Asciminib: A Novel TKI for the Treatment of Chronic Myeloid Leukemia

Deeter R. Neumann, PharmD, BCOP
Clinical Oncology Pharmacist – Hematology and Cellular Immunotherapy
Seattle Cancer Care Alliance, UW Medicine
Seattle, WA

The treatment for chronic myeloid leukemia (CML) was transformed in 2001 when the tyrosine kinase inhibitor (TKI), imatinib, was approved by the United States Food and Drug Administration (FDA).1 Today, TKIs on the market demonstrate the ability to reduce a patient’s leukemic burden and restore their life expectancy back to normal.2-6 However, limitations to TKI therapy still exist and are marked by drug toxicity, drug resistance, or both.⁷

The recent approval of asciminib by the FDA provides a promising option for patients that have developed either toxicity to or resistance against earlier lines of TKI treatment.⁸

Asciminib Pharmacology
Prior to the development of asciminib, all marketed TKIs for CML exerted their pharmacologic activity via binding to the catalytic adenosine triphosphate (ATP) site in ABL1.7 Mutations to the ABL1 ATP catalytic site result in the inability of TKIs to modulate BCR-ABL1 activity, thus leading to the loss of TKI response and disease progression. One mutation, T315I, is particularly problematic in that it confers resistance to all TKIs used for the treatment of CML except ponatinib.⁹ Unlike ponatinib and the other TKIs indicated for CML, asciminib exhibits a novel mechanism of action, allowing it to circumvent all ATP catalytic site mutations. Asciminib accomplishes this feat by acting as a selective allosteric inhibitor of BCR-ABL1 kinase activity.

In its wild-type structure, ABL1 displays autoinhibition via the binding of an N-terminal myristoyl group to a C-terminal myristoyl pocket on the kinase domain. In the pathogenic formation of the BCR-ABL1 fusion protein, the BCR protein fragment replaces the N-terminal myristoyl group of ABL1. Without the myristoyl group present, the myristoyl pocket is left vacant, and ABL1 loses the capacity to self-regulate kinase activity. This results in BCR-ABL1 being a constitutively active kinase.⁷ Asciminib is able to bind to the myristoyl pocket and is thus capable of turning off BCR-ABL1 kinase activity.⁷ As we will see, the dose needed to effectively inhibit BCR-ABL1 is dependent on the presence of the T315I mutation and is reflected in the FDA approved label.10

Dose Finding Study and Pharmacokinetic Analysis of Asciminib
The maximum tolerated dose of asciminib was evaluated in the phase 1 trial reported by Hughes et al.11 In this trial, adult patients with relapsed/refractory chronic-phase (CP) or accelerated-phase CML were enrolled. Enrolled patients must have failed treatment with at least two different TKIs or were unable to tolerate prior TKI therapy. Seventy percent of the patients enrolled had been previously treated with three or more TKIs, and at the time of the report, 33 patients (22%) harbored the T315I mutation.11

Final pharmacokinetic (PK)-pharmacodynamic (PD) modeling demonstrated that appropriate inhibitory concentrations of asciminib would be maintained in 100% of patients without the T315I mutation when asciminib was dosed at 40 mg twice daily.11 For the limited number of patients harboring the T315I mutation, doses greater than 150 mg twice daily were required to achieve a major molecular response (MMR). Based on these findings, asciminib dosed at 40 mg BID and 200 mg BID were selected for further investigation.

Asciminib is a highly protein bound molecule that is predominantly metabolized by the liver via direct glucuronidation (27.9%) and CYP450 oxidation (37.8%). Additionally, biliary secretion via breast cancer resistance protein (BCRP) plays a role in the elimination of asciminib (31.1%). A minimal amount of asciminib is also cleared by the kidneys (2.5% unchanged).¹² The half-life of asciminib was determined to be 8 hours, allowing for steady state levels to be achieved by day 3 of dosing.¹¹ The special population PK studies performed by Hoch et al. focused on individuals with renal and hepatic dysfunction.

