Scemblix (asciminib)

P1/2, N=34, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2031 --> Nov 2031

Asciminib broadens therapeutic choices for patient's refractory or intolerant to 2 prior lines of treatment in a cost-effectiveness manner. The costs of drugs significantly impact the overall cost of the disease, emphasizing the importance of the selected discount rates for each drug. Given the relatively low incidence of CML, the introduction of asciminib has a limited budgetary impact, warranting individualized decisions based on patient`s clinical characteristics.

Molecular dynamics simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the -C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.

The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839)...In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.

It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. In contrast, the allosteric inhibitor asciminib strongly reduces Abl's activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.

P=N/A, N=168, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

Y139D and T315I mutations are extremely resistant to asciminib. Ponatinib and omacetaxine show potential for treating asciminib-resistant chronic myeloid leukemia.

P=N/A, N=550, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=124, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

P2, N=104, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

P3, N=199, Active, not recruiting, Novartis Pharmaceuticals | Phase classification: P3b --> P3

They include the broader availability of cost-effective generic imatinib, and soon other generic second-generation tyrosine kinase inhibitors (TKIs). For asciminib, longer-term follow-up is needed to better evaluate its safety and efficacy compared with ponatinib. Allogeneic stem cell transplantation represents a valid alternative to newer-generation TKIs, with a better treatment value when TKIs are priced at >$40,000/year.

P=N/A, N=550, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

P2, N=182, Recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2025 --> Feb 2026

P2, N=50, Recruiting, M.D. Anderson Cancer Center

P2, N=50, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P=N/A, N=31, Completed, Novartis Pharmaceuticals

P2, N=104, Recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2027 --> Apr 2025

P1/2, N=34, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2030 --> Jan 2031

Each of the 5 ATP-competitive inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) has a well-defined spectrum of resistance mutations. Growing clinical experience will soon allow to also elucidate the full spectrum of mutations conferring resistance to asciminib (that appear not to be confined to the myristate binding pocket)...Novel technologies like next-generation sequencing and digital polymerase chain reaction have recently been explored for BCR::ABL1 KD mutation testing; they have both advantages and disadvantages that are discussed in this article. This review also provides suggestions for interpretation and clinical translation of mutation testing results, which may not always be straightforward, particularly in cases of low-level or unknown mutations.

He began maintenance BCNU/cytoxan, then several cycles 6-MP/MTX/vincristine. On day +554 after diagnosis, he relapsed and started decitabine/venetoclax, then decadron + dasatinib, then MVP, followed by 3 cycles of inotuzumab...As his condition worsened he was put on ponatinib, then asciminib before expiring on day +940...On day +447 he started blinatumomab + IT MTX + nilotinib...The patient underwent leukapheresis and started HiDAC + mitoxantrone + etoposide + dasatinib...Likewise, many undocumented adults are the parents of US citizen minors who would benefit economically from their survival. For consideration we will explore cost analysis to further elucidate the potential benefit of allowing coverage of HSCT.

2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

T315I mutation in ABL KD confers broad-spectrum resistance to all 1st- and 2nd-generation ABPIs including Imatinib (IMA), Dasatinib (DAS), Nilotinib (NIL) and Bosutinib (BOS). This result suggests synergistically enhanced inhibitory activity of dual blockade using AXI combined with ASC specifically for T315I mutant CML. This approach will be promising against CML cells carrying compound mutation with T315I mutation, which is highly resistant even to Ponatinib or Asciminib.

229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.

Also, with >2 years of follow-up, ASC demonstrated superior efficacy and better safety and tolerability compared with bosutinib in pts with CML-CP without the T315I mutation after ≥2 prior TKIs in the phase 3 ASCEMBL study (NCT03106779)...In addition to pts receiving ASC as their 2L TKI, a separate cohort of newly diagnosed pts will be included, and these pts may receive up to 4 weeks of prior treatment with imatinib or an approved second-generation TKI (Table)...Dose escalation of ASC in 2L and 1L is another treatment strategy and results from ASC2ESCALATE will add to the growing body of evidence for using ASC to treat pts with CML-CP. Recruitment for pts using ASC as their 2L TKI began November 2022, and as of July 10, 2023, 5 pts have been enrolled in this cohort; Up to 92 and 90 pts are estimated to enroll in the 2L and 1L cohorts, respectively, across 90 sites.

Treatment was ruxolitinib and hydroxyurea...He started dasatinib and decitabine, which resulted in a drop from 28...However, hyperuricemia and renal failure led to a change in regimen and the patient was started on asciminib and ropeginterferon alfa-2b-njft in January 2022...He received cladribine and cytarabine, but was found to have leukemic infiltration of the spinal cord five months later...However, he always maintained a high CALR burden. This patient's mutational profile and disease course argue for the importance of early testing for CALR and BCR-ABL in addition to JAK2 and MPL in the setting of an MPN and for further research into the underlying causes of these overlap conditions.

