Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial

Key Points

• •Asciminib showed increasingly superior efficacy and favorable safety/tolerability vs all IS-TKIs, consistent with the primary analysis.
• •The week 96 analysis of the ASC4FIRST trial confirms asciminib as a valuable frontline option for CML-CP.

Visual Abstract

Abstract

Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic-phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from the ASC4FIRST trial, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years' median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4% [95% confidence interval (CI), 13.6-31.3]; 1-sided P < .001) and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7% [95% CI, 17.6-41.8]; 1-sided P < .001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1% [95% CI, 2.3-28.0]; 1-sided P < .05), suggesting possible clinical benefit, although the study was not designed to formally confirm statistical significance for this secondary end point. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5%; 46.5%), imatinib (23.2%; 47.5%), and 2G TKIs (54.9%; 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215-0.997). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP. This trial was registered at www.clinicaltrials.gov as NCT04971226.

In the primary analysis of the phase 3 randomized trial ASC4FIRST, an allosteric inhibitor, asciminib, demonstrated superior efficacy with improved safety and tolerability compared with investigator-selected tyrosine kinase inhibitors (TKIs) in patients with newly diagnosed chronic myeloid leukemia (CML). Cortes et al now report the planned secondary (week 96) analysis with a median follow-up of 2.2 years, showing a further efficacy advantage and a consistently favorable safety profile for asciminib relative to investigator-selected TKIs, especially second-generation TKIs. The longer-term follow-up further supports asciminib as a frontline therapeutic option for patients with chronic-phase CML.

82505a52-bb9f-4091-808c-14bb3ff598f6

Introduction

Almost all patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) are treated with ATP-competitive tyrosine kinase inhibitors (TKIs).¹ TKIs have revolutionized the CML treatment landscape, transforming a fatal disease into a manageable chronic condition with life expectancy approaching that of the general population.^2,3 However, >50% of newly diagnosed patients do not achieve major molecular response (MMR; BCR::ABL1^IS ≤0.1%) at 12 months,^{4, 5, 6, 7} up to approximately half achieve MR^4.5 (BCR::ABL1^IS ≤0.0032%) within 2 years,^{8, 9, 10, 11, 12, 13} and ∼40% with imatinib and ∼60% with nilotinib achieve MR^4.5 within 10 years.^14,15 Early optimal responses decrease the risk of disease progression and are a harbinger of later optimal deep responses.^{16, 17, 18} With ATP-competitive TKIs, 15.7% to 33.0% of newly diagnosed patients require treatment switch, and 17.8% to 25.0% discontinue treatment in the first year, mainly due to intolerance and primary resistance.^{19, 20, 21} With continued use of TKIs, low-grade adverse events (AEs) that affect daily quality of life (QOL) and treatment compliance are common, and more severe AEs might require treatment change.^{22, 23, 24, 25} Frontline treatment options offering improved disease control and QOL are still needed.

Asciminib, an allosteric BCR::ABL1 inhibitor that specifically targets the ABL myristoyl pocket (STAMP), was designed to enhance efficacy and minimize off-target activity for a more favorable safety and tolerability profile vs ATP-competitive TKIs.^26,27 Results from the pivotal phase 3 ASCEMBL (median follow-up, 3.7 years) and phase 1 dose-finding (median exposure, 5.9 years) studies demonstrated durable efficacy and continued favorable safety and tolerability with long-term asciminib use in patients with resistance to or intolerance of previous TKIs.^28,29 These results provided rationale for exploration of asciminib in newly diagnosed CML-CP.

In the ASC4FIRST primary analysis, asciminib demonstrated statistically significant superior efficacy, meeting both primary objectives, and improved safety and tolerability compared with all ATP-competitive investigator-selected TKIs (IS-TKIs).³⁰ The MMR rate at week 48 was 67.7% with asciminib and 49.0% with all IS-TKIs; the treatment difference, adjusted for prerandomization-selected TKI and baseline European Treatment and Outcome Study long-term survival (ELTS) risk category, was 18.9% (95% confidence interval [CI], 9.6-28.2; P < .001).³⁰ The MMR rate within the imatinib stratum was 69.3% with asciminib and 40.2% with imatinib; the treatment difference, adjusted for baseline ELTS risk category, was 29.6% (95% CI, 16.9-42.2; P < .001).³⁰ Within the second-generation (2G) TKI stratum, the MMR rate was 66.0% with asciminib and 57.8% with 2G TKIs; the treatment difference, adjusted for ELTS risk category, was 8.2% (95% CI, −5.1 to 21.5).³⁰ Although this difference did not reach statistical significance, it should be noted that the study was not designed to formally confirm statistical significance for this outcome. Patients receiving asciminib vs imatinib or 2G TKIs required fewer dose reductions (14.0% vs 21.2% vs 48.0%) and interruptions (39.0% vs 45.5% vs 52.9%).³⁰

We report longer-term efficacy and safety results from the secondary (week 96) analysis of the ASC4FIRST trial after a median follow-up of ∼2.2 years (data cutoff: 22 October 2024).

Methods

Trial oversight

The protocol was approved by the institutional review board at each site and was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation, with applicable local regulations. All patients provided written informed consent. An independent data monitoring committee assessed safety data at defined intervals.

Trial design and patients

Trial design and patient eligibility for ASC4FIRST (ClinicalTrials.gov identifier: NCT04971226) were previously described.³⁰ Briefly, in this phase 3, multicenter, open-label, randomized trial, patients (aged ≥18 years) diagnosed with CML-CP per European LeukemiaNet 2020¹ criteria within 3 months before enrollment were eligible. Treatment with previous TKIs was permitted with imatinib, nilotinib, dasatinib, or bosutinib for ≤2 weeks before randomization.

Investigators in consultation with patients selected a TKI (imatinib or a 2G TKI) before randomization. This prerandomization-selected TKI is what the patient would take if randomized to the comparator (henceforth IS-TKI) group. Patients were randomized 1:1 to receive either asciminib 80 mg once daily or an IS-TKI at approved doses for frontline therapy (imatinib 400 mg daily, nilotinib 300 mg twice daily, dasatinib 100 mg daily, or bosutinib 400 mg daily) stratified by prerandomization-selected TKI and ELTS risk category. Dose modifications of IS-TKIs were per the investigator’s discretion and in accordance with institutional practice and local labels.

