Phase Ib trial of zanubrutinib plus obinutuzumab in CLL/SLL and R/R FL

The therapeutic potential and efficacy of Bruton’s tyrosine kinase inhibitors (BTKi) against B-cell malignancies, have long been established. In fact, the first generation BTK inhibitor, ibrutinib, is an approved regimen for multiple malignancies, including chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).¹ Nevertheless, off-target toxicities are a key issue with ibrutinib treatment. Second generation BTKi with better selectivity, like zanubrutinib, might improve safety and tolerability of BTKi treatment in patients with B-cell malignancies.

For that, Constantine Tam, a member of our Scientific Advisory Board, and colleagues, conducted a phase Ib trial (NCT02569476)² to investigate the safety and preliminary efficacy of zanubrutinib plus obinutuzumab in patients with CLL/SLL or follicular lymphoma (FL). The results of this study were published in Blood Advances² and are summarized below.

Study design

• Multicenter, open label, two-part, phase Ib trial that included adult patients with relapsed/refractory (R/R) or naïve CLL/SLL or FL without prior exposure to BTKi:

• • Part 1: For establishing the safety of zanubrutinib plus obinutuzumab
  • Part 2: For evaluating zanubrutinib’s preliminary activity

• In Part 1 of the study, 12 patients received until disease progression (DP) or intolerable toxicity (28-day cycles):
  • Zanubrutinib: 160 mg twice daily or 320 mg once daily
  • Obinutuzumab: 100 mg over 4 hours on Day 1, 900 mg on Day 2, 1000 mg on Days 8 and 15 in Cycle 1. In Cycles 2–6, 1000 mg on Day 1

Dose limiting toxicities (DLTs) up to 29 days after the initial dose were evaluated.

• In Part 2, patients from Part 1 (n = 8) continued zanubrutinib at either 160 mg twice daily or 320 mg once daily in combination with obinutuzumab as above, for six 28-day cycles. Additional patients were also enrolled to the following expansion cohorts (Figure 1):

• • R/R CLL/SLL (n = 20)
  • Naïve CLL/SLL (n = 25)
  • R/R FL (n = 33)
• The primary endpoints of the trial were safety and tolerability. Secondary endpoints included preliminary efficacy and measurable residual disease (MRD) in CLL patients who achieved a complete response (CR).

AE, adverse event; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma, PD, progressive disease; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma; TN, treatment-naïve.

Results

• Patient baseline characteristics from both parts of the study are shown below in Table 1

Table 1. Patient baseline characteristics²

ECOG PS, Eastern Cooperative Oncology Group performance status; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma.
Characteristic	Part 1 (N = 12)	Part 2
		CLL/SLL (n = 45)	R/R FL (n = 36)
Median age, years (range)	68 (51–86)	68 (38–82)	59 (34–86)
ECOG PS, n (%)  0  1  2	9 2 1	20 (44) 24 (53) 1 (2)	28 (78) 6 (17) 2 (6)
Prior treatment status, n (%)  Naïve  R/R	0 12	20 (44) 25 (56)	0 (0) 36 (100)
Rituximab-refractory for R/R FL, n (%)	—	—	14 (39)
Refractory to most recent line of therapy, n (%)	—	—	12 (33)
Median number of prior therapies (range)	n = 12	n = 25	n = 36
2 (1–9)	1 (1–4)	2 (1–9)
Bulky disease, cm  Node > 5  Node > 10	— —	15 (33) 0 (0)	17 (47) 4 (11)
Molecular risk factors (n = 39), n (%)  Unmutated IGHV  del(17p)/p53 mutation  del(11q)  Complex karyotype	—  —  — —	19 (49) 16 (41) 10 (26) 9 (23)	—  —  — —

• Every patient received six cycles of obinutuzumab, while treatment exposure to zanubrutinib was 29 months (range, 8–37) for patients with CLL/SLL and 20 months (range, 2–37) in those with R/R FL
• No DLTs were observed with either 160 mg twice daily or 320 mg once daily zanubrutinib. Both doses were deemed safe with an acceptable toxicity profile
• Safety analysis in Part 2 of the study (CLL/SLL, n = 45; FL, n = 36) showed that 96% of patients with CLL/SLL and 83% of those with FL developed treatment-related adverse events (AEs). The most commonly observed AEs are shown in Table 2. In brief, the most common Grade ≥ 3 AE in both CLL/SLL and FL patients was neutropenia
• Serious AEs were observed in 49% of patients with CLL/SLL and 33% of those with FL, with pneumonia occurring most frequently
• AEs of special interest are shown in Table 2