Its efficacy and safety profile in patients with chronic-phase chronic myeloid leukaemia (CML) have been shown in the Phase 3 ASCEMBL study, comparing asciminib 40 mg twice daily versus bosutinib 500 mg once daily...All had received prior chemotherapy in combination with a TKI (imatinib, N=3; dasatinib, N=5; ponatinib, N=5), with 3 patients having undergone allogeneic haematopoietic stem cell transplantation (allo-HSCT)...ConclusionAsciminib demonstrated promising clinical efficacy with satisfactory tolerance in this cohort of Ph+ leukaemias failing multiple lines of therapy. Further investigation of its therapeutic role in Ph+ ALL is warranted.

Background ASCEMBL trial has demonstrated superior efficacy of Asciminib (ASC) over Bosutinib in terms of molecular response, and event-free survival. These findings contribute valuable insights to the understanding of ASC and PON treatments in pts with specific disease characteristics and may have implications for personalized therapy decisions in the absence of clinical trials comparing these drugs. Our aim is to expand our PSM cohort.

Eighteen patients (in which no mutations were found) switched to third-line treatment after a median time of 11 months (0-45) (ponatinib, 8 pts; nilotinib, 1 pt; dasatinib, 3 pts; imatinib, 3 pts; bosutinib, 1 pts; asciminib, 2 pts). Our findings, collected from the prospective cohort of the CML Italian observational registry, show that CP-CML patients failing frontline 2G-TKI therapy, despite a complex management, may have still an acceptable prognosis and survival due to the availability of both multiple TKI options and SCT.

However, 85% of this cohort is mainly treated with imatinib, limiting applying this experience in NIL treated pts...There is another case developed myocardial infarction while on DESC dose of NIL, who switched the treatment to Asciminib. Achieving early and sustained MR4 with frontline NIL treatment facilitates DESC approach without compromising molecular response and might promote the TFR rate by extending MR4 duration. This DESC strategy can bridge CML pts on NIL frontline therapy prior to NIL discontinuation for TFR attempt.

The present study demonstrated that a half of baseline conc ABPIs in combination with ASC is as effective as other ABPIs not just in WT but also in other ABL1 KDM CML cell lines. Different CML cell lines harboring different ABL KDM has different treatment spectrum on optimal ABPI drug as well as optimal drug conc. This result will be useful to design future clinical trial of dual blockade of ASC with other ABPIs considering the ABL KDM profiles.

P2, N=104, Recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2024 --> Nov 2027

P=N/A, N=425, Completed, Novartis Pharmaceuticals

P1, N=40, Recruiting, Marlise Luskin, MD | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2023 --> Nov 2025

Newer BCR-ABL TKIs provide superior cancer outcomes but with increased risk of acute arterial thrombosis, which further increases in patients with cardiovascular comorbidities and mitigates survival benefits compared to imatinib...Of the new agents, bafetinib decreased EC viability and increased microvessel permeability while asciminib and radotinib did not impact any EC function tested. In summary, the vasculotoxic TKIs (dasatinib, ponatinib, nilotinib) cause EC toxicity but with mechanistic differences, supporting the potential need for drug-specific vasculoprotective strategies. Asciminib and radotinib do not induce EC toxicity at clinically relevant concentrations suggesting a better safety profile.

Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.

The recent update of the ASCEMBL study demonstrated a superior efficacy with a good tolerability of Asc compared to bosutinib in chronic phase chronic myeloid leukemia (CP-CML) patients (pts) intolerant or refractory to ≥2 TKIs (Rea et al., 2022) Here we present the real-world clinical outcomes of 77 3rd + line Italian CP-CMLpts who received Asc through a Managed Access Program (MAP) approved by Novartis in 41 Italian institutions...Forty-three pts (55.8%) had a prior exposure to ponatinib and 38 of them (88.4%) had ponatinib as last TKI before switching to Asc...In this heavily pre-treated population of CML pts most of whom with a high comorbidity burden, Asc demonstrated fast and sustained responses. Collectively, these results continue to confirm that Asc has a promising role as standard of care in pts with CP-CML treated with ≥2 prior TKI.

P=N/A, N=440, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2028 --> Feb 2024 | Trial primary completion date: Jul 2028 --> Feb 2024

Background: In patients (pts) with CML, the BCR::ABL1 T315I gatekeeper mutation confers treatment resistance to all approved ATP-competitive tyrosine kinase inhibitors (TKIs) except ponatinib and olverembatinib; thus pts harboring this mutation have limited treatment options. Asciminib demonstrated effectiveness in pts with CML and the T315I mutation in routine medical practice, including ponatinib pre-treated pts, a population with limited available treatment options. Effectiveness estimates were consistent with those observed in clinical trials. Although the number of pts was small, this global study reports on one of the largest cohorts of pts with CML and the T315I mutation.