Janssen Requests FDA Approval of Imbruvica-rituximab Combo for First-line Treatment of CLL/SLL

Janssen is seeking approval from the U.S. Food and Drug Administration (FDA) for a combination of Imbruvica (ibrutinib) with rituximab to be used as a first-line treatment for people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The supplemental New Drug Application (sNDA) requesting Imbruvica’s label extension was based on data from the open-label, randomized E1912 Phase 3 trial (NCT02048813), where the combination cut the risk of disease progression or death by 65% and lowered the risk of death from any cause by 83%, compared with standard rituximab plus chemo.

The sNDA is being reviewed by the FDA under its Real-Time Oncology Review pilot program. The main purpose of the program is to improve the review process of safe and effective medications, so that they can become available to patients as soon as possible.

Imbruvica — jointly developed and commercialized 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 to treat 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 E1912 trial, sponsored by the National Cancer Institute and carried out by the ECOG-ACRIN Cancer Research Group, enrolled 529 patients who were 70 or younger and had untreated CLL or SLL.

In the study, participants were randomly assigned to be treated with six cycles of Imbruvica in combination with rituximab, or with six cycles of standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (collectively known as the FCR combo).

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

Data from a planned interim analysis of E1912 were recently published in The New England Journal of Medicine and presented at the 2018 American Society of Hematology Annual Meeting.

After three years, 89.4% of the patients treated with Imbruvica-rituximab combo were alive and progression-free, compared with 72.9% of those treated with the FCR combo. This meant that the trial met its primary endpoint of PFS.

Analysis also showed that the Imbruvica combination extended overall survival. At three years, 98.8% of the participants treated with the Imbruvica-rituximab combo were still alive, compared to 91.5% of those treated with the FCR combo.

The incidence of severe (grade 3), life-threatening (grade 4), or fatal (grade 5) adverse events was similar in both treatment groups: 80.1% for Imbruvica and 79.7% for FCR.

However, serious infectious complications were more frequent among patients receiving the standard treatment regimen (20.3%) than among those treated with the Imbruvica combo (10.5%).

“ECOG-ACRIN’s E1912 is a landmark head-to-head clinical trial of an Imbruvica-based regimen versus FCR, the most common chemoimmunotherapy regimen established to date for the frontline treatment of younger adult patients with CLL,” Craig Tendler, MD, vice president of clinical development and global medical affairs at Janssen research and development, said in a press release.

“We look forward to working closely with the FDA to bring this new Imbruvica-based chemotherapy-free option to younger adult CLL patients based on the significant delay in disease progression and survival benefit as demonstrated in the E1912 study,” Tendler said.