Comparative patient-reported tolerability (PRT): A multiplicity-controlled analysis of LIBRETTO-531, a randomized controlled trial (RCT) in medullary thyroid cancer (MTC).
Authors: Brose Marcia S. , Robinson Bruce , Wirth Lori J. , Capdevila Jaume , Wadsley Jonathan , Sherman Eric Jeffrey , Tahara Makoto , Hoff Ana , Hu Mimi I-Nan , Gao Ming , Vaisman Fernanda , Churchill Collin , Lin Boris K. , Maeda Patricia H , Gilligan Adrienne M. , Lin Yan , Payakachat Nalin , Hadoux Julien , Elisei Rossella 
Published: June 2024

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Background: In cancers with longer natural histories, progression free survival (PFS) alone may not adequately capture the impact of treatment side effects (SE) and may, therefore, be complemented by robust measures of patient-reported tolerability (PRT) to quantify overall SE burden. Here, we pioneer the use of a novel, scalable, quantitative PRT metric as a key secondary endpoint to support the regulatory review and inform clinical decision-making of selpercatinib use in LIBRETTO-531 (NCT04211337), an RCT that demonstrated the PFS benefit (HR=0.28) of selpercatinib over vandetanib/cabozantinib (control) in RET-mutant MTC. Methods: We first assessed PRT using the single Functional Assessment of Cancer Therapy (FACT) item GP5, asking patients to rate “bothered by treatment side effects” from 0 to 4. Patients who reported “3=quite a bit” or “4=very much” on GP5 were classified as “high SE bother,” a validated meaningful cutoff for treatment SE burden. In a second pre-specified step, PRT was defined as the proportion of time on treatment (PTOT) with “high SE bother” and was compared between selpercatinib vs. control arms in the tolerability evaluable population. PRT was tested at a 1-sided significance level of 0.025, conditional on achieving statistical significance for PFS and treatment failure-free survival by BICR. To complement PRT, other patient-reported outcomes including health-related quality of life (HRQoL, using EORTC QLQ-C30) and symptomatic adverse events (AEs; using PRO-CTCAE) were evaluated. We calculated the PTOT that patients reported clinically meaningful impairment of HRQoL (using pre-specified cutoff scores) and highly symptomatic AEs (scores of 3 or 4). Results: Patients on selpercatinib (n=161) had a significantly better PRT (lower PTOT with high SE bother) than control (n=81) (8% vs. 24%, p<.0001). Sensitivity analyses using different cutoffs for high SE bother showed consistent results (p<.0001). On QLQ-C30, patients on selpercatinib reported significantly less PTOT with HRQoL impairment across physical (36% vs. 52%), role (2% vs. 11%), cognitive (4% vs. 8%), emotional (6% vs. 11%), and social (2% vs. 8%) functions (all p<0.01) vs. control. On PRO-CTCAE, patients on selpercatinib reported significantly less PTOT with diarrhea (5% vs. 38%), fatigue (6% vs. 21%), taste change (3% vs. 15%), decreased appetite (2% vs. 15%), hand/foot syndrome (2% vs. 9%) (all p<.001) vs. control. Conclusions: Through the incorporation of a novel, single question and quantifiable metric that measured time on treatment under high SE bother into the LIBRETTO-531 study, we demonstrated superior PRT and improved PFS for selpercatinib in patients with RET-mutant MTC versus vandetanib/cabozantinib. This simplified PRT metric deserves further adoption as a quantitative endpoint to complement PFS in future RCTs.