Real-World Comparative Effectiveness of Covalent Bruton Tyrosine Kinase
Inhibitors Among Patients With Relapsed/Refractory Mantle Cell Lymphoma

P1139

Tycel Phillips,1 Taavy A. Miller,2 Jingru Wang,2 Amy Pierre,2 Gregory A. Maglinte,3 Erlene K. Seymour3
1City of Hope, Duarte, CA, USA; 2Flatiron, New York, NY, USA; 3BeiGene USA, Inc, San Mateo, CA, USA

RE SU LTS

Data Source and Study Design
This retrospective observational cohort study used the nationwide, longitudinal, electronic
health record-derived, Flatiron Health database, comprising de-identified patient-level
data originated from ~280 US cancer clinics (~800 sites of care; primarily community
oncology settings) and curated via technology-enabled abstraction1,2
The study design is shown in Figure 1••

Figure 1. Study Design
Data cutoff
30 Nov 2023
Initiation of index
therapya(2L/3L cBTKi monotherapy)

Follow-up period

Baseline assessment period(time from the index date to date of death, or lastknow electronic medical encounter date in the
database in the absence of an observed death)(period between initial MCL diagnosis[2011 or later] until the index date)Index date(start date of the patient’s first treatment with 2L/3L cBTKi monotherapy: zanubrutinib,acalabrutinib, or ibrutinib)
aIndex therapy was defined as the patient’s first exposure to 2L/3L zanubrutinib, acalabrutinib, or ibrutinib.

Study Population
Eligible adults were included from the real-world database
Inclusion criteria were:International Classification of Disease code for non-Hodgkin lymphoma (NHL), as
identified by structured data
≥2 documented clinical visits on different days occurring on or after January 1, 2011
Diagnosis of MCL on or after January 1, 2011, as confirmed by a review ofunstructured data
Received treatment with ≥2 lines of treatment, where 2L treatment for MCL wasreceived on or after January 1, 2018
Treated with zanubrutinib, acalabrutinib, or ibrutinib monotherapy in the 2L/3L setting
Patients were excluded if they were treated with a BTKi prior to their first cBTKi
monotherapy in the 2L/3L setting

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•

•

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Study Outcomes
Patient baseline demographic and clinical characteristics were described
RW treatment patterns were evaluated, as well as clinical outcomes:
RW time to next treatment (rwTTNT), defined as time from index date to the start of thenext treatment or death, whichever occurred first
RW overall survival (rwOS), defined as time from index date to date of death

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•

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Statistical Methods
For continuous variables, descriptive statistics included medians, interquartile range(IQR), and minimum and maximum values; for categorical variables, frequencies andpercentages were reported
Survival curves were generated using Kaplan-Meier analyses and log-rank test was used
to compare the survival distributions across treatment groups
In unadjusted analyses, rwTTNT and rwOS were compared between 2L/3L cBTKi
treatment groups without any covariate adjustment. Median survival estimates, survival
probabilities at 1, 3, 6, 9, and 12 months after the index date, and 95% confidence
intervals (CIs) were reported
In adjusted analyses, propensity scores were estimated using multivariable logistic
regression models, and inverse probability of treatment weighting was conducted toestimate the average treatment effectCox proportional hazards regression models were used to generate unadjusted or adjusted
hazard ratios (HR) for the treatment comparisons with associated 95% CIs and P values

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••
•
•

Ibrutinib(n=194)

Age at 2L start (range), years
74 (34, 85)Male, n (%)
448 (74%)
Race, n (%)
White
458 (76%)
Black or African American
21 (3.5%)Asian
9 (1.5%)
Other race
48 (8.0%)
Unknown/not documented
66 (11%)Ethnicity, n (%)
Hispanic or Latino
34 (5.6%)
Non-Hispanic or Latino
451 (75%)
Unknown/not documented
117 (19%)
SES index, n (%)
1 – lowest SES
70 (12%)297 (16%)3118 (20%)
4143 (24%)
5 – highest SES
112 (19%)
Unknown/not documented
62 (10%)
Disease subtype, n (%)
Blastoid MCL
41 (6.8%)
Pleomorphic MCL
20 (3.3%)
Leukemic MCL
30 (5.0%)
MCL, NOS
511 (85%)
Stage at initial diagnosis, n (%)
I
11 (1.8%)II
18 (3.0%)
III
68 (11%)IV
381 (63%)
Unknown/not documented
124 (21%)
Bulky disease at initial diagnosis, n (%)
Yes
105 (17%)
No/unknown
497 (83%)
ECOG PS at index start, n (%)a0-1364 (60%)
2-460 (10.0%)
Unknown
178 (30%)
TP53 status at index start, n (%)b
Positive27 (4.5%)
Negative or unknown/not575 (96%)
documented
Ki67 status at index start, n (%)b<10%
27 (4.5%)
11%-30%122 (20%)
31%-50%116 (19%)>50%
159 (26%)
Unknown/not documented
178 (30%)
LDH at index start, n (%)b<0.67 ULN
111 (18%)≥1.50 ULN
46 (7.6%)
0.67-0.99 ULN
190 (32%)
1.00-1.49 ULN
79 (13%)
Unknown/not documented
176 (29%)
Number of LOT prior to index, n (%)c1487 (81%)
2115 (19%)
Time from start of 1L to index of
22 (7, 46)
first BTKi, median (IQR), months
Patient disposition at data cutoff, n (%)
Confirmed death
273 (45%)
Still on therapy at data cutoff
135 (22%)74 (46, 85)
79 (74%)74 (34, 85)
229 (76%)