End points

The 2 primary end points in ASC4FIRST were MMR rates at week 48 with asciminib vs IS-TKIs and with asciminib vs imatinib in the imatinib stratum, as previously described.³⁰ In this analysis, the 2 key secondary objectives in ASC4FIRST were to compare the efficacy of asciminib with (1) that of all IS-TKIs and (2) that of imatinib in the imatinib stratum. The 2 key secondary end points associated with both objectives were MMR rates at week 96.

The secondary safety objective was to characterize the safety and tolerability profile of asciminib vs 2G TKIs (nilotinib, dasatinib, or bosutinib), and the related end point was the time to study treatment discontinuation due to AEs (TTDAEs).

Statistical analyses

The MMR rate at week 96 with asciminib and all IS-TKIs was calculated based on the full analysis set (all patients to whom study treatment was randomly assigned; supplemental Table 1, available on the Blood website). The MMR rate at week 96 with asciminib and imatinib was calculated based on the imatinib stratum. A Cochran-Mantel-Haenszel χ² test, stratified by both randomization stratification factors for the first key secondary objective and by baseline ELTS risk groups for the second key secondary objective, was used to compare MMR rates at week 96. Full details have been previously described.³⁰ Although the MMR rate at week 96 for asciminib vs 2G TKIs was a prespecified secondary end point, it was not included in the testing hierarchy. As a result, it was not α controlled, and the study was not formally designed to confirm statistical significance for this outcome.

TTDAE was defined as the time from the date of the first dose of study treatment to discontinuation of study treatment due to an AE (including death due to AE). Discontinuation due to reasons other than AEs, including death due to other reasons, were considered competing risks. For patients receiving ongoing treatment without discontinuation on or before the analysis cutoff date, time was censored at the cutoff date. Comparisons of TTDAE were conducted between all patients receiving asciminib (n = 200) vs 2G TKIs (n = 102) as a secondary safety objective, asciminib (n = 200) vs IS-TKIs (n = 201), and asciminib (n = 200) vs imatinib (n = 99) as supplementary analyses. The estimated cumulative incidence rates and 95% CIs at specified scheduled visits are presented for each treatment group (asciminib and 2G TKIs). The comparison of TTDAE between asciminib and 2G TKIs was implemented via the log-rank test of the cause-specific hazard for the event of interest. The overall familywise type I error control (1-sided type I error rate of 2.5%) was achieved with use of the graphical gatekeeping multiple-testing procedure.

Results

Patients

A total of 405 patients with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized 1:1 to receive asciminib (n = 201) or an IS-TKI (n = 204) between 5 November 2021 and 20 December 2022. Patients in the prerandomization-selected imatinib stratum (n = 203) were randomized 1:1 to receive asciminib (n = 101) or imatinib (n = 102). Patients in the prerandomization-selected 2G TKI stratum (n = 202) were randomized 1:1 to receive asciminib (n = 100) or a 2G TKI (n = 102; nilotinib, n = 49; dasatinib, n = 42; bosutinib, n = 11).

Efficacy analyses were conducted in all patients randomized to study treatment; comparisons were between all asciminib and all IS-TKIs, between asciminib and imatinib in the imatinib stratum (primary end points), and between asciminib and 2G TKIs in the 2G TKI stratum (secondary end point; supplemental Table 1). Safety analyses were conducted in the safety analysis set according to actual treatments received; comparisons were between asciminib, imatinib, and all 2G TKIs or individual 2G TKIs (nilotinib, dasatinib, or bosutinib). One patient assigned to receive imatinib received nilotinib instead and was considered in the imatinib group for efficacy analyses and in the 2G TKI group for safety analyses. Four patients who were not treated were included in the efficacy analyses but not in the safety analyses.

Baseline characteristics were described previously (supplemental Table 2).³⁰ The median duration of follow-up for the week 96 analysis was 26.9 months with asciminib (25.0 and 28.2 months with asciminib in the imatinib and 2G TKI strata, respectively) and 26.3 months with IS-TKIs (24.2 and 27.7 months with imatinib and 2G TKIs, respectively).

At the cutoff (22 October 2024), 164 (81.6%), 53 (52.0%), and 70 patients (68.6%) remained on treatment with asciminib, imatinib, and 2G TKIs, respectively; 36 (17.9%), 47 (46.1%), and 31 (30.4%) had discontinued, respectively. As in the primary analysis,³⁰ the 2 main reasons for discontinuation in patients receiving asciminib, imatinib, and 2G TKIs, respectively, were unsatisfactory therapeutic effect (n = 19 [9.5%], n = 29 [28.4%], n = 13 [12.7%]) and AEs (n = 12 [6.0%], n = 13 [12.7%], n = 13 [12.7%]; Table 1; supplemental Figure 1). Among patients receiving asciminib, imatinib, and 2G TKIs, 2 (1.0%), 3 (2.9%), and 1 (1.0%), respectively, progressed to the accelerated or blast phase.

Table 1.

Patient disposition

	Randomized patients, n (%)
	Full analysis set		Imatinib full analysis set		2G TKI full analysis set
	All asciminib (n = 201)	All IS-TKIs (n = 204)	Asciminib (n = 101)	Imatinib (n = 102)	Asciminib (n = 100)	2G TKI (n = 102)
Patients randomized	201 (100)	204 (100)	101 (100)	102 (100)	100 (100)	102 (100)
Treated	200 (99.5)	201 (98.5)	100 (99.0)	100 (98.0)	100 (100)	101 (99.0)
Not treated	1 (0.5)	3 (1.5)	1 (1.0)	2 (2.0)	0	1 (1.0)
Treatment ongoing∗,†	164 (81.6)	123 (60.3)	83 (82.2)	53 (52.0)	81 (81.0)	70 (68.6)
Discontinued from treatment	36 (17.9)	78 (38.2)	17 (16.8)	47 (46.1)	19 (19.0)	31 (30.4)
Before week 48	19 (9.5)	39 (19.1)	11 (10.9)	27 (26.5)	8 (8.0)	12 (11.8)
At week 48 to before week 96	14 (7.0)	32 (15.7)	6 (5.9)	17 (16.7)	8 (8.0)	15 (14.7)
At or after week 96	3 (1.5)	7 (3.4)	0	3 (2.9)	3 (3.0)	4 (3.9)
Reason for discontinuation
Unsatisfactory therapeutic effect	19 (9.5)	42 (20.6)	8 (7.9)	29 (28.4)	11 (11.0)	13 (12.7)
Treatment failure per ELN1	10 (5.0)	28 (13.7)	6 (5.9)	19 (18.6)	4 (4.0)	9 (8.8)
Confirmed loss of MMR	4 (2.0)	3 (1.5)	2 (2.0)	2 (2.0)	2 (2.0)	1 (1.0)
Other	5 (2.5)	11 (5.4)	0	8 (7.8)	5 (5.0)	3 (2.9)
AE	12 (6.0)	26 (12.7)	6 (5.9)	13 (12.7)	6 (6.0)	13 (12.7)
Progressive disease	2 (1.0)	4 (2.0)	2 (2.0)	3 (2.9)	0	1 (1.0)
Physician decision	1 (0.5)	0	0	0	1 (1.0)	0
Protocol deviation	1 (0.5)	2 (1.0)	1 (1.0)	1 (1.0)	0	1 (1.0)
Patient decision	1 (0.5)	3 (1.5)	0	1 (1.0)	1 (1.0)	2 (2.0)
Pregnancy	0	1 (0.5)	0	0	0	1 (1.0)

Adapted from Cortes et al.³¹

ELN, European LeukemiaNet.

^∗Ongoing at the time of data cutoff (22 October 2024).

^†A patient assigned to receive imatinib received nilotinib instead. Hence, this patient is considered in the imatinib stratum for efficacy analysis and in the 2G TKI stratum for safety analysis.

Efficacy

At week 96, the MMR rate remained superior with asciminib (74.1%) vs all IS-TKIs (52.0%); the rate difference after adjustment for prerandomization-selected TKI and ELTS risk groups at baseline was 22.4% (95% CI, 13.6-31.3; 1-sided P < .001), meeting the first key secondary objective. The MMR rate also remained superior with asciminib (76.2%) vs imatinib (47.1%); the rate difference after adjustment for ELTS risk groups at baseline was 29.7% (95% CI, 17.6-41.8; 1-sided P < .001), meeting the second key secondary objective. The MMR rate was numerically higher with asciminib (72.0%) vs 2G TKIs (56.9%); the rate difference after adjustment for ELTS risk groups at baseline was 15.1% (95% CI, 2.3-28.0; 1-sided P < .05). The study was not designed to formally confirm statistical significance for this secondary efficacy end point.

The MMR rate at week 96 was consistently higher with asciminib vs all IS-TKIs and asciminib vs imatinib across all assessed demographic and prognostic subgroups and was higher with asciminib vs 2G TKIs across most demographic and prognostic subgroups (supplemental Figure 2).

Response rates at and by week 96 are reported in Table 2. Secondary efficacy end points MR⁴ (BCR::ABL1^IS ≤0.01%) and MR^4.5 rates, respectively, were higher with asciminib (48.8% and 30.9%) vs all IS-TKIs (27.5% and 17.7%), with asciminib (52.5% and 35.6%) vs imatinib (23.5% and 11.8%), and with asciminib (45.0% and 26.0%) vs 2G TKIs (31.4% and 23.5%) at week 96.

Table 2.

Molecular responses at and by week 96

		Patients with molecular response, n (%)
		Full analysis set		Imatinib full analysis set		2G TKI full analysis set
		All asciminib (n = 201)	All IS-TKIs (n = 204)	Asciminib (n = 101)	Imatinib (n = 102)	Asciminib (n = 100)	2G TKI (n = 102)
At week 96 Key secondary end points	MMR	149 (74.1)	106 (52.0)	77 (76.2)	48 (47.1)	—	—
	Treatment difference, % (95% CI)*	22.4 (13.6 to 31.3)†		29.7 (17.6 to 41.8)‡		—
	Adjusted 1-sided P value	<.001		<.001		—
At week 96 Other secondary end points	MMR	—	—	—	—	72 (72.0)	58 (56.9)
	Treatment difference, % (95% CI)*	—		—		15.1 (2.3 to 28.0)‡
	Unadjusted 1-sided P value	—		—		<.05§
	MR4	98 (48.8)	56 (27.5)	53 (52.5)	24 (23.5)	45 (45.0)	32 (31.4)
	MR4.5	62 (30.9)	36 (17.7)	36 (35.6)	12 (11.8)	26 (26.0)	24 (23.5)
By week 96 Other secondary end points	MMR	163 (81.1)	125 (61.3)	81 (80.2)	57 (55.9)	82 (82.0)	68 (66.7)
	MR4	106 (52.7)	70 (34.3)	57 (56.4)	29 (28.4)	49 (49.0)	41 (40.2)
	MR4.5	73 (36.3)	44 (21.6)	41 (40.6)	16 (15.7)	32 (32.0)	28 (27.5)

^∗The widths of CIs have not been adjusted for multiplicity and thus may not be used in place of hypothesis testing.

^†After adjusting for prerandomization-selected TKI and ELTS risk category.

^‡After adjusting for ELTS risk category.

^§This analysis was not included in the testing hierarchy; therefore, the study was not designed to formally confirm statistical significance for this secondary efficacy end point.

The cumulative incidences of MMR (Figure 1), MR⁴, and MR^4.5 (supplemental Figure 3) were higher with asciminib vs all IS-TKIs, imatinib, and 2G TKIs by week 96.

Figure 1.

The cumulative incidence of MMR is presented for all asciminib vs all IS-TKIs (A), asciminib vs imatinib in the imatinib stratum (B), and asciminib vs 2G TKIs in the 2G TKI stratum (C). ∗Nonresponders were censored at their last molecular assessment date. †Discontinuation from treatment for any reason without previous achievement of MMR was considered a competing event. Adapted from Cortes et al.³¹

Almost all patients who achieved MMR (161/166 patients receiving asciminib and 128/131 receiving all IS-TKIs), MR⁴ (111/114 patients receiving asciminib and 74/76 receiving all IS-TKIs), and MR^4.5 (87/88 patients receiving asciminib and 51/52 receiving all IS-TKIs) maintained these responses by the week 96 cutoff. The Kaplan-Meier estimated probabilities of maintaining MMR, MR⁴, and MR^4.5, respectively, for ≥96 weeks were 96.2% (95% CI, 91.0-98.4), 97.0% (95% CI, 91.1-99.0), and 98.6% (95% CI, 90.2-99.8) with asciminib, and 97.0% (95% CI, 90.8-99.0), 97.0% (95% CI, 88.5-99.2), and 96.6% (95% CI, 77.9-99.5) with all IS-TKIs.

The probability of event-free survival was higher with asciminib vs IS-TKIs. The proportion of patients who had an event was 14.4% and 29.4% with asciminib and IS-TKIs, respectively, 16.8% and 35.3% with asciminib and imatinib in the imatinib strata, and 12.0% and 23.5% with asciminib and 2G TKIs in the 2G TKI strata (supplemental Figure 4). The proportion of patients with a progression-free survival or overall survival event, respectively, was 2.5% and 1.0% with asciminib, and 3.9% and 2.0% with IS-TKIs.

BCR::ABL1 mutations

Baseline mutations were detected in 3 patients who received asciminib. Two patients, with K294Q and R473Q mutations, continued receiving study treatment at cutoff and had best responses of complete cytogenetic response and MR⁴, respectively. One patient with the M237V mutation discontinued treatment due to an AE and received imatinib as postprotocol therapy. None developed postbaseline BCR::ABL1 mutations.

Postbaseline treatment-emergent BCR::ABL1 mutations, detected by next-generation sequencing, were reported in 10 patients (5.0%) receiving asciminib and 7 (3.4%) receiving IS-TKIs (Table 3). These included A433D (n = 2) and A337V/V506M, A337T/A344P/P465Q/I502N, A337T/V506M, L340Q, A337T, A337T/L340Q, A337T/F497L, and A337V (n = 1 each) with asciminib; and L248V/E255V/G250E, F317L, L248V/E450G, and E459K (n = 1 each) with imatinib; and Y253H (n = 3) with nilotinib. Consistent with the primary analysis, mutations observed with asciminib and IS-TKIs were generally close to their distinct binding sites: most mutations observed with asciminib were in/near the myristoyl pocket, whereas those with IS-TKIs were in/near the ATP-binding domain.³⁰ More patients discontinued due to unsatisfactory therapeutic effect or progressive disease with IS-TKIs than asciminib, but the identification of a specific mutation was less frequent in these patients (supplemental Table 3). Among 19 patients who discontinued asciminib and 42 who discontinued IS-TKIs due to unsatisfactory therapeutic effect, 8 (42.1%) and 6 (14.3%), respectively, had identified postbaseline BCR::ABL1 mutations. Among 2 who discontinued asciminib and 4 who discontinued IS-TKIs due to progressive disease, 1 (50.0%) and 0 had postbaseline BCR::ABL1 mutations.

Table 3.

Postbaseline treatment-emergent BCR::ABL1 mutations

Patients	Postbaseline mutations∗	Time from start of therapy to assessment of first mutation (d)	Discontinuation reason	Postprotocol therapy (2L+)	Last disease/survival status
Asciminib	Myristoyl pocket
1	A433D	166	Treatment failure per ELN1	Bosutinib, dasatinib	CP/alive
2	A337V, V506M†	337		Dasatinib	CP/alive
3	A337T, A344P,† P465Q,† I502N†	169		Dasatinib	AP/alive
4	A433D	210		Dasatinib, olverembatinib	AP/alive
5	A337T, V506M†	254		Ponatinib	Discontinued study
6	L340Q	337		Not available	Discontinued study‡
7§	A337T	615	Confirmed loss of MMR	Dasatinib	Discontinued study‡
8	A337T, L340Q	288	Unsatisfactory therapeutic effect (other)	Dasatinib	CP/alive
9	A337T,† F497L†	169	Progressive disease (BP)	Ponatinib	BP/death after HSCT
10§	A337V	673	Ongoing on study‖	Not applicable
Imatinib	ATP-binding domain
1	L248V, E255V,† G250E†	134	Treatment failure per ELN1	Flumatinib, olverembatinib	BP/death after HSCT
2§	F317L†	394		Imatinib	CP/alive
3	L248V, E450G†	169		Nilotinib	CP/alive
4§	E459K	673	Confirmed loss of MMR	Dasatinib	CP/alive
Nilotinib	ATP-binding domain
5§	Y253H	603	Treatment failure per ELN1	Dasatinib	CP/alive
6	Y253H	105		Dasatinib, ponatinib	CP/alive
7	Y253H†	169	Ongoing on study¶	Not applicable

Adapted from Cortes et al.³¹

2L+, second line and beyond; AP, accelerated phase; BP, blast phase; ELN, European LeukemiaNet; HSCT, hematopoietic stem cell transplant.

^∗A patient with multiple mutations is only counted once.

^†Variant allele frequency was <20%.

^‡Follow-up data were not available for patients who discontinued the study.

^§Patients with new mutations since the week 48 data cutoff (28 November 2023).

^‖Ongoing on study day 757 with BCR::ABL1^IS ≤1%.

^¶Ongoing on study day 922 with BCR::ABL1^IS ≤0.1%.

Of 10 patients with postbaseline treatment-emergent mutations with asciminib, 9 discontinued study treatment and 1 was still receiving asciminib by the week 96 cutoff. Of 9, 8 went on to receive second-line therapy or beyond with ATP-competitive TKIs. At the last disease status assessment in these 9 patients who discontinued, 3 remained in CML-CP, 2 had accelerated phase CML during postprotocol therapy, and 3 discontinued with no follow-up data available. One patient, who discontinued due to blast-phase CML, started postprotocol therapy, received a transplant, and died due to complications after hematopoietic stem cell transplant. The variant allele frequency was <20% in 4 of 10 patients who received asciminib. Of 7 patients with postbaseline treatment-emergent mutations with IS-TKIs (4 with imatinib and 3 with nilotinib), 6 discontinued study treatment and received subsequent therapy with other TKIs, and 1 was still receiving nilotinib by the cutoff. At the last disease status assessment in these 6 patients who discontinued, 5 remained in CML-CP, and 1 progressed to blast-phase CML and died after hematopoietic stem cell transplant. The variant allele frequency was <20% in 4 of 7 patients who received IS-TKIs.

Safety

The safety analysis population comprised 401 patients, 200 receiving ≥1 dose of asciminib (imatinib stratum, n = 100; 2G TKI stratum, n = 100) and 201 receiving ≥1 dose of IS-TKIs (imatinib, n = 99; 2G TKIs, n = 102; supplemental Table 1).

The median duration of exposure was 26.6 months (range, 0.2-35.6) with asciminib, 23.1 months (range, 0.6-33.6) with imatinib, and 26.6 months (range, 0.3-34.5) with 2G TKIs. A relative dose intensty of >90% was observed in 87.0% of patients receiving asciminib and 74.1% receiving IS-TKIs (supplemental Table 4). The median average daily dose was 80 mg for asciminib, 400 mg for imatinib, 600 mg for nilotinib, 100 mg for dasatinib, and 316 mg for bosutinib.

Grade ≥3 AEs were reported in 44.5%, 49.5%, and 59.8% of patients receiving asciminib, imatinib, and 2G TKIs, respectively (Table 4). Grade ≥3 AEs (reported in ≥10% of patients in any treatment group) occurring with asciminib vs all IS-TKIs included thrombocytopenia (13.0% vs 10.0%) and neutropenia (10.5% vs 17.9%); with asciminib vs imatinib were thrombocytopenia (12.0% vs 6.1%), neutropenia (8.0% vs 18.2%), and leukopenia (2.0% vs 11.1%); and with asciminib vs 2G TKIs were thrombocytopenia (14.0% vs 13.7%) and neutropenia (13.0% vs 17.6%). A total of 21 patients (10.5%) receiving asciminib and 10 (5.0%) receiving IS-TKIs reported any-grade hypertension. Of 21 patients with hypertension on asciminib, 10 had other cardiovascular risk factors, 13 had higher than normal baseline blood pressure readings, and 7 had previous medical history of hypertension.

Table 4.

AEs regardless of relationship to study drug (reported in at least 10% of patients)

Adverse event	Patients, n (%)
	Asciminib						IS-TKIs
	Imatinib stratum (n = 100)		2G TKI stratum (n = 100)		All asciminib (n = 200)		Imatinib treated (n = 99)		2G TKI treated (n = 102)		All IS-TKIs (n = 201)
	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3
Patients with ≥1 event	97 (97.0)	48 (48.0)	94 (94.0)	41 (41.0)	191 (95.5)	89 (44.5)	95 (96.0)	49 (49.5)	102 (100)	61 (59.8)	197 (98.0)	110 (54.7)
Thrombocytopenia∗	26 (26.0)	12 (12.0)	30 (30.0)	14 (14.0)	56 (28.0)	26 (13.0)	28 (28.3)	6 (6.1)	35 (34.3)	14 (13.7)	63 (31.3)	20 (10.0)
Neutropenia†	25 (25.0)	8 (8.0)	26 (26.0)	13 (13.0)	51 (25.5)	21 (10.5)	31 (31.3)	18 (18.2)	36 (35.3)	18 (17.6)	67 (33.3)	36 (17.9)
COVID-19	13 (13.0)	0	30 (30.0)	0	43 (21.5)	0	20 (20.2)	0	24 (23.5)	1 (1.0)	44 (21.9)	1 (0.5)
Leukopenia‡	17 (17.0)	2 (2.0)	21 (21.0)	2 (2.0)	38 (19.0)	4 (2.0)	29 (29.3)	11 (11.1)	21 (20.6)	5 (4.9)	50 (24.9)	16 (8.0)
Diarrhea	14 (14.0)	0	21 (21.0)	0	35 (17.5)	0	28 (28.3)	0	28 (27.5)	2 (2.0)	56 (27.9)	2 (1.0)
Headache	18 (18.0)	1 (1.0)	15 (15.0)	0	33 (16.5)	1 (0.5)	9 (9.1)	0	24 (23.5)	0	33 (16.4)	0
Myalgia	15 (15.0)	0	16 (16.0)	1 (1.0)	31 (15.5)	1 (0.5)	18 (18.2)	0	17 (16.7)	0	35 (17.4)	0
Fatigue	15 (15.0)	0	15 (15.0)	1 (1.0)	30 (15.0)	1 (0.5)	15 (15.2)	1 (1.0)	20 (19.6)	0	35 (17.4)	1 (0.5)
Rash	9 (9.0)	0	20 (20.0)	0	29 (14.5)	0	11 (11.1)	2 (2.0)	24 (23.5)	1 (1.0)	35 (17.4)	3 (1.5)
Lipase increased	20 (20.0)	6 (6.0)	7 (7.0)	0	27 (13.5)	6 (3.0)	15 (15.2)	2 (2.0)	15 (14.7)	5 (4.9)	30 (14.9)	7 (3.5)
Arthralgia	16 (16.0)	3 (3.0)	10 (10.0)	1 (1.0)	26 (13.0)	4 (2.0)	10 (10.1)	1 (1.0)	9 (8.8)	0	19 (9.5)	1 (0.5)
Anemia	11 (11.0)	1 (1.0)	14 (14.0)	3 (3.0)	25 (12.5)	4 (2.0)	26 (26.3)	5 (5.1)	26 (25.5)	7 (6.9)	52 (25.9)	12 (6.0)
Abdominal pain	11 (11.0)	0	11 (11.0)	1 (1.0)	22 (11.0)	1 (0.5)	3 (3.0)	0	11 (10.8)	1 (1.0)	14 (7.0)	1 (0.5)
Hypertension	14 (14.0)	8 (8.0)	7 (7.0)	3 (3.0)	21 (10.5)	11 (5.5)	5 (5.1)	2 (2.0)	5 (4.9)	5 (4.9)	10 (5.0)	7 (3.5)
Constipation	9 (9.0)	0	11 (11.0)	0	20 (10.0)	0	4 (4.0)	0	14 (13.7)	1 (1.0)	18 (9.0)	1 (0.5)
Nausea	8 (8.0)	0	11 (11.0)	0	19 (9.5)	0	21 (21.2)	0	19 (18.6)	0	40 (19.9)	0
Pruritus	9 (9.0)	0	10 (10.0)	0	19 (9.5)	0	4 (4.0)	0	5 (4.9)	0	9 (4.5)	0
ALT increased	9 (9.0)	3 (3.0)	8 (8.0)	1 (1.0)	17 (8.5)	4 (2.0)	7 (7.1)	2 (2.0)	21 (20.6)	8 (7.8)	28 (13.9)	10 (5.0)
Upper respiratory tract infection	9 (9.0)	0	8 (8.0)	0	17 (8.5)	0	12 (12.1)	1 (1.0)	11 (10.8)	0	23 (11.4)	1 (0.5)
Nasopharyngitis	11 (11.0)	0	4 (4.0)	0	15 (7.5)	0	7 (7.1)	0	8 (7.8)	0	15 (7.5)	0
Dry eye	3 (3.0)	0	11 (11.0)	0	14 (7.0)	0	4 (4.0)	0	5 (4.9)	0	9 (4.5)	0
Vomiting	6 (6.0)	0	8 (8.0)	0	14 (7.0)	0	13 (13.1)	0	7 (6.9)	0	20 (10.0)	0
Back pain	5 (5.0)	0	7 (7.0)	0	12 (6.0)	0	12 (12.1)	1 (1.0)	10 (9.8)	0	22 (10.9)	1 (0.5)
Blood alkaline phosphatase increased	10 (10.0)	0	2 (2.0)	0	12 (6.0)	0	13 (13.1)	0	6 (5.9)	0	19 (9.5)	0
Cough	4 (4.0)	0	8 (8.0)	0	12 (6.0)	0	7 (7.1)	0	13 (12.7)	0	20 (10.0)	0
Lymphopenia§	8 (8.0)	3 (3.0)	4 (4.0)	2 (2.0)	12 (6.0)	5 (2.5)	17 (17.2)	5 (5.1)	7 (6.9)	1 (1.0)	24 (11.9)	6 (3.0)
Blood bilirubin increased	2 (2.0)	0	6 (6.0)	0	8 (4.0)	0	2 (2.0)	1 (1.0)	11 (10.8)	0	13 (6.5)	1 (0.5)
AST increased	2 (2.0)	1 (1.0)	4 (4.0)	0	6 (3.0)	1 (0.5)	7 (7.1)	1 (1.0)	16 (15.7)	2 (2.0)	23 (11.4)	3 (1.5)
Muscle spasms	4 (4.0)	0	2 (2.0)	0	6 (3.0)	0	19 (19.2)	0	5 (4.9)	0	24 (11.9)	0
Periorbital/face edema‖	0	0	2 (2.0)	0	2 (1.0)	0	21 (21.2)	1 (1.0)	1 (1.0)	0	22 (10.9)	1 (0.5)

