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Novartis study points to larger role for targeted leukemia drug

People with chronic myeloid leukemia, a simmering cancer of the bone marrow, are often treated with one of several targeted drugs that, over the past two decades, have helped to substantially prolong survival from the disease.

Study results revealed Friday suggest that Scemblix, the newest of those therapies, can be both safer and more effective, potentially supporting wider use of it as an initial treatment. The results are from a late-stage clinical trial run by Scemblix’s maker, Novartis, and will be presented at the American Society of Clinical Oncology’s annual meeting.

In the trial, dubbed ASC4FIRST, Scemblix led to treatment responses in significantly more participants than did other targeted drugs, which included the mainstay therapy Gleevec as well as more recently introduced medicines. Additionally, more people given Novartis’ drug experienced what’s called a “deep molecular response,” which over time can be considered a remission and allow treatment to be stopped.

Study researchers also reported “markedly favorable safety and tolerability” for Scemblix, compared to Gleevec and the other so-called kinase inhibitors it was tested against.

“This combination of potency and safety may enable more patients to achieve treatment-free remission, the ultimate goal of CML therapy,” said Timothy Hughes, the lead author of the ASC4FIRST study and an oncologist at the University of Adelaide, Australia, in a statement provided by ASCO.

Scemblix is already approved in the U.S. and elsewhere for CML that’s previously been treated with two or more kinase inhibitors. Based on the results of the ASC4FIRST trial, which Novartis in January said succeeded, the drugmaker has submitted for U.S. approval in people newly diagnosed with CML.

If approved in the first-line setting, Scemblix would join Gleevec and three other kinase inhibitors that are currently available as first-line CML treatments. Their arrival in the 2000s and 2010s helped to triple the five-year survival rate for the disease, to roughly 70% among people diagnosed between 2012 and 2018, according to ASCO.

Yet people with CML still cycle through different therapies, typically because their cancer develops resistance to treatment or side effects become intolerable.

“Patients with chronic myeloid leukemia often have to be on treatment for a very prolonged period, and more than 40% of patients who are newly diagnosed with CML fail to achieve the major molecular response after a year of treatment,” said Oreofe Odejide, a medical oncologist at the Dana-Farber Cancer Institute, in a press conference held Wednesday under a publishing embargo. “And then [some] also have to switch treatments because of adverse events.”

Friday’s results indicate Scemblix may help on both fronts.The drug works differently than other kinase inhibitors approved before it, targeting a certain “pocket” on a mutant protein that drives CML proliferation. This difference might make Scemblix more selective in its binding and therefore less toxic, according to Jorge Cortes, director of the Georgia Cancer Center and an ASC4FIRST study investigator.

Novartis designed its trial to compare Scemblix to available kinase inhibitors selected by participants’ treating physicians. Just over 400 adults with recently diagnosed, chronic-phase CML were enrolled and randomized to receive either Scemblix or the selected kinase inhibitor. (Along with Gleevec, approved first-line kinase inhibitors include the drugs Sprycel, Tasigna and Bosulif.)

Results showed that, after 48 weeks, 68% of patients given Scemblix achieved a “major molecular response,” versus 49% of those on other kinase inhibitors. This laboratory measure looks at levels of mutant protein in the body. A major response means that levels are less than or equal to 0.1% on a so-called International Scale.

“Major molecular response … predicts for better event-free survival,” said Cortes, at the ASCO press conference. “But probably more important is that it’s a good predictor for the deep molecular responses in the long term, particularly the sustained deep molecular responses that make the patients eligible for considering treatment discontinuation.”

Nearly two-fifths of Scemblix-treated patients met the threshold for those deep molecular responses in the trial, compared to 21% of those on the other kinase inhibitors.

Novartis also designed ASC4FIRST with a twist. Before patients were randomized to either the Scemblix or control groups, their physicians chose whether they would get Gleevec, which is typically used with older individuals, or one of the more potent, second-generation kinase inhibitors. For the main study analysis, Novartis then compared patients selected to receive Gleevec but randomized to Scemblix, to those who were randomized to the control group.

Here, too, Scemblix outperformed. Major molecular responses were observed in 69% of Gleevec-selected patients who received Scemblix, versus 40% who went on to get one of the control drugs. This comparison was a main objective of the study.

Patients were similarly grouped prior to randomization by whether they were selected for a second-generation kinase inhibitor, but the study wasn’t powered to detect a statistical difference on that score.

It’s common for newer drugs to offer better efficacy or safety. But it’s rarer that they’re both safer and more potent. In ASC4FIRST, Scemblix was associated with lower rates of study discontinuation, dose adjustment or treatment interruptions than the comparator kinase inhibitors. And there were fewer side effects classified as medically significant with Scemblix than with either Gleevec or the second-generation drugs. The most common adverse events were low platelet and neutrophil counts.

In its current labeling, Scemblix carries cautions about the risk of pancreatic toxicity, hypertension and cardiovascular toxicity.

Scemblix “has a nice balance of efficacy and tolerability,” said Odejide. “This is really poised to potentially change the management of first-line treatment of chronic myeloid leukemia.”

Researchers will continue to follow patients through 96 weeks, testing whether earlier molecular responses lead to better outcomes. Other studies will test progression-free survival or overall survival.

For Novartis, the results position the company to extend a legacy in CML treatment. Gleevec, which had roots in the Swiss firm Ciba-Geigy, became a top-seller for Novartis, which also later developed Tasigna. Executives hope Scemblix can find similar commercial success.

“Our goal is to make this, over time, the leading CML treatment in the world,” said Novartis CEO Vas Narasimhan on a recent earnings call. He added that Novartis has long patent protection on the medicine, which also may not be eligible for drug price negotiations in the U.S. since CML is a rare form of cancer.