72 (38, 85)
140 (72%)

82 (77%)≤5≤55 (4.7%)
17 (16%)231 (77%)
11 (3.7%)
7 (2.3%)24 (8.0%)28 (9.3%)

145 (75%)
9 (4.6%)≤519 (9.8%)
21 (11%)7 (6.5%)80 (75%)20 (19%)15 (5.0%)227 (75%)
59 (20%)12 (6.2%)
144 (74%)
38 (20%)9 (8.4%)21 (20%)16 (15%)31 (29%)23 (21%)7 (6.5%)29 (9.6%)
48 (16%)62 (21%)
67 (22%)59 (20%)36 (12%)32 (16%)28 (14%)40 (21%)45 (23%)30 (15%)19 (9.8%)≤5≤5≤595 (89%)

23 (7.6%)
11 (3.7%)
17 (5.6%)250 (83%)

13 (6.7%)
7 (3.6%)8 (4.1%)166 (86%)• Adjusted models showed significantly longer rwTTNT and rwOS for 2L/3L zanubrutinib

••

A―

1.00

C1.00

1.00

0.75

0.75

0.75

0.75

0.50
0.25

0.50
0.25
0.00

0B1.0015 (14%)92 (86%)46 (15%)255 (85%)

44 (23%)150 (77%)

68 (64%)9 (8.4%)30 (28%)185 (61%)33 (11%)
83 (28%)111 (57%)
18 (9.3%)
65 (34%)6 (5.6%)17 (5.6%)≤5

101 (94%)284 (94%)

190 (98%)

7 (6.5%)22 (21%)16 (15%)32 (30%)30 (28%)11 (3.7%)
61 (20%)59 (20%)74 (25%)96 (32%)9 (4.6%)39 (20%)41 (21%)53 (27%)52 (27%)22 (21%)6 (5.6%)33 (31%)13 (12%)33 (31%)49 (16%)23 (7.6%)
95 (32%)38 (13%)96 (32%)40 (21%)17 (8.8%)
62 (32%)28 (14%)47 (24%)85 (79%)22 (21%)240 (80%)
61 (20%)162 (84%)
32 (16%)rwOS

25 (10, 57)

19 (7, 45)

22 (6, 43)

0.75
0.50
0.25

0 20

20 40
40 60
Time, monthsTime, months
132

323260 80

660

0.50
0.25
0.00

Number at risk
Number at risk
301
301 72
Aclabrutinib Aclabrutinib
194
194 45
Ibrutinib
Ibrutinib
107
107 15
Zanubrutinib Zanubrutinib

20 40
40 60
Time, monthsTime, months

60 80

80

72

1616220045

1515440015

1

1000

0

Table 2. Unadjusted, Multivariate, and Propensity-Score Adjusted Hazard Ratios forrwTTNT and rwOS Comparing 2L/3L cBTKi Monotherapy Among Patients with R/R MCL
OutcomeaZanubrutinib vs Acalabrutinib
HR (95% CI)

P Value

Unadjusted

0.77 (0.56-1.06)

Multivariate (Cox model)

Zanubrutinib vs Ibrutinib

0 20

Number at risk
Number at risk
All 602All 602 270

D1.00

1.00

0.75

0.75

0.50
0.25

20 40
40 60
Time, monthsTime, months

60 8080270

1407272140

Zanubrutinib Zanubrutinib
AcalabrutinibAcalabrutinib
Ibrutinib
Ibrutinib

0.50
0.25
0.00

00 20

Number at risk
Number at risk
Aclabrutinib Aclabrutinib
301
301 106Ibrutinib
Ibrutinib
194 89
194Zanubrutinib Zanubrutinib
107 25107