Based on the safety analysis set. The numbers represent counts of patients. Shown are AEs that occurred during treatment or within 30 days after receiving the last dose of study medication. A patient with multiple severity grades for an AE is counted only under the maximum grade.

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

^∗Includes thrombocytopenia and decreased platelet count.

^†Includes neutropenia and decreased neutrophil count.

^‡Includes leukopenia and decreased white blood cell count.

^§Includes lymphopenia and decreased lymphocyte count.

^‖Includes periorbital edema and face edema.

The frequency of AEs leading to treatment discontinuation with asciminib, imatinib, and 2G TKIs, respectively, was 5.0%, 13.1%, and 12.7% (supplemental Table 5).³⁰ Grade ≥3 AEs leading to treatment discontinuation included increased lipase, thrombocytopenia, cerebrovascular accident, hepatotoxicity, neuralgia, neutropenia, and pancreatitis (0.5%, each) with asciminib; neutropenia (1.0%), alanine aminotransferase increased (1.0%), aspartate aminotransferase increased (1.0%), asthenia (1.0%), lymphopenia (2.0%), metastatic gastric cancer (1.0%), and periorbital/face edema (1.0%) with imatinib; thrombocytopenia (2.0%) with nilotinib; cardiac failure, colitis, muscular weakness, and pleural effusion (2.4% each) with dasatinib; and generalized edema (9.1%) with bosutinib. The proportion of patients with dose reductions or interruptions was 18.5% and 46.5%, respectively, with asciminib, 23.2% and 47.5% with imatinib, and 54.9% and 63.7% with 2G TKIs (supplemental Table 6).

The hazard ratio for TTDAEs with asciminib vs 2G TKIs was 0.46 (95% CI, 0.215-0.997), with asciminib vs all IS-TKIs was 0.42 (95% CI, 0.216-0.814), and with asciminib vs imatinib was 0.38 (95% CI, 0.178-0.818; Figure 2). Over the first 2 years of treatment, the risk of discontinuation due to AEs trended lower with asciminib than with 2G TKIs, all IS-TKIs, and imatinib.

Figure 2.

TTDAE is presented for asciminib vs 2G TKIs in the 2G TKI stratum (A), all asciminib vs all IS-TKIs (B), and asciminib vs imatinib in the imatinib stratum (C). ∗Event of interest is discontinuation of study treatment due to AE, including death due to AE. †Discontinuations of study treatment due to reasons other than AEs, including death due to other reasons, were the competing risks. Adapted from Cortes et al.³¹

Hematologic and nonhematologic first-ever AEs (in ≥10% of patients in any treatment group) occurred less frequently after the first 6 months of treatment with asciminib vs all IS-TKIs, asciminib vs imatinib, and asciminib vs 2G TKIs (supplemental Figure 5).

