Intrapatient Comparative Analysis of Zanubrutinib Plus Obinutuzumab Efficacy in Relapsed/Refractory Follicular Lymphoma Using the Growth Modulation Index

P1143

Krimo Bouabdallah,1 Shanmei Liao,2 Richard Delarue,3 Laura Dima,4 Dirk Weber,3 Laurent Dumartin4
Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France; 2BeiGene (Shanghai) Co, Ltd, Shanghai, China; 3BeiGene Switzerland, GmbH, Basel, Switzerland; 4BeiGene, Paris, France

1

INTRODUCTION• Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma1• The global, randomized, phase 2 ROSEWOOD (NCT03332017) study evaluated zanubrutinib plus obinutuzumab (ZO) vs• Median GMI was 2.7 (95% CI, 1.6-4.9) in the ZO arm (Figure 3) vs 0.9 (95% CI, 0.5-1.7) in the O arm (Figure 4)• In the ZO arm, 63.3% of patients (95% CI, 53.8%-71.9%) had a GMI of ≥1.33 (Table 1)•Figure 3. KM Analysis of GMI in the ZO Arm
100
80

study using the GMI clinical endpointPFS was defined in the ROSEWOOD study as the time from random assignment to the first documentation of progressive diseaseor death due to any cause, whichever occurred first, and was assessed by independent central review2024681012182022GMI30

1574411111080
70

CensoredO

GMI, median (95% CI): 0.9 (0.6-1.7)801009080Survival, %050
4030
2010024681012

14

16

18

11110GMI
13

53

130
10No. at risk:
PFSn 145 135
PFSn-1 140 133

12141618202224262830

3234363840

42<144≥1 and <1.33Months116117

961009291

7983

6774

6266

56624555

38
48

35
44

25
38

2234

1532

1030

929

525

324

321

121

120

0
19

KM, Kaplan-Meier; PFSn, PFS with the current treatment under evaluation; PFSn−1, PFS with the last prior treatment; ZO, zanubrutinib + obinutuzumab.

≥1.33

<1100

≥1 and <1.33

Censored
PFSn
PFSn-190
80

≥1.33

60
50
40
30
20
10

No. at risk:
PFSn 72
PFSn-1 69

2468

10121416

18202224

26

28

30

32

34

36

38

40

63
63

4254

34
47

30
41

2740

1932163115291224

1118

2.6 (0-80.2)
63.3 (53.8-71.9)

917815813512KM, Kaplan-Meier; PFSn, PFS with the current treatment under evaluation; PFSn−1, PFS with the last prior treatment; O, obinutuzumab.

3113
92
7161
54

100

052

1

10

Censored
ZO

GMI, median (95% CI): 3.1 (1.3-4.9)
GMI ≥1.33 (95% CI): 61.8% (49.2%-73.0%)605040201000No. at risk:
ZO 7734.4 (22.2-49.2)

2468101214161820

22111110GMI
2011533GMI, Growth Modulation Index; KM, Kaplan-Meier; ZO, zanubrutinib + obinutuzumab.

0 (NE-NE)
65.6 (50.8-77.8)

REFERENCES

1. Carbone A, et al. Nat Rev Dis Primers. 2019;5(1):83.
2. Zinzani PL, et al. J Clin Oncol. 2023;41(33):5107.

34.1 (23.7-46.4)

3. Penel N, et al. Ann Oncol. 2013;24(2):537.

≥1 and <1.33

4.1 (0.1-75.6)

5. Cousin S, et al. Ann Oncol. 2013;24(10):2681.

4. Italiano A, et al. Cancers. 2020;12(11):3246.

61.8 (49.2-73.0)

GMI, Growth Modulation Index; ITT, intent to treat; NE, not estimable; ZO, zanubrutinib + obinutuzumab.

DISCLOSURES

Effect of Prior Lines of Therapy on GMI

KB: Honoraria: BeiGene, Takeda; Travel, accommodations, expenses: BeiGene, Takeda. SL: Employment, stock or other ownership, and travel, accommodations, expenses:
BeiGene. RD: Past employment: Celgene/Bristol Myers Squibb; Employment: BeiGene; Stock or other ownership: Celgene/Bristol Myers Squibb, BeiGene. L. Dima, DW:
Employment, may hold stock: BeiGene. L. Dumartin: Employment, stock or other ownership: BeiGene, Novartis; Travel and accommodation expenses: BeiGene, Novartis.

• Patients in the ZO arm with 2 prior lines (n=63) had a median GMI of 2.5 (95% CI, 0.9-NE), with 65.6% of patients (95% CI, 50.8%-77.8%)

Months12Figure 6. KM Curves of GMI in Patients With >2 Prior Lines of Therapy in the ZO Arm<1≥1.33

034.1 (25.9-43.3)

GMI in patients with >2 prior lines, survival (95% CI), %701030

GMI in patients with 2 prior lines, survival (95% CI), %Figure 2. KM Curves of PFSn and PFSn−1 in the O Arm

870

GMI in ITT population, survival (95% CI), %101090ZO(n=145)

40
20

6

GMI, Growth Modulation Index; KM, Kaplan-Meier; NE, not estimable; ZO, zanubrutinib + obinutuzumab.

