PATIENT-REPORTED OUTCOME (PRO)–BASED RECURRENTSYMPTOMATIC

DETERIORATION PREDICTS DISEASE PROGRESSION: RESULTS FROM THE ALPINE
TRIAL
Authors: Daniel Serrano,1, Jennifer R. Brown,2 Mazyar Shadman,3 Tommi Salmi,4 Timothy
Victor,5 and Gisoo Barnes6
1The Psychometrics Team, Sheridan, WY, USA
2Dana-Farber Cancer Institute, Boston, MA, USA
3Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington,Seattle, WA, USA
4BeiGene International GmbH, Basel, Switzerland
5BeiGene USA, Inc., San Mateo, CA, USA; University of Pennsylvania, Philadelphia, PA, USA
6BeiGene USA, Inc., San Mateo, CA, USA

Background: Time to deterioration or time until definite deterioration analyses of key PRO
symptoms (eg, fatigue) and functioning (eg, physical function) are routinely employed in oncology
trials to evaluate the effects of treatment on a single deterioration event. However, PRO-based
deterioration has “transient” event times: a patient may experience multiple fatigue deteriorations
over time. Transient event times are best modeled as recurrent events. This study focuses onfatigue deterioration given that anemia-mediated fatigue is common in chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) and examines the association between
recurrent PRO-based deterioration and progression-free survival (PFS).
Aims: This study examines the association between time to recurrent PRO-based deteriorationand disease progression.
Methods: The ALPINE trial (BGB-3111-305; NCT03734016) was a multinational, open-label,randomized, phase 3 study of adult patients with relapsed or refractory (R/R) CLL/SLL to compare
the efficacy and safety of zanubrutinib versus ibrutinib monotherapy (Brown et al. NEJM. 2023).
Anchor-based meaningful within-patient change thresholds defining EORTC-QLQ-C30 (C30)
fatigue deterioration were computed using median change from baseline (CFBL) to cycle 13 dataanchored on the C30 global health scale. Unique recurrent fatigue deterioration (RFA-D) eventsfrom cycles 4 to 43 were identified using the threshold. PFS and RFA-D events were modeled via
EHA 2024

Cox and Cox frailty proportional hazards, respectively, within a joint survival model (JM). TheRFA-D event frailty prediction of PFS was used to evaluate the relationship between RFA-D
events and PFS. The JM included a linear mixed model for CFBL in C30 pain scores to adjust forchanges in pain and assess the association between change in pain and RFA-D events andprogression. All 3 models were adjusted for geographic region, age, del(17p)/TP53 mutation
status, refractory status, and cancer type (CLL vs. SLL). All analyses were conducted using theJMBayes2 package in R version 4.3.2, applying to the ITT population with both PFS and RFA-D
event data.
Results: Of the 602 patients, 149 (24.8%) experienced zero RFA-D events; and 249 (41.4%), 95(15.8%), 65 (10.8%), 33 (5.5%), 10 (1.7%), and one (0.2%) experienced one, two, three, four,five, or six RFA-D events, respectively. Patients were censored if they experienced no recurrent
events or no progression by study end. In the PFS model, after adjusting for stratification factors
and CFBL in pain and prediction by risk of RFA-D events, zanubrutinib was associated with a31% reduction in the risk of investigator-assessed progression events (hazard ratio [HR]=0.69;
P=0.0193) when compared with ibrutinib (Table). Increasing RFA-D events were positively
associated with increased risk of progression (association parameter, 3.46; P=0.0467),
irrespective of treatment. In the recurrent event model for fatigue deterioration, there was nodifference between arms in risk of RFA-D events (P=0.7120). Increasing pain deterioration wasassociated with increased risk of RFA-D events, irrespective of treatment (P=0.0024).
Summary/Conclusion: After predicting PFS from the risk of RFA-D events and adjusting forbaseline stratification factors and CFBL in pain, zanubrutinib remained more protective thanibrutinib against progression. Recurrent fatigue deterioration predicted the risk of diseaseprogression before disease progression confirmation by the investigator. Analyses of otherdisease-related PRO endpoints in the ALPINE trial are being completed and will be reported.

EHA 2024

Table. JM survival submodel estimates
EventEﬀect
Progression
Zanubru�nib
Progression
Region Asia
Progression
Del(17p) present
Progression
Older than 65 years
Progression
Not refractory
Progression
CLL
Progression
C30 Pain
Progression
RFA-D frailty
RFA-D
Zanubru�nib
RFA-D
Region Asia
RFA-D
Del(17p) present
RFA-D
Older than 65 years
RFA-D
Not refractory
RFA-D
CLL
RFA-D
C30 PainaAssocia�on parameter and not HR.

EHA 2024

HR (95% CI)
0.69 (0.50–0.94)
1.04 (0.68–1.58)
1.66 (1.19–2.39)
1.32 (0.96–1.80)
0.76 (0.55–1.04)
0.66 (0.29–1.83)
1.00 (1.00–1.01)
3.46 (0.07–6.38)a0.94 (0.69–1.25)
0.98 (0.71–1.33)
0.84 (0.66–1.06)
1.22 (1.01–1.47)
0.96 (0.79–1.17)
0.67 (0.46–1.04)
1.01 (1.00–1.01)

P value0.01930.82600.00440.09200.09710.32070.39400.04670.71200.89400.14820.03310.69490.08130.0024