Most AEs of special interest were less frequently reported with asciminib than with all IS-TKIs (supplemental Figure 6). The frequency of clinical events associated with hepatotoxicity (3.5% vs 2.0%) and acute pancreatitis (1.0% vs 1.0%) was comparable with asciminib vs IS-TKIs.

Four patients (2.0%) receiving asciminib and 3 (2.9%) receiving 2G TKIs experienced ≥1 arterial occlusive event (AOE; Table 5). After the primary analysis was conducted,³⁰ 3 new AOEs were reported with asciminib, and 1 new AOE was reported with bosutinib. New AOEs reported with asciminib were angina pectoris and arteriosclerosis of the coronary artery (in 2 new patients) and peripheral arterial occlusive disease (in a patient who reported arteriosclerosis of the coronary artery at week 48).³⁰ Almost all patients with AOEs had cardiovascular risk factors at baseline (supplemental Table 7).

Table 5.

Rates of AOEs

Arterial occlusive event	Patients, n (%)
	Asciminib			IS-TKIs
	Imatinib stratum (n = 100)	2G TKI stratum (n = 100)	All asciminib (n = 200)	Imatinib treated (n = 99)	2G TKI treated (n = 102)	All IS-TKIs (n = 201)
Patients with ≥1 event	2 (2.0)	2 (2.0)	4 (2.0)	0	3 (2.9)	3 (1.5)
Angina pectoris∗	1 (1.0)	0	1 (0.5)	0	0	0
Cerebrovascular accident	1 (1.0)	0	1 (0.5)	0	0	0
Peripheral arterial occlusive disease∗,†	0	1 (1.0)	1 (0.5)	0	0	0
Myocardial infarction‡	0	0	0	0	1 (1.0)	1 (0.5)
Myocardial ischemia‡	0	0	0	0	1 (1.0)	1 (0.5)
Arteriosclerosis coronary artery∗,†	0	2 (2.0)	2 (1.0)	0	0	0
Cerebral infarction∗,§	0	0	0	0	1 (1.0)	1 (0.5)
Vertebral artery arteriosclerosis‖	0	0	0	0	1 (1.0)	1 (0.5)

Based on the safety analysis set. Adapted from Cortes et al.³¹

^∗New AOEs reported during the secondary analysis of ASC4FIRST.

^†Peripheral arterial occlusive disease was detected in a patient who reported arteriosclerosis of the coronary artery at week 48.

^‡Patient received dasatinib on treatment; myocardial infarction and myocardial ischemia occurred in the same patient.

^§Patient received bosutinib on treatment.

^‖Patient received nilotinib on treatment.

No on-treatment deaths were reported at the week 96 cutoff. Deaths occurring during survival follow-up were previously described.³⁰ Since the primary analysis, 1 additional death due to unknown cause occurred during survival follow-up in a 42-year-old man who received treatment with imatinib.

Discussion

After ∼2.2 years of follow-up (almost 1 year of additional follow-up after the primary analysis)³⁰ in the pivotal phase 3 ASC4FIRST study, asciminib demonstrated continued statistically significant superior efficacy compared with imatinib and improved efficacy compared with 2G TKIs in patients with newly diagnosed CML-CP.

The MMR rate difference between asciminib and 2G TKIs almost doubled to 15.1% (95% CI, 2.3-28.0) at week 96 from 8.2% (95% CI, −5.1 to 21.5) at week 48, and the CI remained >0, suggesting a possible clinical benefit of asciminib over 2G TKIs; care should be taken in interpreting this difference as the study was not designed to formally confirm statistical significance for this secondary end point. The increased rate difference may be attributed to more new patients achieving MMR at week 96 with asciminib vs 2G TKIs in the 2G TKI stratum (11.0% vs 7.8%), and of those with MMR during the primary analysis, more maintaining MMR (92.4% vs 84.7%) and fewer discontinuing (6.1% vs 13.6%), specifically discontinuing due to AEs (1.5% vs 10.2%).³⁰

MMR rates at week 96 remained higher with asciminib than with IS-TKIs across all assessed demographic and prognostic subgroups, demonstrating a robust and consistent treatment benefit with asciminib. High overall MMR rates at week 96 with asciminib (74.1%) in the ASC4FIRST study were comparable to 12-month MMR rates with asciminib (79.2%) in the ASCEND study evaluating safety and efficacy of asciminib in frontline CML-CP.¹²

Achievement of early MMR is associated with an improved probability of achieving subsequent and sustained deep molecular responses, which predict successful treatment-free remission (TFR).^{1,18,32, 33, 34} In ASC4FIRST, higher MR⁴ and MR^4.5 rates with asciminib in the first year of treatment were sustained after >2 years of follow-up,³⁰ which may translate to patients being eligible to attempt TFR, but longer follow-up is needed to confirm durability of these responses. These results confirm the inhibitory effect of asciminib on BCR::ABL1, and the sustained efficacy of asciminib.

Mutations were infrequent overall. Most mutations with asciminib were in or near the myristoyl pocket, and with IS-TKIs were in the ATP-binding domain, consistent with their respective binding sites.²⁶ Among patients who discontinued due to treatment failure or disease progression, 58.3% receiving asciminib had postbaseline treatment-emergent BCR::ABL1 mutations vs 15.6% receiving IS-TKIs. Patients who discontinued IS-TKIs due to treatment failure per European LeukemiaNet 2020 recommendations were predominantly those who received imatinib (n = 19) vs 2G TKIs (n = 9),¹ suggesting that discontinuation was likely due to less potent inhibition of BCR::ABL1 rather than emergence of resistance mutations. More patients receiving IS-TKIs than asciminib had treatment failure with no mutation identified, suggesting treatment failure with asciminib was mostly driven by myristoyl pocket mutations, whereas with IS-TKIs it was usually not BCR::ABL1 mediated.³⁵ When no kinase domain mutations are found, no 2G TKI is more effective than others and the best treatment option remains uncertain.^1,35,36 In ASC4FIRST, because most emergent BCR::ABL1 mutations with asciminib were related to the myristoyl pocket and the allosteric mechanism, subsequent treatment with ATP-competitive TKIs remained feasible for most patients with asciminib failure, alleviating concerns about treatment sequencing. After 21 months in the ASCEND study, emergence of BCR::ABL1 mutations conferring resistance to ATP-competitive TKIs was uncommon with asciminib.¹² With longer follow-up in ASCEND (34 months), 3 patients with asciminib resistance had the M244V P-loop mutation.³⁷ Hence, resistance mutations are not always restricted to the myristoyl pocket, underscoring the need for broader mutational profiling to guide subsequent therapy.

