ASH: Novartis' 3rd-gen kinase inhibitor tops Pfizer's Bosulif in head-to-head leukemia trial

Tyrosine kinase inhibitors, or TKIs, were a game changer for patients with chronic myeloid leukemia (CML). But many patients still miss out on the benefits because their cancer develops resistance, or they can’t tolerate the side effects. Novartis is working on a new drug for these patients—and its latest data look good.

That drug, asciminib, beat Pfizer’s Bosulif—a second-generation TKI commonly used in third-line CML treatment—in a head-to-head phase 3 study. At the 24-week mark, asciminib logged a major molecular response (MMR) rate of 25.5%, nearly doubling the 13.2% figure put up by its foe.

On paper, the MMR rate refers to lowering the amount of the BCR-ABL gene—a mutation linked to chronic myeloid leukemia—beneath a certain threshold in a patient’s blood. But what does it mean practically?

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John Tsai, M.D. (Novartis)

Patients who reach this threshold within 18 months of treatment are more likely to survive their cancer without related complications cropping up or the cancer returning, said John Tsai, M.D., head of global drug development and chief medical officer at Novartis.

“What you really want to do is achieve that MMR so you don’t have to cycle the patient to the next drug,” Tsai said.

Studies have shown that in the second-line setting, at least three out of five patients can’t get to this threshold. Because there's no standard of care for third-line treatment, the higher-than-optimal level of BCR-ABL puts them at greater risk of their cancer progressing.

The ASCEMBL study, presented virtually Tuesday at the annual meeting of the American Society of Hematology, pitted asciminib against Bosulif in 233 patients who had tried at least two other TKIs. Novartis’ drug beat Bosulif not only on MMR, but also another efficacy measure—banishing cells that express the abnormal Philadelphia chromosome in the bone marrow—in 40.8% of patients, compared with Bosulif’s 24.2%.

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Asciminib looked to be more tolerable, too. Just 5.8% of patients taking asciminib quit the study because of side effects, compared with 21.1% of those taking Bosulif, and a lower proportion of asciminib patients needed to either adjust their dose or stop treatment because of side effects (37.8% versus 60.5%). Patients for whom Bosulif was not working were allowed to switch to asciminib on the investigator’s judgment.

Two of the 157 patients taking asciminib died (1.3%), one of a stroke and the other from an arterial embolism, when a blood clot blocks an artery. Of the 76 patients taking Bosulif, one patient (1.3%) died of septic shock.

The most common side effects in the asciminib arm were low platelet levels and low white blood cell levels, which affected one-fifth of those patients. Other side effects were more common in the Bosulif patients, including diarrhea, which afflicted 71.1% of those patients and nausea, which struck 46.1% of them. About one-quarter of Bosulif patients developed a rash or elevated liver enzymes, while about one-fifth of them suffered low platelet and white blood cell levels.

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Unlike earlier-generation TKIs—including Novartis’ Gleevec and Tasigna—that bind to the ATP pocket of the BCR-ABL enzyme, asciminib attaches to a different part of the enzyme, the ABL myristoyl pocket. Novartis figures this different mechanism could help fight resistance to TKIs and tamp down side effects.

Next up, the study will report more data at the one-year mark, and Novartis plans to submit regulatory filings for asciminib in the first half of 2021. It hopes asciminib will spare very ill patients from a stem cell transplant and—if it can go into earlier lines of treatment—save other patients from progressing into third-line care in the first place, Tsai said.