Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial

Abstract

Background: The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients.

Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety.

Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR.

Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning.

Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.

Keywords: Bintrafusp alfa; Correlative biomarkers; Efficacy; Recurrent or metastatic nasopharyngeal cancer; Safety.

Fig. 1

Trial Profile. ∗Among 5 patients did not meet eligibility criteria: Active brain metastasis (n = 1), no target lesion (n = 3), and isolated local relapse (n = 1). # Among 7 patients withdrawn due to adverse events: Secondary malignancy (n = 4), skin reaction (n = 2), epistaxis (n = 1).

Fig. 2

Tumor response assessment based on RECIST v1.1 per independent review. (A) Waterfall plot of change from baseline in tumor size (n = 38). Baseline was defined as the last measurement taken before the randomisation date. For each patient, the best (minimum) percentage change from baseline in the sum of diameters for all target lesions was represented by a vertical line, plotted in order of greatest percentage increase to greatest percentage decrease. Only patients with measurable disease at baseline and at least one post-baseline assessment were included in the waterfall plots. (B) Spider plot of the longitudinal change from baseline in tumor size (n = 38). The blue line represents responder; yellow line represents non-responder. (C) Swimmer plot on treatment exposure and response duration (n = 38).

Fig. 3

Bar chart showing the percentage of patients with strong TGFβ1 suppression (low week 8/baseline level) among patients with HPD vs non-HPD progressors vs non-progressors (per RECIST v1.1). Abbreviations: HPD: Hyper-progression; Non-HPD progressors, progressive disease not fulfilling the definition of HPD; Non-progressors = complete response (CR) + partial response (PR) + stable disease (SD).