Outcomes from a new study funded by Novartis found asciminib (Scemblix®; Novartis) to be a potentially safer and more effective treatment option for people with newly diagnosed chronic myeloid leukemia (CML) when compared to current standard treatments with tyrosine kinase inhibitors (TKIs).

The results from this study will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago, Illinois.

Changing the standard-of-care
The phase 3 ASC4FIRST clinical trial compared asciminib with available TKI therapies that are the current standard-of-care treatment for chronic phase CML. A total of 405 patients with recently diagnosed chronic phase CML were randomly assigned to receive asciminib (201 patients) or an investigator selected TKI (204 patients).

In the TKI arm, 102 patients received imatinib and 102 received a stronger second-generation TKI. Investigators selected the TKI based on the overall health of the patient and patient preference. Typically, younger patients who did not have additional health concerns received treatment with a second generation TKI as they could tolerate more potent drugs better.

In this study the median age of the participants was 52 years and 65% of the participants were men. Around 54% of the participants were White and 44% of the participants were Asian. Cancer centers in 29 countries enrolled patients in this study.

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The median follow-up was 16.3 and 15.7 months for asciminib and investigator-selected SoC TKIs, respectively.[1]  Nearly 20% more patients treated with asciminib achieved MMR at week 48 vs. investigator-selected SoC TKIs and nearly 30% more patients achieved MMR at week 48 vs. imatinib alone.[1] Patients treated with asciminib also achieved deeper rates of molecular responses (MR4 and MR4.5) compared with investigator-selected SoC TKIs and imatinib alone. [1]

Overalla
asciminib (n=201)
vs. investigator-selected SoC TKIs (n=204)
Imatinib stratumb
asciminib (n=101)
vs. imatinib (n=102)
2G TKI stratumc
asciminib (n=100) vs. 2G TKIs (n=102)
 

Primary endpoints

Week 48 MMR rates67.7% vs. 49.0%69.3% vs. 40.2% –
Week 48 MMR Treatment difference (95% CI)18.9%
(9.6%–28.2%)
29.6%
(16.9%–42.2%)
Adjusted 1-sided
p-value
<.001<.001
Secondary endpointsdWeek 48 MMR rates66.0% vs. 57.8%
Week 48 MR439% vs. 21%43% vs. 15%35% vs. 26%
Week 48 MR4.517% vs. 9%18% vs. 5%16% vs. 13%
a All patients receiving asciminib (n=201) or investigator-selected SoC TKIs (n=204). Treatment difference after adjusting for pre-randomization selected TKI and EUTOS long-term survival (ELTS) risk groups at baseline.
b The 203 patients within the pre-randomization-selected imatinib stratum were randomized to receive either asciminib (n=101) or imatinib (n=102). Treatment difference after adjusting for ELTS risk groups at baseline.
c The 202 patients within the pre-randomization selected 2G TKIs stratum were randomized to receive either asciminib (n=100) or 2G TKIs (n=102: nilotinib, 48%; dasatinib, 41%; bosutinib, 11%).
d Secondary endpoints were not powered for statistical significance.

 

Important Findings

  • As of November 28, 2023, treatment was ongoing for 86% of the patients receiving asciminib, 62% of the patients receiving imatinib, and 75% of the patients receiving a second generation TKI.
  • After 48 weeks, 68% of patients in the asciminib arm had achieved a major molecular response compared to 49% in the TKI arm (including both imatinib and second generation TKIs).
  • A deep molecular response was observed in 39% of patients in the asciminib arm in comparison to 21% in the TKI arm. People who have a deep molecular response may eventually be considered in remission and could stop treatment.
  • In a subset analysis, patients who were selected to receive imatinib but randomized to asciminib were compared to the imatinib arm, and 100 patients selected for a second generation TKI but randomized to asciminib were compared to the second generation TKI arm. A major molecular response was reached in 40% of the patients in the imatinib arm in comparison to 69% in the corresponding asciminib subset. In the second generation TKI arm, 58% of the patients reached a major molecular response compared to 66% in the corresponding asciminib subset.
  • Overall, asciminib also demonstrated a favorable safety and tolerability profile vs. imatinib and 2G TKIs, with fewer grade ≥3 AEs, dose adjustments, and half the rate of AEs leading to treatment discontinuation [1]
  • TKIs have transformed CML treatment, but unmet need remains; many newly diagnosed patients do not meet molecular response goals, and many discontinue or change treatment due to intolerance [2-19]

Adverse events
In the study, most adverse events (AE) were fewer in the asciminib arm when compared to the TKI arm. The most frequent adverse events in the asciminib arm were low platelet count (13%) and low neutrophil count (10%).

