NEW YORK – Newly diagnosed chronic myeloid leukemia patients fared better on Novartis' investigational STAMP inhibitor Scemblix (asciminib) than on standard tyrosine kinase inhibitors, according to Phase III data presented at the American Society of Clinical Oncology's annual meeting on Friday.
In the randomized ASC4FIRST clinical trial, patients on Scemblix had better major molecular response rates — based on assessment of BCR-ABL transcript levels — than with Novartis' Gleevec (imatinib) and other TKIs, and Scemblix was more tolerable, too. Patients were eligible for the study if they had typical BCR-ABL1 transcripts, e14a2 or e13a2, as detected by real-time quantitative PCR.
Upon diagnosis, CML patients can receive a number of TKIs, Jorge Cortes, the director of the Georgia Cancer Center at Augusta University, said during a Wednesday press conference ahead of the meeting. But even on the established frontline TKIs like Gleevec, Novartis' Tasigna (nilotinib), Bristol Myers Squibb's Sprycel (dasatinib), and Pfizer's Bosulif (bosutinib), Cortes noted that about half of patients do not achieve major molecular responses at 12 months.
Scemblix has a unique mechanism of action versus these standard TKIs. It binds to the ABL myristoyl pocket, which could result in greater selectivity and less toxicity, according to Cortes. The drug is already approved in the US and in Europe for later-line CML patients, including patients with Philadelphia chromosome-positive CML in the chronic phase who've received at least two prior TKIs. In the US, the drug is also approved for Philadelphia chromosome-positive CML in the chronic phase whose cancers harbor T315I mutations.
In the ASC4FIRST study, patients were eligible to enroll if they had newly diagnosed Philadelphia chromosome-positive CML in the chronic phase and had not received prior TKIs. Patients were randomized upfront to receive either Scemblix or one of two control options: Gleevec or a second-generation TKI chosen by their physicians. Physicians had to choose which TKI their patients would receive — Gleevec or a second-generation drug — before study participants underwent randomization, allowing for a cohort of patients who were randomized to Scemblix but would have otherwise gotten Gleevec.
The study's two primary endpoints included comparing major molecular response rates at 48 weeks with Scemblix against any of the comparator TKIs and with Scemblix versus Gleevec. For the latter endpoint, researchers considered only the patients whose doctors would have prescribed Gleevec had they not been randomized to the Scemblix arm and compared their outcomes to patients who were randomized to receive Gleevec.
Among 201 patients who received Scemblix, 67.7 percent of patients had a major molecular response at 48 weeks, whereas the same was true for 49 percent of 204 patients who received any of the comparator drugs. For the second primary endpoint, 69.3 percent of 101 patients who received Scemblix, but had been pre-stratified to the Gleevec arm, achieved a major molecular response at 48 weeks. The same was true for 40.2 percent of 102 patients who received Gleevec.
"This was a very significant difference in favor of asciminib," Cortes said. Although this is an early readout from ASC4FIRST, Cortes also noted that more patients on Scemblix seem to have deeper molecular responses than on comparator TKIs.
Notably, Cortes highlighted that more patients discontinued treatment in the Gleevec and second-generation TKI arms than in the Scemblix arm, and so far, there are more patients still receiving Scemblix than there are patients receiving comparator TKIs. As of the study's data cutoff last November, 36.3 percent of patients in the Gleevec group and 23.5 percent on other TKIs had discontinued treatment. By comparison, in the Scemblix arm, 14.9 percent of patients who would have received Gleevec and 12 percent who would have received another TKI had discontinued treatment.
Patients generally experienced fewer hematologic and non-hematologic toxicities on Scemblix than on other TKIs, too. "Overall, the safety profile seems to be equivalent or better for nearly all adverse events that we see with tyrosine kinase inhibitors, emphasizing the safety of asciminib," Cortes said. "This strong benefit-risk profile may change the treatment paradigm in chronic myeloid leukemia."
"This is really poised to potentially change the management of first-line treatment of chronic myeloid leukemias," Oreofe Odejide, a hematologic oncologist at the Dana-Farber Cancer Institute, echoed during the media briefing.
Despite the promising early readout, major molecular response is a surrogate endpoint, and Scemblix hasn't directly shown that it improves patients' overall survival compared to standard TKIs. But as Cortes and Odejide pointed out, showing an overall survival benefit is difficult to do in CML, since patients often end up taking these drugs for the rest of their lives.
For a cancer like CML in the chronic phase, where treatment discussions are centered around long-term disease management, Cortes said major molecular response may be a good predictor of which patients could discontinue treatment. "Today, we know that [treatment discontinuation] is a reality for about 25 percent of patients overall," he said. "We want to see if we can get more patients to those deep molecular responses and get these deep molecular responses to be more sustained when we attempt discontinuation."
The possibility of having treatment-free periods is an important consideration for patients with this cancer, as are the treatment's side effects and its impact on quality of life, Odejide agreed.
Novartis has previously said that it will seek regulatory approval for Scemblix in Philadelphia chromosome-positive CML in the chronic phase based on data from ASC4FIRST during the first half of 2024.