.0% of patients across the same groups. Treatment discontinuation occurred in 12.7% and 11.9% of the pamufetinib 100 mg and 50 mg groups, respectively, compared with no discontinuations in the control group.¹

Investigators attributed the unfavorable FVC trajectory partly to pamufetinib's off-target inhibition of MET, AXL, and Src alongside its intended PDGFR, VEGFR, and CSF1R targets, since MET signaling supports alveolar epithelial repair after lung injury.³ Subgroup analyses stratified by IPF status and prior antifibrotic treatment showed results consistent with the overall population, with no benefit favoring pamufetinib.¹

The findings indicate no advantage to switching from standard antifibrotic monotherapy to pamufetinib in patients progressing despite treatment, leaving nintedanib and pirfenidone the only approved options for CF-ILD.

References

1. Okuda R, Nishioka Y, Kondoh Y, et al. Pamufetinib (TAS-115) for chronic fibrosing interstitial lung diseases with a progressive phenotype: a double-blind, multicenter, phase 2b clinical trial. Am J Respir Crit Care Med. 2026;212(8):1770-1777. doi:10.1093/ajrccm/aamag125

2. Nishioka Y, Homma S, Ogura T, et al. Exploratory phase 2 study of the novel oral multi-kinase inhibitor TAS-115 in patients with idiopathic pulmonary fibrosis. Respir Investig. 2023;61:498-507. doi:10.1016/j.resinv.2023.04.008