Table 2. Most common AEs and AEs of special interest reported in Part 2 of the study²

AEs, adverse events; AF, atrial fibrillation; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; IRR, infusion-related reactions; SLL, small lymphocytic lymphoma; URT, upper respiratory tract.
Most common AEs (≥ 15%), n (%)	All Grade AEs		Grade ≥ 3 AEs
	CLL/SLL (n = 45)	FL (n = 36)	CLL/SLL (n = 45)	FL (n = 36)
URT infection	23 (51.1)	14 (38.9)	0 (0)	0 (0)
Neutropenia	20 (44.4)	6 (16.7)	14 (31.1)	5 (13.9)
Contusion	15 (33.3)	10 (27.8)	0 (0)	0 (0)
Cough	12 (26.7)	8 (22.2)	0 (0)	0 (0)
Diarrhea	12 (26.7)	6 (16.7)	0 (0)	0 (0)
Fatigue	12 (26.7)	9 (25.0)	1 (2.2)	0 (0)
Pyrexia	10 (22.2)	—	0 (0)	—
Thrombocytopenia	8 (17.8)	7 (19.4)	3 (6.7)	2 (5.6)
Pneumonia	7 (15.6)	—	4 (8.9)	—
AEs of special interest, n (%)
Infections	39 (87)	24 (67)	17 (38)	7 (19)
Diarrhea	12 (27)	6 (17)	0 (0)	0 (0)
IRR	11 (24)	5 (14)	1 (2)	0 (0)
Hypertension	4 (9)	3 (8)	3 (7)	3 (8)
Major hemorrhage	0 (0)	1 (3)	0 (0)	0 (0)
AF	0 (0)	0 (0)	0 (0)	0 (0)

• Preliminary efficacy outcomes of zanubrutinib plus obinutuzumab in the different disease cohorts are shown below in Table 3.
• At data cutoff, five patients with CLL/SLL and four with FL died, mainly due to PD. Overall, 73% of patients with CLL/SLL and 50% of patients with FL remained on treatment at the cutoff date. Treatment discontinuation occurred in 24% of patients with CLL/SLL and 50% of those with FL due to:
  • PD: (CLL/SLL, n = 5; FL, n = 14)
  • AEs: (CLL/SLL, n = 4; FL, n = 1)
  • Patient decision: (CLL/SLL, n = 1; FL, n = 2)
  • Metastatic squamous cell carcinoma: (CLL/SLL, n = 1)
  • Investigator decision: (CLL/SLL, n = 1; FL, n = 1)
  • Other reasons: (CLL/SLL, n = 1)

Table 3. Preliminary efficacy outcomes²

EFS, event-free survival; CLL, chronic lymphocytic leukemia; CR, complete response; DoR, duration of response; FL, follicular lymphoma; NE, not estimable; NR, not reached; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SLL, small lymphocytic lymphoma. *Median follow-up was 29 months. †Median follow-up was 20 months.
Outcome, n (%)	CLL/SLL*		FL†
	Naïve (n = 20)	R/R (n = 25)	R/R (n = 36)
ORR	20 (100)	23 (92)	26 (72)
CR	6 (30)	7 (28)	14 (39)
PR	14 (70)	16 (64)	12 (33)
SD	0 (0)	2 (8)	6 (17)
PD	0 (0)	0 (0)	4 (11)
ORR for patients with del(17p)/p53 mutation, n/N (%)	6/6 (100)	8/10 (80)	—
Median DoR, months (range)	NR		NR (18.4–NE)
Median PFS, months (range)	NR		25 (0.7–36.0)
EFS for DoR at 24 months, % (95% CI)	90.4 (76.5–96.3)		62.3 (37.0–79.9)

Conclusion

The results of this phase Ib trial showed that the combination of zanubrutinib plus obinutuzumab is well tolerated in patients with CLL/SLL or FL. With the exception of neutropenia, the toxicity profile was consistent with previous reports of that with single agent zanubrutinib. It should be noted, that no Grade ≥ 3 diarrhea, no atrial fibrillation and low incidence of hypertension (< 10%) were reported here with the use of zanubrutinib. The preliminary efficacy of this combination showed very promising activity, especially in patients with naïve CLL/SLL (100% overall response rate [ORR]) and R/R CLL/SLL (92% ORR). The ORR was also good in patients with R/R FL (72%) considering their heavily pretreated nature. However, promising, large-scale prospective trials are needed to validate these results.