20 4040 60
Time, monthsTime, months

60 80

80

106

2929

66008940

40990025330000

LI M I TATI ON S

• The limited sample size and follow-up period with 2L/3L zanubrutinib restricted the ability
to discern smaller differences in effectiveness compared with the other evaluated cBTKis• The included oncology practices may not have represented all practice sites within the US• Lack of certain data (eg, specific variables, loss to follow-up) could have introduced bias

HR (95% CI)

P Value.11

0.66 (0.48-0.92).01

0.82 (0.59-1.12).20

0.68 (0.49-0.94).02

R E FE R E N C E S

IPTW minimally adjustedb

0.81 (0.59-1.11).20

0.67 (0.48-0.94).02

1. Ma X et al. medRxiv. 2023. doi: https://doi.org/10.1101/2020.03.16.20037143

IPTW fully adjustedc

0.84 (0.61-1.17).30

0.64 (0.44-0.93).02

2. Birnbaum B et al. ArXiv. 2020. https://doi.org/10.48550/arXiv.2001.09765

Unadjusted

0.66 (0.44-1.01).06

0.66 (0.43-1.02).06

D I S C LOS U R E S

Multivariate (Cox model)

0.69 (0.46-1.06).09

0.64 (0.41-0.99).04

IPTW minimally adjustedb

0.69 (0.45-1.05).08

0.61 (0.40-0.95).03

IPTW fully adjustedc

0.74 (0.48-1.13).20

0.56 (0.35-0.91).02

rwTTNT

102 (53%)
40 (21%)

0.25
0.00

0.00
0 20

0.50

00

Zanubrutinib Zanubrutinib
AcalabrutinibAcalabrutinib
Ibrutinib
Ibrutinib

0.75

00.25

801.00

0.00

0.50

0.00

Number at risk
Number at risk
All 602All 602 132≤510 (5.2%)
21 (11%)124 (64%)35 (18%)145 (48%)
54 (18%)

―1.00

0.00

6 (2.0%)6 (2.0%)38 (13%)186 (62%)65 (22%)26 (24%)41 (38%)vs 2L/3L ibrutinib and trends for improved outcomes for 2L/3L zanubrutinib over 2L/3L
acalabrutinib (Table 2)
In the fully adjusted model, rwTTNT (HR 0.64, 95% CI 0.44-0.93, P=.02) and rwOS
(HR 0.56, 95% CI 0.35-0.91, P=.02) was significantly improved with 2L/3L zanubrutinib
vs 2L/3L ibrutinib
Fully adjusted HRs for rwTTNT and rwOS for 2L/3L zanubrutinib vs 2L/3L acalabrutinib
were 0.84 (95% CI 0.61-1.17; P=.30) and 0.74 (95% CI 0.48-1.13; P=.20), respectively

Figure 2. Kaplan-Meier Curves Reflecting rwTTNT for (A) cBTKi Overall, (B) by cBTKi Therapy, and rwOS for (C) cBTKi Overall, (D) by cBTKi Therapy, Among Patients with R/R MCL
Who Received 2L/3L cBTKi Monotherapy≤5≤59 (8.4%)
71 (66%)24 (22%)Extracted from unstructured documents using natural language processing when ECOG information from structured data were unavailable inthe baseline ECOG table. ECOG values represent the score closest to the index date. ECOG values of 5 were transformed to “unknown” forde-identification purposes. Additional information is provided in Flatiron’s Knowledge Center.
bAs documented with dates occurring at any point from initial diagnosis to 30 days after index date (either 2L or 3L start).
cIndex referred to start of 2L for the total R/R MCL (2L+) cohort, the start of 3L for the 3L subcohort who initiated 3L, and theearliest BTKi monotherapy start date (either 2L or 3L) for the BTKi monotherapy 2L/3L subcohort.
1L, first-line, LDH, lactose dehydrogenase; LOT, line of treatment; MCL, mantle cell lymphoma; NOS, not otherwise specified;ES, socioeconomic status; ULN; upper limit of normal.
arwTTNT and rwOS
Among the overall population, unadjusted median rwTTNT and rwOS were 11.1 (95% CI
9.2-12.9) and 29.2 (95% CI 24.3-36.5) months, respectively (Figure 2)
Unadjusted median rwTTNT were 16.8 (95% CI 11.8-23.7) months for 2L/3L zanubrutinib,11.5 (95% CI 8.6-14.6) months for 2L/3L acalabrutinib, and 8.6 (95% CI 7.2-11.3) months
for 2L/3L ibrutinib. Median rwOS was not reached for 2L/3L zanubrutinib (95% CI 23.7NR), and the unadjusted median rwOS was 27.4 (95% CI 22.7-36.5) months for 2L/3Lacalabrutinib and 29.3 (95% CI 21.1-40.5) months for 2L/3L ibrutinib (Figure 2)

for differences in rwTTNT and rwOS across cBTKis are warranted

Real-world
overall survival

M E T H OD S

MCLdiagnosis

Acalabrutinib(n=301)• Future research into identifying factors influencing utilization of cBTKis, and reasons

Real-world
overall survival

effectiveness of zanubrutinib, acalabrutinib, and ibrutinib monotherapy in second- or
third-line (2L/3L) treatment among patients with R/R MCL in the United States (US)

1 Jan 2018

Zanubrutinib(n=107)

Characteristic• To describe the RW characteristics and utilization patterns, and evaluate the comparative

1 Jan 2011

Overall(N=602)••

who received 2L/3L zanubrutinib had significantly longer rwTTNT and rwOS
compared with 2L/3L ibrutinib, and there was a trend favoring improved clinicaloutcomes for 2L/3L zanubrutinib compared with 2L/3L acalabrutinib

Real-world
overall survival

Table 1. Baseline Demographic and Clinical Characteristics of Patients with R/R MCL
Who Received 2/3L cBTKi Monotherapy• Among patients with R/R MCL treated with cBTKi monotherapies in the US, patients

Real-world
overall survival

OB JE C T I VE••

Real-world time tonext treatment•••Treatment Patterns
Among patients who received 2L/3L cBTKi monotherapy, 107 (17.8%), 301 (50.0%)
and 194 (32.2%) patients received 2L/3L zanubrutinib, acalabrutinib, and ibrutinib,
respectively
Most patients received cBTKi monotherapy as 2L treatment (79%, 80%, and 84% forzanubrutinib, acalabrutinib, and ibrutinib, respectively) (Table 1)
Median (IQR) follow-up from the start of 2L cBTKi monotherapy was 17 (9-31), 35 (20-51),
and 53 (35-62) months for zanubrutinib, acalabrutinib, and ibrutinib, respectively

Real-world time tonext treatment•

contributed to the rapidly evolving treatment landscape for relapsed/refractory (R/R)
mantle cell lymphoma (MCL)
Newer cBTKis (second-generation acalabrutinib and next-generation zanubrutinib)
were developed to address concerns with off-target inhibition and side effects, withzanubrutinib being more selective against several off-target kinases than acalabrutinib
and ibrutinib
There is no direct evidence from randomized controlled trials to discern between
the efficacy of available cBTKi therapies for R/R MCL, and little is known about theirutilization and comparative effectiveness in the real-world (RW) setting

Patient Baseline Characteristics
Of the 1,377 patients with R/R MCL who received any therapy in the 2L+ setting, 602
patients received 2L/3L cBTKi monotherapy for MCL and were included in this study
Median age at the start of 2L therapy was 74 years (range 34-85), and the majorityof patients were male (74%), identified as White (76%), did not identify as Hispanic orLatino (75%), had Stage IV disease (63%) and an Eastern Cooperative Oncology GroupPerformance Status (ECOG PS) score of 0-1 (60%) (Table 1)
Most patients (96%) had undocumented and/or negative tests for TP53 status

Real-world time tonext treatment• The recent availability of covalent Bruton tyrosine kinase inhibitors (cBTKis) has

C ON C LU S I ON S

Real-world time tonext treatment

INTRODUCTION

Reference treatment was acalabrutinib for zanubrutinib vs acalabrutinib, and ibrutinib for zanubrutinib vs ibrutinib.
The minimally adjusted model adjusted for: age, sex, time from 1L to 2L, time from 2L to 3L; absolute SMDs post-IPTW were <0.2, indicatingthat balance between cohorts was achieved.
cThe IPTW fully adjusted model adjusted for: age, sex, time from 1L to 2L, time from 2L to 3L, ECOG stage at initial diagnosis, LDH status, bulky
disease status, and Ki67 status; absolute SMDs post-IPTW were <0.2, indicating that balance between cohorts was achieved.
IPTW, inverse probability of treatment weighting; LDH, lactose dehydrogenase; MCL, mantle cell lymphoma; SMD, standardized
mean difference.

TP: Consultant: BeiGene. TAM, JW, AP: Employment, Flatiron Health, Inc., an independent
member of the Roche Group, and stock ownership in Roche. GAM, EKS: Employment andmay hold stock: BeiGene.

ab

AC K N OW LE D GE M E N TS
This study was sponsored by BeiGene, Ltd. Editorial assistance was provided by SNELL,
and supported by BeiGene.
Presented at EHA 2024; June 13-16, 2024; Madrid, Spain/Virtual Conference