Asciminib had a lower rate of discontinuation and lower rates of dose adjustment or treatment interruptions. Treatment was most often discontinued because it did not work, or because of unwanted side effects. Finally, blood clots, a severe side effect of TKIs, were present in only 1% of the participants who took asciminib.

In newly diagnosed patients, the safety profile was consistent with previous registration studies with no new safety concerns observed. [1] Fewer grade ≥3 AEs, dose adjustments to manage AEs, and half the rate of AEs leading to treatment discontinuation were reported for asciminib vs. both imatinib and 2G TKIs. [1]

AsciminibImatinib2G TKIs
Grade ≥3 AEsa38%44%55%
AEs leading to treatment discontinuationa5%11%10%
AEs leading to dose adjustments/ interruptionsa30%39%53%
In patients who experienced ≥1 adverse event.

 

“Asciminib is the first CML treatment to show significantly better efficacy compared to investigator-selected standard-of-care TKIs,” noted the lead study author Timothy Hughes, MD, from the South Australian Health and Medical Research Institute (SAHMRI) and University of Adelaide, Australia.

“This randomized trial demonstrated that asciminib achieved a statistically superior efficacy when compared to all TKIs available for newly diagnosed patients with chronic phase CML. Importantly, safety and tolerability of asciminib was also excellent. This combination of potency and safety may enable more patients to achieve treatment-free remission, the ultimate goal of CML therapy,” Hughes added.

“When you combine superior response with the excellent safety and tolerability profile of asciminib, we have a very promising potential frontline option for newly diagnosed patients to support them in achieving their treatment goals,” Hughes concluded.

A favorable safety profile
“Asciminib demonstrated superior efficacy compared to current standard-of-care targeted therapies, and was accompanied by a more favorable safety profile with fewer adverse events, drug interruptions, and drug discontinuations,” said  Oreofe O. Odejide, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts

“The excellent combination of efficacy and tolerability of asciminib versus current first-line treatments positions it to be a potential treatment choice for patients with chronic myeloid leukemia,” Odejide concluded.

What’s Next
Researchers will continue to follow the participants to understand the long-term safety profile of asciminib and to determine if reaching an MMR earlier continues to be a way to predict outcomes. Additional studies will measure overall survival, progression-free survival, and if treatment-free remission is reached.

“Patients living with CML need efficacious and well-tolerated treatment options that help them achieve meaningful outcomes as they manage their chronic condition,” noted Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis.

“The compelling ASC4FIRST data highlight the potential of asciminib to achieve better results than standard-of-care in newly diagnosed adults, while maintaining a favorable safety and tolerability profile. These results reinforce Scemblix as a proven treatment in Ph+CML-CP, as we continue to build on our 20-year legacy in CML innovation.”

“CML is a chronic condition and the side effects of standard-of-care can be challenging for patients. They often affect their daily life and can lead to high rates of treatment switching,” said Gerald Clements, CML caregiver, patient advocate and Steering Committee Treasurer at CML Advocates Network.

“Effective care that can be tolerated long-term is a key unmet need. By potentially bringing asciminib to patients when they are first diagnosed, they may have an opportunity to be on a highly effective treatment while also maintaining their day-to-day from the start,” Clements concluded.

Clinical trials
A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP – ClinicalTrials.gov ID – NCT04971226

Highlights of prescribing information
Asciminib (Scemblix®; Novartis) [Prescribing Information]

Reference
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Featured image: General Views during ASCO 2023. Photo courtesy: 2023 – 2024 © ASCO/Nick Agro.

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