An Era of Firsts in CML: Asciminib Challenges SOC TKIs

*Editor’s note: This article was written prior to the accelerated approval of asciminib.

When asciminib (Scemblix) bested standard-of-care (SOC) investigator-selected tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) enrolled in the phase 3 ASC4FIRST trial (NCT04971226), it became the first and only agent in a randomized phase 3 trial to improve upon first- and second-generation SOC TKIs for this patient population.¹

Not only did asciminib yield superior major molecular response (MMR) rates vs SOC TKIs, “[data were] suggestive that [treatment with asciminib] could lead us to have more patients who would eventually meet the criteria for treatment discontinuation and hopefully discontinue treatment successfully,” Jorge E. Cortes, MD, said in an interview with OncologyLive. “I would like to use [asciminib if it is approved] as the first drug for most of my patients.”

Following these encouraging data, the agent received priority review on July 29, 2024, from the FDA for the treatment of those with newly diagnosed Philadelphia chromosome (Ph)–positive CML in chronic phase. This has given hope to physicians that a new option may soon emerge.²

As advancements have been made in drug development and promising drugs such as asciminib are standing strong with potential to receive FDA approval, care for patients with hematologic malignancies has rapidly evolved.
In an era of precision medicine and rapid growth, Cortes has been named theinaugural editor in chief of the peer-reviewed, open-access journal Blood Global Hematology, which is set to publish its first articles in early 2025. Cortes is currently director for the Georgia Cancer Center and the Cecil F. Whitaker Jr, GRA Eminent Scholar Chair in Cancer in Augusta.^3,4

“The idea of this journal is to learn from parts of the world where their approach is different, not better, not worse, just different,” Cortes explained. “Understanding those elements can help everybody, so it’s a space for those investigators with a particular focus in low- and middle-income countries to present the research, show us what is happening in their field and area, how they’re making advances, and how they’re making innovations with the resources that they have. We can learn about their population, and everybody benefits from learning from each other. Sometimes this kind of research is more impactful because it’s applicable to more places all over the world; [there are] approaches that may be great but are not available to everybody.”

The addition of the Blood Global Hematology journal to oncology literature marks another exciting development in the field, according to Cortes, who noted that it will feature “research that adapts to populations [and] takes advantage of the resources. [Research will also] describe populations that we know very little about because they’re not in our genetic profiling [and will] describe the use of health resources in a different way.”

Cortes and colleagues will discuss all the latest advancements in hematology, includingreal-world patient-care scenarios and data on asciminib, at the 29th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma. The meeting is slated to occur February 27 through March 2, 2025, in Miami Beach, Florida. Joining cochair Cortes are fellow cochairs Andre H. Goy, MD, of John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, and Sagar Lonial, MD, FACP, of Winship Cancer Institute of Emory University in Atlanta, Georgia.⁵

“The part of the conference that I lead is the leukemia component. I’m sure we’re going to be talking a lot about asciminib, frontline [administration of therapy], and how it works,” Cortes noted. “There are a lot of new developments where there are still data to understand [and] new data coming out. How do we apply these [findings] to the clinic? It’s going to be another fantastic meeting.”

Unpacking the Latest in CML: Asciminib Shines vs SOC TKIs

Findings from ASC4FIRST published in TheNew England Journal of Medicine showed that patients with newly diagnosed Ph-positive CML in chronic phase treated with asciminib (n = 201) achieved a 48-week MMR rate of 67.7% vs 49.0% in the SOC TKI arm (n = 204) for a treatment difference of 18.9% (95% CI, 9.6%-28.2%; adjusted 2-sided P < .001). A greater treatment difference of 29.6% (95% CI, 16.9%-42.2%; adjusted 2-sided P < .001) was observed when an asciminib analysis population (n = 101) was compared with a full analysis set of patients who received imatinib (Gleevec; n = 102), as patients experienced 48-week MMR rates of 69.3% vs 40.2%, respectively.⁶ Furthermore, an 8.2% difference (95% CI, –5.1% to 21.5%) in 48-week MMR rates was observed among patients who received asciminib (n = 100) vs second-generation TKIs (n = 102); rates were 66.0% vs 57.8%, respectively.

“Now it’s only 48-week [data], so we need to wait for longer results, [but] we do know that these early responses historically have correlated well with long-term outcomes, particularly with achievement of the deeper molecular responses [and] eligibility for treatment-free remission, which is what we ultimately want to get to with a better drug,” Cortes said. “Whether it turns out to be a better drug [is yet to be determined], but as a primary end point [and] as an early time point, [the data are] very exciting. The difference was quite significant [with asciminib vs imatinib or all other TKIs].”

Findings on Asciminib’s Safety Profile Show the Agent Is Well Tolerated

Regarding safety, grade 3 or higher adverse effects (AEs) occurred at a lower rate in the asciminib arm (38.0%) than in the second-generation TKI arm (54.9%) and imatinib arm (44.4%). AEs leading to treatment discontinuation also occurred at a lower rate in the experimental arm than in the second-generation TKI and imatinib arms, at rates of 4.5% vs 11.1% vs 9.8%, respectively.⁶

“It’s well tolerated, and although we have the perception that it’s a new drug, we’ve been using asciminib for 10 years,” Cortes said. “The phase 1 study started in 2014, so we have patients who have been receiving this drug for 10 years, and we do have long-term follow-up. It is a clean drug, and I like that, particularly because even if some patients are not going to be able to stop therapy, at least they have something that provides as little toxicity and respects quality of life as much as possible.”

The most common any-grade AEs that occurred in the safety population of patients who received asciminib (n = 200) vs all comparator TKIs (n = 201) in ASC4FIRST were thrombocytopenia (28.0% vs 31.3%, respectively), neutropenia (25.0% vs 32.8%), leukopenia (19.0% vs 24.4%), COVID-19 (17.5% vs 19.4%), diarrhea (15.5% vs 25.9%), fatigue (14.0% vs 15.9%), and headache (13.5% vs 14.9%).

“The question is: Will it be approved by the FDA?” Cortes asked. “If it is approved, then who is the right candidate to receive asciminib? How do we incorporate it [into care]? We have 4 drugs approved for frontline CML treatment—how do you choose? We’re going to have to learn about that [and] develop algorithms and strategies. I see it benefiting patients who are interested in stopping treatment at some point; if we are [trying to increase the] probability of having a patient be eligible for [discontinuation], that could be a patient to [receive asciminib]. But also, patients who may be more prone to AEs and who we are concerned about [experiencing AEs such as] arterial-occlusive events, diarrhea, and pleural effusions [may benefit from the agent] because of its very clean toxicity profile.”

Findings from ASC4FIRST presented at the 2024 American Society of Clinical Oncology Annual Meeting showed that more patients were continuing treatment with asciminib (n = 201; 86.1%) vs all SOC TKIs (n = 204; 68.6%) at the November 28, 2023, data cutoff, with median follow-ups of 16.3 months vs 15.7 months, respectively.7 Currently, asciminib is FDA approved for the treatment of adults with Ph-positive CML in chronic phase who have previously received 2 or more TKIs.²

“Getting more information as to the benefit in that [frontline] setting would be important, and [we] also [want to determine] whether you can switch to asciminib in a patient who is having a good response, but not the deep molecular response that they need for treatment discontinuation,” Cortes said. “Could that be another way of [giving therapy] and getting the benefit of treatment discontinuation?” 

References

1. Novartis Scemblix shows superior major molecular response (MMR) rates vs. standard-of-care TKIs in phase III trial for newly diagnosed patients with chronic myeloid leukemia. News release. Novartis. January 8, 2024. Accessed October 14, 2024. bit.ly/3NqCdYe
2. Novartis Scemblix granted FDA priority review for the treatment of adults with newly diagnosed CML. News release. Novartis. July 29, 2024. Accessed October 14, 2024. bit.ly/3NrAbal
3. New from the American Society of Hematology (ASH): Blood Global Hematology. American Society of Hematology. Updated April 15, 2024. Accessed October 14, 2024. bit.ly/3YjV1hY
4. ASH names editor-in-chief of new journal: Blood Global Hematology. News release. American Society of Hematology. April 16, 2024. Accessed October 16, 2024. bit.ly/3Abbdc3
5. 29th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma. Physicians’ Education Resource, LLC. Accessed October 14, 2024. bit.ly/4dNn91o
6. Hochhaus A, Wang J, Kim DW, et al; ASC4FIRST Investigators. Asciminib in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2024;391(10):885-898. doi:10.1056/NEJMoa2400858
7. ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): primary results. J Clin Oncol. 2024;42(suppl 17):LBA6500. doi:10.1200/JCO.2024.42.17_suppl.LBA6500