The safety and tolerability profile of asciminib in ASC4FIRST remained consistent with that in the primary analysis and the established profile in late-line patients in ASCEMBL (median exposure, 3.0 years) and the phase 1 monotherapy study (median exposure, 5.9 years).^28,29 Half as many patients discontinued asciminib as discontinued IS-TKIs despite more stringent, protocol-mandated criteria for discontinuation of asciminib. The frequency of AEs leading to treatment discontinuation with asciminib, imatinib, and 2G TKIs, respectively, was 5.0%, 13.1%, and 12.7%.³⁰ The rate of AEs leading to discontinuation was approximately lower by half with asciminib than with imatinib, nilotinib, dasatinib, and bosutinib. Only 4 additional patients had lipase elevations since the primary analysis, and no new patients discontinued asciminib due to this.³⁰ No additional patients discontinued treatment with asciminib or IS-TKIs due to pancreatitis,³⁰ and the incidence was similar or lower with asciminib than with other TKIs, suggesting a class effect. Occurrence of hypertension has been reported to be associated with TKIs.^{38, 39, 40} Although no patient discontinued therapy because of hypertension and most instances were manageable, more patients receiving asciminib than IS-TKIs reported hypertension, underscoring the need for adequate monitoring and management. The nonoverlapping pattern of AEs that led to discontinuation of asciminib vs each individual TKI demonstrates the distinct safety profile observed with asciminib that can help optimize treatment of newly diagnosed CML-CP. No patients reported AOEs with imatinib, consistent with its known favorable vascular safety profile.⁴¹

Fewer patients had dose reductions or interruptions due to AEs with asciminib (14.0% and 33.0%) than imatinib (21.2% and 37.4%) and 2G TKIs (43.1% and 51.0%). Imatinib is generally associated with low-grade AEs and considered tolerable.^1,42 This analysis of the ASC4FIRST trial demonstrates fewer grade ≥3 AEs, discontinuations due to AEs, and dose reductions or interruptions with asciminib vs imatinib, suggesting improved tolerability.

Asciminib’s consistent safety and tolerability after longer follow-up in ASC4FIRST, considered with its enduring safety in ASCEMBL and the phase 1 study,^{27, 28, 29,43, 44, 45} suggest long-term tolerability for patients who cannot stop therapy. Rapid and robust early and deep molecular responses with asciminib also suggest potential for accelerated TFR eligibility. We plan to investigate TFR with asciminib in future analyses.

As treatment sustainability becomes increasingly important in clinical decision-making, especially in the context of reduced costs for imatinib and generic 2G TKIs, the ASC4FIRST data suggest that asciminib offers sustained efficacy alongside favorable safety and tolerability, with lower rates of AEs, dose modifications, and treatment discontinuations. These attributes support its use as a frontline option, particularly for patients who prioritize long-term adherence and QOL. Long-term results from asciminib trials (ASC4START,⁴⁶ ASC2ESCALATE,⁴⁷ and ASCEND¹²) and future real-world studies, and health economics and outcome research, will be essential to fully establish its role in the treatment landscape.

The ASC4FIRST week 96 analysis continues to support the findings in the primary analysis.³⁰ Asciminib offers a better benefit-risk profile than all IS-TKIs, imatinib, and 2G TKIs in patients with newly diagnosed CML-CP and presents a valuable frontline option for this patient population.

Conflict-of-interest disclosure: J.E.C. received grants from Novartis, Pfizer, and Bristol Myers Squibb; and consulting fees from Novartis and Pfizer. N.T. received research funding and honoraria from, and is a member of the speakers bureau and board of directors or advisory committee for, Novartis, Pfizer, and Otsuka. T.P.H. received honoraria for advisory boards and symposia from Novartis, Takeda, and Terns; and grants from Novartis. J.W. acted in a consulting or advisory role for AbbVie. D.-W.K. received grants from Novartis, Bristol Myers Squibb, Pfizer, Ilyang, and Takeda. J.M. received research funding from BeiGene and Novartis. Y.-T.G. received consulting fees and honoraria from Novartis, AstraZeneca, Antengene, Amgen, EUSA Pharma, Pfizer, and Johnson & Johnson; and honoraria from MSD, Roche, Astellas, and AbbVie. P.l.C. received honoraria from Novartis, Incyte, Blueprint, Pfizer, Bristol Myers Squibb, and AOP Orphan Pharmaceuticals. G.E. provided consultancy for Incyte Corporation, Novartis, and Pfizer. D.J.A. provided consultancy for AbbVie and Celgene; and received research funding from AbbVie, Celgene, AstraZeneca, and Novartis. F.B. has membership on the board of directors or advisory committees for, provided consultancy for, and received organizational grant funding from CML Advocates Network, MPN Advocates Network, Associazione Italiana contro le Leucemie, i Linfomi e il Mieloma ONLUS, and CLL Advocates Network; and provided consultancy for and received organizational grant funding from Novartis, Jazz, Celgene, Incyte, and Takeda. G.C.I. provided consultancy for Novartis and Kura Oncology; and received research funding from Novartis, Kura Oncology, and Syndax. R.A.L. provided consultancy for Novartis, Takeda, Astellas, CVS/Caremark, and Epizyme; and received research funding from Novartis, Takeda, Astellas, Gilead, Rafael Pharmaceuticals, and Cellectis. S.K., R.J., T.M., and L.Y. are employees of Novartis Pharma. A.H. received institutional research support from Novartis, Bristol Myers Squibb, Incyte, Enliven, Terns Pharmaceuticals, and Pfizer; and personal fees from Novartis and Incyte. The remaining authors declare no competing financial interests.