The study found increases in both exposure and maximum plasma concentrations in individuals with severe renal impairment (absolute glomerular filtration rate (aGFR) < 30 mL/min and not yet requiring dialysis) and individuals with mild (Child-Pugh class A) and severe hepatic impairment (Child-Pugh class C).12 While PK parameters were impacted, asciminib’s therapeutic window proved to be large enough to conclude that renal and hepatic impairment have little effect on its safety profile. This led to the FDA approving the label for asciminib with no dose adjustments for patients with kidney or liver dysfunction and prescribed 40 mg BID.¹²

Liver and kidney dysfunction may not be a major determinant for the metabolism of asciminib; however, drug-drug interactions (DDIs) should be evaluated for each patient. Asciminib is a substrate of CYP3A4, and an inhibitor of CYP3A4, CYP2C9, and P-glycoprotein (P-gp).¹⁰ Clinicians should consult the prescribing information for guidance on the management of DDIs with asciminib, as the recommendations vary from close monitoring to the avoidance of concomitant medications depending on the prescribed dose of asciminib.¹⁰

Efficacy of Asciminib
The results of two pivotal trials led to the FDA approval of asciminib. The ASCEMBL study was an open-label, active-controlled, multicenter, phase 3 trial comparing asciminib with bosutinib.13 Eligible patients were randomized to receive either asciminib 40 mg twice daily or bosutinib 500 mg once daily, and the study’s primary endpoint was the rate of MMR at 24 weeks.¹³ At 24 weeks, 25.5% of patients receiving asciminib obtained a MMR compared to only 13.2% of patients receiving bosutinib, and the benefit of asciminib was irrespective of the number of previous lines of TKI therapy.¹³

Updated efficacy data was recently presented at the 2021 American Society of Hematology (ASH) Annual Meeting.¹⁴ At 48 weeks of treatment, 33.2% of patients receiving asciminib achieved MMR compared to 18.6% in those receiving bosutinib.14 While initial results for the ASCEMBL study helped asciminib gain an accelerated approval in patients treated with two or more TKIs, the 48 week update demonstrated continued superiority with asciminib.^8,13,14

For individuals with known T315I mutations, the efficacy of asciminib continues to be evaluated in the pivotal study, CABL001X2101.⁸ CABL001X2101 is an ongoing study that expands on the results of the previously reported dose finding trial.8,11 At the time of the FDA’s review, 45 patients with T315I mutated CP CML who have failed at least one other line of TKI therapy were enrolled. The efficacy analysis evaluated MMR at 24 weeks, of which 42% of patients achieved when treated with asciminib. By week 96 of asciminib treatment, 49% of the patients achieved MMR.⁸

While the pivotal trials showcase the efficacy of asciminib, it is important to evaluate the safety profile of asciminib as this is an important consideration for the selection of TKI therapy in CML.

Safety of Asciminib
The safety profile of asciminib was closely evaluated in the phase 1 dose finding trial reported by Hughes et al.¹¹ Asciminib demonstrated a profile of low severity adverse events (AEs), with 92% of nonhematologic AEs being grade 1 or 2. The most frequent nonhematologic AEs were asymptomatic increases in the lipase or amylase level, rash, and constitutional symptoms. The most common cardiovascular AE was hypertension reported in 19% of patients. All grade thrombocytopenia was the most commonly reported hematologic AE with 22% of patients, and 9.3% experiencing Grade 3 or 4 thrombocytopenia. All grade anemia and neutropenia were reported in 11.3% and 10.7%, respectively.11 The incidence of thrombocytopenia and neutropenia were higher in the Phase III ASCEMBL study, while anemia was similar.¹³ Clinical pancreatitis was experienced by five patients in the dose finding study (3 patients at the 80 mg BID dose level, 1 patient at the 150 mg BID dose level, and 1 patient at the 200 mg once daily dose level); however, clinical pancreatitis was not reported in the ASCEMBL study.^11,13 The 48- week update to the ASCEMBL trial demonstrates that the safety profile remains similar to the primary analysis originally reported by Réa et al.¹⁴ While the updated results indicate that myelosuppression occurs earlier in treatment with asciminib, both thrombocytopenia and neutropenia were the most common AEs leading to treatment discontinuation (3.2% and 2.6%, respectively).¹⁴ These AEs are important to consider, particularly when considering dose adjustments.

