First interim results from a phase III randomized trial of zanubrutinib vs ibrutinib in patients with relapsed/refractory CLL/SLL: ALPINE trial

The advent of Bruton’s tyrosine kinase (BTK) inhibitors has transformed the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), prolonging progression-free survival (PFS) and overall survival (OS) in patients who otherwise have limited treatment options. Ibrutinib, a first-in-class irreversible BTK inhibitor, is efficacious, though it is associated with off-target effects due to non-specific kinase inhibition and interference with anti-CD20 monoclonal antibodies. Zanubrutinib, a second-generation, highly selective BTK inhibitor, was designed to minimize off-target inhibition.

ALPINE (NCT03734016) is a global, phase III, randomized trial of zanubrutinib vs ibrutinib in patients with previously treated CLL/SLL, and results of the trial have previously been reported by the Lymphoma Hub when zanubrutinib met the primary endpoint of non-inferior objective response rate (ORR). The ALPINE investigators hypothesized that zanubrutinib may minimize off-target inhibition and improve efficacy. The first interim analysis of the ALPINE trial was presented by Peter Hillmen at the European Hematology Association (EHA)2021 Virtual Congress and the key findings are summarized here.     

Study design

Patients with R/R CLL/SLL with ≥1 prior treatment and measurable lymphadenopathy were eligible. Patients (n = 415) were randomized to receive either zanubrutinib 160 mg twice daily or ibrutinib 420 mg three times a day. Patients were stratified by age, geographic region, refractory status, and del(17p)/TP53 mutation status.

• The primary endpoint was ORR as assessed by the investigators.
• The secondary endpoints included any-grade atrial fibrillation, duration of response, PFS, OS, time to treatment failure, partial response with lymphocytosis or higher, patient reported outcomes, and safety.

Baseline characteristics

The baseline characteristics were well balanced in both arms, as shown in Table 1. Less than 20% of patients had del(17p) and/or mutant TP53, and between 26–30% had del(11q) in both arms.

Table 1. Baseline characteristics*

ECOG, Eastern Cooperative Oncology Group. *Adapted from Hillmen, et al.1 †Two patients with missing value.
Characteristic, % (unless otherwise stated)	Zanubrutinib (n = 207)	Ibrutinib (n = 208)
Median age (range), years	67 (35–90)	67 (36–89)
Age ≥65 years	62	62
Sex, male	69	75
Disease stage
Binet stage A/B or Ann Arbor stage I/II	59	60
Binet stage C or Ann Arbor stage III/IV	41	40
ECOG performance status ≥1	62	64
Median prior lines of therapy (range)	1 (1–6)	1 (1–8)
≥3 prior lines	7	10
Prior chemoimmunotherapy	80	76
del(17p) and/or mutant TP53	20†	18
del(17p)	12	13
TP53 mutated	14†	12
del11q	30	26
Bulky disease (≥5 cm)	51	51

Results

Efficacy

• At a median follow-up of 15 months, zanubrutinib demonstrated a significantly higher ORR compared with ibrutinib (78% vs 63%, 2-sided p = 0.0006 compared with pre-specified alpha of 0.0099 for interim analysis) (Table 2).

• Zanubrutinib also demonstrated a higher ORR compared with ibrutinib in patients with del(11q) (95% vs 84%) and del(17p) (83% vs 54%).
• Similarly, at a median follow-up of 14 months, improved PFS (95% vs 84%, p = 0.0007) was noted in the zanubrutinib arm compared with the ibrutinib arm.
• ORR was better for the zanubrutinib arm compared with the ibrutinib arm when patients were stratified by demographics and disease characteristics.

• At 18 months, 42 patients on ibrutinib had progressive disease compared with 20 patients receiving zanubrutinib.
• OS rates were similar in both the zanubrutinib (97%) and ibrutinib (93%) arms at 12 months (p = 0.1081).

Table 2. Investigator-assessed ORR*

CI, confidence interval; CR, complete response; CRi, complete response with incomplete bone marrow recovery; nPR, nodular partial response; ORR, overall response rate; PD, progressive disease; PR, partial response; PR-L, partial response with lymphocytosis; PD, progressive disease; SD, stable disease. *Adapted from Hillmen, et al.1 †Superiority 2-sided p = 0.0006 compared with pre-specified alpha of 0.0099.
All patients
ORR, %	Zanubrutinib (n = 207)	Ibrutinib (n = 208)
Primary endpoint†
ORR (PR+CR) (95% CI)	84 (72–84)	63 (56–69)
CR/CRi	2	1
nPR	1	0
PR	76	61
ORR (PR-L+PR+CR)	88	81
PR-L	10	19
SD	8	14
PD	1	1
Discontinued or new therapy prior to first assessment	3	4
Patients with del(17p)
ORR, %	Zanubrutinib (n = 24)	Ibrutinib (n = 26)
ORR (PR+CR)	83	54

Safety

• Any grade adverse events (AEs) were reported in >95% of patients in both the zanubrutinib and ibrutinib arms, and both arms reported >50% Grade ≥3 AEs.
• Fatal AEs were observed in 4% vs 6% and treatment discontinuation due to AEs was observed in 8% vs 13% in the zanubrutinib and ibrutinib arms, respectively.
• Arthralgia and muscle spasms were more common in the ibrutinib arm, while upper respiratory tract infection, hypertension, and cough were more common in the zanubrutinib arm.
• Incidence of atrial fibrillation and flutter of any grade—a key secondary endpoint—was lower for zanubrutinib compared with ibrutinib (3% vs 10%, p = 0.0014) (Table 3). 
• No differences were observed for hemorrhage and hypertension between the two arms. The greater incidence of neutropenia in the zanubrutinib arm compared with ibrutinib (28% vs 22%) did not translate into incident sepsis in the zanubrutinib arm (Table 3).

Table 3. AEs of special interest*

AEs, adverse events. *Adapted from Hillmen, et al.1 †Cardiac disorders leading to treatment discontinuation. ‡2-sided p = 0.0014 compared with prespecified alpha of 0.0099 for interim analysis. §Includes hemorrhages that were serious or Grade ≥3 or central nervous system hemorrhages of all grades. ǁIncluding neutropenia, neutrophil count decreased, and febrile neutropenia, thrombocytopenia and platelet count decreased.
AEs, %	Zanubrutinib (n = 204)		Ibrutinib (n = 207)
	Any grade	Grade ≥3	Any grade	Grade ≥3
Cardiac disorders†	14	3	25	7
Atrial fibrillation and flutter	3‡	1‡	10	2
Hemorrhage	36	3	36	3
Major hemorrhage§	3	3	4	3
Hypertension	17	11	16	11
Infections	60	13	63	18
Neutropeniaǁ	28	19	22	15
Thrombocytopeniaǁ	9	3	13	3
Secondary primary malignancies	8	5	6	2
Skin cancers	3	2	5	1

Conclusion

The interim findings from the ALPINE trial demonstrated that zanubrutinib has a superior response rate and improved PFS compared with ibrutinib in patients with R/R CLL/SLL. The key secondary endpoint, rate of atrial fibrillation or flutter, was also lower in the zanubrutinib arm compared with ibrutinib. These findings support the hypothesis that the use of more selective BTK inhibitors with sustained BTK occupancy improves efficacy and safety outcomes for patients.