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SAN DIEGO -- The chemotherapy-free combination of ibrutinib (Imbruvica) plus rituximab (Rituxan) topped the most active chemoimmunotherapy regimen for younger, newly diagnosed chronic lymphocytic leukemia (CLL) patients, a phase III ECOG trial found.

At a median 33.4 months follow-up, ibrutinib plus rituximab improved both progression-free (HR 0.35, 95% CI 0.22-0.50, P<0.00001) and overall survival (HR 0.17, 95% CI 0.05-0.54, P<0.0003) compared with fludarabine and cyclophosphamide plus rituximab (FCR) in patients ages 70 and under, Tait Shanafelt, MD, of Stanford University School of Medicine in California, reported here.

"This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients," Shanafelt said during a late-breaking press briefing at the American Society of Hematology (ASH) meeting. "There's also a paradigm shift from a 6-month course of intravenous chemotherapy to chronic treatment with a pill that this trial brings about."

He emphasized that the new ibrutinib-based regimen was less toxic than FCR.

"Obviously in cancer trials, as physicians, we want to improve the effectiveness of a treatment or reduce its side effects, and this trial is one of the rare circumstances where we have done both with a single therapy," he said.

Any grade ≥3 adverse events (AEs) were significantly lower in the ibrutinib-rituximab arm compared with the FCR arm (58.5% vs 72.1%, respectively, P=0.004).

Notably, the combination did not significantly improve progression-free survival in patients with IgVH-mutated disease (HR 0.44, 95% CI 0.14-1.35, P=0.07).

While ibrutinib was first approved by the FDA for first-line CLL in 2016, the pivotal trial looked at patients ages 65 and up and used chlorambucil as the comparator -- described as "not a very effective therapy" by one expert and "wimpy" by another. As such, ibrutinib had never been compared to the best available first-line regimen in younger patients.

The results of this ECOG trial come on the heels of the ALLIANCE trial, also presented this year at ASH, which demonstrated superiority, in terms of 2-year progression-free survival of ibrutinib with or without rituximab, over a more tolerable chemoimmunotherapy for older CLL patients (≥65). But ALLIANCE found no difference between ibrutinib plus rituximab vs ibrutinib alone (HR 1.00, 95% CI 0.62-1.62, P=0.49).

Shanafelt cautioned that while other studies can help inform whether rituximab is indeed adding benefit in younger CLL patients, they don't provide definitive evidence. He cited a study from , mostly in the relapsed setting, which showed that while adding rituximab to ibrutinib resulted in quicker remissions and a slight improvement in overall response rates, this did not translate to a survival benefit.

"Without direct evidence, and given that there is a survival advantage in the ECOG trial for younger patients, we have to proceed with some caution," said Shanafelt.

"Cross-trial comparisons are dangerous," said Aaron Gerds, MD, MS, of the Cleveland Clinic in Ohio and chair of the ASH Committee on Communications. "Even trials repeated in similar populations can show different results, so it's tough to extrapolate across those two studies."

"Thankfully, there is a trial in the United Kingdom -- the FLAIR trial -- that had the two arms that we had in the ECOG trial, plus a third arm of ibrutinib alone," said Shanafelt. "That trial started about a year after the ECOG trial, but will give us a definitive answer to the question."

In the current study, the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients were randomized 2:1 to daily oral ibrutinib plus rituximab or FCR from 2014 to 2016. Patient characteristics were well balanced for age, sex, ECOG performance status (only 0-2 were eligible), Rai stage, and adverse mutation status. Patients were excluded if they had a 17p deletion on fluorescence in situ hybridization.

Gerds told 口袋女优 that this regimen will likely make it into practice when one of two things happen: the FDA approves changes in the drugs' labels, or the regimen makes it into practice guidelines such as those from the National Comprehensive Cancer Network (NCCN). Gerds guessed the latter will have occurred by this time next year.

"If it's in the guidelines, that gives a lot of leverage to practicing physicians to prescribe it and get it covered," he said.

"One of the barriers to uptake of new treatments is always, how comfortable and familiar docs in the community are with this?" he added. "The level of comfort is really high."

He noted that physicians treating CLL patients across the country are by and large familiar with rituximab and ibrutinib, and know the toxicity overlap isn't huge.

Specific grade ≥3 AEs significantly reduced in the ibrutinib arm compare with FCR included neutropenia (22.7% vs 43.7%, respectively), anemia (2.6% vs 12.0%), and thrombocytopenia (2.9% vs 13.9%). Any infection (7.1% vs 19.0%) and neutropenic fever (2.3% vs 15.8%) were also significantly reduced, though infection alone only favored the ibrutinib-treated group numerically (5.4% vs 8.2%).

Some AEs occurred more frequently with the chemotherapy-free regimen, however. Atrial fibrillation (2.9% vs 0.0%) and hypertension (7.4% vs 1.9%) were substantially more common, with bleeding (1.1% vs 0.0%) and diarrhea (2.6% vs 0.6%) also more numerous.

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