Dose Adjustments and Toxicity Management
The prescribing information for asciminib provides recommendations for dose adjustments due to AEs. The AEs requiring dose adjustment include neutropenia and/or thrombocytopenia, asymptomatic elevations in amylase or lipase, and all Grade 3 or higher nonhematologic AEs.¹⁰ The management of all AEs require holding asciminib until near resolution; however, when managing neutropenia or thrombocytopenia, the time to resolution and if it is recurrent dictate whether a dose reduction is warranted.¹⁰

While there were no reports of clinical pancreatitis in the ASCEMBL study, there were five cases documented in the phase 1 dose finding study, and all cases occurred at higher doses.^11,13 Trial investigators discontinued asciminib in the setting of clinical pancreatitis, and the cases were noted to have resolved within 10 days. One of the five patients was rechallenged and was able to tolerate continued therapy. The study notes that three of the five patients had experienced pancreatitis with previous TKIs. As such, CML patients harboring the T315I mutation where a higher dose is indicated and who have a history of elevated amylase/lipase and/or clinical pancreatitis to another TKI therapy, may be at greater risk for developing pancreatitis on asciminib.

In addition to monitoring for pancreatitis, the safety analysis performed in the special population PK study conducted by Hoch et al. revealed that patients with severe renal impairment had a higher incidence of increased amylase levels or neutropenia.¹² While the FDA approved asciminib’s label without dose modifications in renal or hepatic impairment, it would not be unreasonable to consider a lower initial dose of asciminib and increase the dose as tolerated in patients with extensive renal dysfunction.

Place in Treatment and Future Directions
The current National Comprehensive Cancer Network (NCCN) Guidelines for CML recommend selecting frontline TKI therapy based on “risk score, toxicity profile, patient’s age, ability to tolerate therapy, and the presence of comorbidities.”¹⁵ The NCCN recommendations are also based on the lack of an overall survival benefit between imatinib and second-generation TKIs. However, given the ability of the second-generation TKIs to decrease the risk of disease progression, they are preferred for patients with intermediate- or high-risk scores.15 For patients that do not respond to a second-generation TKI or have TKI resistance due to the T315I mutation, ponatinib is an effective option.^15,16 While asciminib showed superiority over bosutinib in the ASCEMBL study, further investigation is needed to truly understand its place in the treatment of CML patients with the T315I mutation.

The treatment of CML patients with the T315I mutation would be better understood from a study investigating asciminib versus ponatinib. The investigators of the ASCEMBL study noted ongoing efforts to optimize ponatinib dosing as the reason for not using it in the comparator arm against asciminib.¹³ However, without this information, the demonstrated safety profile of asciminib in the pivotal studies provides it with an advantage over ponatinib in patients with known cardiovascular comorbidities.^11,13,16

Asciminib will certainly drive further efforts to optimize the treatment of CML. One area of interest to be investigated is the dual inhibition of BCR-ABL1 with asciminib and an ATP catalytic site TKI. Wylie et al. briefly describes the discovery of asciminib, and the original intention to use it along with another TKI in order to improve treatment outcomes and create a barrier to resistance.¹⁷ With preclinical analyses demonstrating an additive effect of asciminib in combination with imatinib, dasatinib, or nilotinib, Novartis continues to investigate the clinical feasibility of these combinations.^17,18 There is also a case report for the use of combination asciminib plus bosutinib to restore control of resistant disease.¹⁹

Finally, the possibility exists for the development of mutations to the myristoyl pocket of BCR-ABL1, which can impact treatment success with asciminib.²⁰ The occurrence of myristoyl pocket mutations in the phase 1 dose finding study were found to be lower than originally predicted from in vitro analyses, but should be considered in patients that do not show a response to or become refractory to asciminib. Myristoyl pocket mutation analysis will likely find its way into the clinical setting as the use of asciminib becomes better established in practice.

Conclusion
The introduction of asciminib into the armamentarium for CML provides another agent for individuals who have developed resistance to or are unable to tolerate previous TKI therapy. The pivotal trials for asciminib demonstrates a safe and effective option for patients with CP CML. Clinicians should be aware of the common AEs, particularly those requiring dose interruptions and/or adjustments. Future studies with asciminib as monotherapy or in combination with other TKIs will allow for a better understanding of asciminib’s place and utility in clinical practice.

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