50

84

GMINo. at risk:
ZO 63Table 1. GMI According to Number of Prior Lines of Therapy in the ZO Arm

62080

60

4401060

GMI, Growth Modulation Index; KM, Kaplan-Meier; O obinutuzumab.

70

25020No. at risk:O 69

CensoredPFSnPFSn-1

6030700Censored
ZO

GMI, median (95% CI): 2.5 (0.9-NE)
GMI ≥1.33 (95% CI): 65.6% (50.8%-77.8%)

90Survival, %900Figure 5. KM Curves of GMI in Patients With 2 Prior Lines of Therapy in the ZO Arm
100

100Figure 1. KM Curves of PFSn and PFSn−1 in the ZO Arm

016Figure 4. KM Analysis of GMI in the O Arm

respectively) but not in the O arm (10.4 vs 11.5 months)
In the ZO arm, the PFSn and PFSn−1 curves diverged early, and separation was maintained over time (Figure 1). In the O arm, there
was no separation between PFSn and PFSn−1 curves (Figure 2)
The most frequent last prior treatments were rituximab-containing regimens (ZO, 69%; O, 60%) and immunochemotherapy(ZO, 54%; O, 51%)

014

GMI, Growth Modulation Index; KM, Kaplan-Meier; ZO, zanubrutinib + obinutuzumab.

• Median PFS with the current treatment was longer than that with the last prior regimen in the ZO arm (28.0 vs 12.1 months,PFS probability• These data further confirm the benefit of ZO as a novel treatment option for R/R FL

40

No. at risk:
ZO 140PFS Analysis

PFS probability

500• A total of 217 patients were randomized to the ZO arm (n=145) or the O arm (n=72) in ROSEWOOD– Patients with no PFSn−1 were excluded from the GMI analysis (ZO, n=5; O, n=3)•

1.33 threshold for meaningful clinical activity compared with the last prior treatment

10RESULTS•

6020• GMI was defined for each patient as the ratio of the PFS with the current treatment under evaluation to the PFS with the last prior••– The median GMI of 2.7 in the overall population in the ZO arm was more than double the30

GMI Model•– GMI was ≥1.33 in >60% of patients

70• This post hoc analysis evaluated the efficacy of ZO in the sequence of treatments received by patients included in the ROSEWOOD

treatment (PFSn/PFSn−1)3-5– A GMI of >1 indicates that the present treatment has extended the duration of PFS compared with the previous treatment– A GMI of ≥1.33 is often used as a threshold for significant clinical activity
The Kaplan-Meier method was used to estimate the GMI distribution, including the median and the proportion of patients in each
GMI interval
The Brookmeyer-Crowley method was used to estimate 95% CIs for median GMI
The Greenwood formula with logit transformation was used to estimate the 95% CIs for the proportion within each GMI interval

comparative efficacy evidence for ZO in R/R FL using each patient as their own control• The majority of patients with R/R FL receiving ZO had a significant improvement in PFS vs PFS
with their last prior treatment, irrespective of the number of prior treatmentsCensoredZO

GMI, median (95% CI): 2.7 (1.6-4.9)
GMI ≥1.33 (95% CI): 63.3% (53.8%-71.9%)

90METHODS•• In this study, a post hoc GMI analysis of data from ROSEWOOD allowed for the generation ofSurvival, %•obinutuzumab monotherapy (O) in patients with relapsed/refractory (R/R) FL who had received ≥2 prior lines of therapy2
Median progression-free survival (PFS) was longer with ZO (28.0 months; 95% CI, 16.1 months-not estimable [NE]) vs O (10.4 months;95% CI, 6.5-13.8 months) (HR, 0.50; 95% CI, 0.33-0.75; P<.001) and compared favorably with PFS with the last prior treatment(12.1 months)2
The absence of clear consensus for standard of care in R/R FL and the heterogeneity of patient populations included in trials limit
the ability to make indirect comparisons across different studies
To overcome this challenge, the Growth Modulation Index (GMI) uses each patient as their own control to evaluate treatment
efficacy by comparing PFS durations with successive treatments

Survival, %•CONCLUSIONSGMI Analysis•

having a GMI of ≥1.33 (Figure 5)
Patients in the ZO arm with >2 prior lines (n=77) had a median GMI of 3.1 (95% CI, 1.3-4.9), with 61.8% of patients (95% CI, 49.2%-73.0%)
having a GMI of ≥1.33 (Figure 6)

ACKNOWLEDGMENTS
The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers. This study was sponsored by
BeiGene, Ltd. Medical writing was provided by Shanen Perumal, PhD, of Nucleus Global, an Inizio company, and supported by BeiGene.

Presented at the EHA2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain