Imbruvica Plus Rituximab Prolongs Survival in Untreated CLL/SLL Patients, Phase 3 Trial Finds

Imbruvica Plus Rituximab Prolongs Survival in Untreated CLL/SLL Patients, Phase 3 Trial Finds

Imbruvica (ibrutinib) in combination with rituximab continues to prolong survival and the time without disease progression in previously untreated adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), data from a Phase 3 trial show.

Study findings were announced in the oral presentation, “Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial,” at the 2019 American Society of Hematology (ASH) Annual Meeting, in Orlando, Florida.

Imbruvica — jointly developed and marketed by Janssen and Pharmacyclics, an AbbVie company — is a first-in-class inhibitor of Bruton’s tyrosine kinase (BTK). BTK is an enzyme that plays an important role in the development and survival of immune B-cells, and is currently being explored as a therapeutic target in different types of B-cell cancers.

Imbruvica has been approved worldwide for at least one indication in more than 95 countries, and in the U.S. for five types of blood cancers.

The U.S. Food and Drug Administration (FDA) is currently reviewing a supplemental New Drug Application Janssen submitted requesting the approval of Imbruvica in combination with rituximab as a first-line treatment for patients CLL or SLL. The submission was based on data from the randomized E1912 Phase 3 trial (NCT02048813).

The trial, sponsored by the National Cancer Institute (NCI) and carried out by the ECOG-ACRIN Cancer Research Group, enrolled 529 patients age 70 or younger with untreated CLL or SLL.

Of these, 354 people were assigned to be treated with six cycles of Imbruvica in combination with rituximab, and 175 with six cycles of standard chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab (collectively known as the FCR combo), until disease progression or unacceptable toxicity.

The study’s primary goal was to assess progression-free survival (PFS), or the time patients lived without their disease worsening. Secondary endpoints included overall survival (OS) and treatment safety assessments.

At a median follow-up of 48 months (four years), 73% of the patients assigned to the Imbruvica-rituximab combo were still receiving treatment.

Data from a planned interim analysis of E1912 showed that after three years, 89.4% of the patients treated with the Imbruvica combo were alive and progression-free, compared with 72.9% of those treated with the FCR combo.

Long-term data from E1912 presented at the meeting continued to show that patients given the Imbruvica combination lived longer and without signs of disease progression, compared to those on the FCR combo. These patients were 61% less likely to see their disease progress, and were 66% more likely to be alive at the time of the analysis.

The incidence of severe (grade 3), life-threatening (grade 4), or fatal (grade 5) adverse events was higher among those treated with the FCR combo (80%) than among on the Imbruvica combo (70%).

Among the 354 patients assigned to Imbruvica, 95 discontinued treatment. More than half (51%) of those who stopped treatment prematurely did so due to adverse events or complications, followed by other reasons (25%) and disease progression or death (24%).

In addition to long-term data from E1912, Janssen presented the latest findings of an integrated analysis from two Phase 3 trials — RESONATE (NCT01578707) and RESONATE-2 (NCT01722487) — investigating the effects of Imbruvica monotherapy in patients with CLL who were followed for up to six years.

According to findings in the poster, “Using Ibrutinib in Earlier Lines of Treatment Results in Better Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma,” patients’ survival, time to disease progression, and treatment response rates all improved when Imbruvica had been included in earlier lines of therapy.

In addition, this integrated analysis showed that Imbruvica was well-tolerated over this extended follow-up period across all lines of therapy, with only 19% of the patients discontinuing treatment due to adverse events.

“We’re pleased to see follow-up results from the Phase 3 E1912 trial, where the investigational use of Imbruvica plus rituximab is shown to extend OS for previously untreated patients with CLL,” Craig Tendler, MD, vice president of Clinical Development and Global Medical Affairs at Janssen, said in a press release.

“In addition, with the integrated analysis of the Phase 3 RESONATE and RESONATE-2 studies, Imbruvica demonstrated an OS benefit in untreated and relapsed patients with improved outcomes in early lines of therapy,” Tendler said.

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