First-line Imbruvica-Gazyva Therapy Extends Survival Without Disease Progression in CLL/SLL Patients, Phase 3 Study Shows

First-line Imbruvica-Gazyva Therapy Extends Survival Without Disease Progression in CLL/SLL Patients, Phase 3 Study Shows

First-line treatment with Imbruvica (ibrutinib) plus Gazyva (obinutuzumab) significantly extends the time patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) live without cancer progression, and it also increases their response to treatment compared with standard chemotherapy plus Gazyva, the interim results of a Phase 3 study show.

The Imbruvica-Gazyva combo had no unexpected safety findings, representing an effective chemotherapy-free treatment option for patients with CLL/SLL, including those with high-risk mutations, the researchers stated.

The data was revealed by Carol Moreno, MD, PhD, in a presentation titled “Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE” at the 60th annual meeting of the American Society of Hematology, which was held Dec. 1 to 4, 2018, in San Diego, California.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are slow-growing non-Hodgkin’s lymphomas that share many similarities. Both affect the same type of white blood cells, called B-cells, but while CLL cancer cells are found primarily in the blood and bone marrow, the tumor cells in SLL are mostly in the lymph nodes.

Imbruvica (ibrutinib) is a potent inhibitor of Bruton’s tyrosine kinase (BTK) inhibitor — a molecule needed for malignant B-cells to survive and proliferate — jointly developed and commercialized by Janssen and Pharmacyclics, an AbbVie company.

The medicine is approved in the U.S. for six different diseases, including CLL/SLL — as a first treatment and for those who failed a prior treatment.

Gazyva (obinutuzumab) is a monoclonal antibody marketed by Genentech, a subsidiary of Roche. The drug binds to CD20, a protein expressed at the surface of B-cells, leading to the destruction of these cells, either directly or indirectly via immune system mediators.

A combination of Gazyva and chlorambucil (a type of chemotherapy) is approved in the U.S. for first-line treatment of CLL patients (those who have not received a prior treatment).

The data now released represents the first interim analysis of the iLLUMINATE Phase 3 clinical trial (NCT02264574), a study designed to evaluate the efficacy and safety of the Imbruvica-Gazyva combo over standard of care chemoimmunotherapy — chlorambucil plus Gazyva — as a first-line treatment for CLL/SLL.

The study was a randomized, open-label trial, conducted at multiple centers in Australia, Canada, Europe, Israel, New Zealand, Russia, Turkey, U.K., and the U.S.

In the study, 229 CLL/SLL patients were randomly assigned to a combination of Imbruvica and Gazyva, or chlorambucil plus Gazyva. Those assigned Imbruvica took three capsules daily and continuously (total of 420 milligrams daily) until their disease progressed or no longer tolerated the medicine.

Gazyva was administered intravenously (into the vein) for six cycles of 28 days. Chlorambucil was also administered as an oral treatment for six cycles of 28 days each. Median treatment duration was 29.3 months with Imbruvica-Gazyva, and 5.1 months with chlorambucil-Gazyva.

An independent committee measured the time patients lived without their cancer worsening (progression-free survival).

Secondary outcomes included progression-free survival in patients with high-risk mutations, overall response rate, overall survival rate, and rate of undetectable minimal residual disease — proportion of patients with no detectable signs of cancer.

The data showed that Imbruvica significantly prolonged the time patients lived without cancer progression. After 30 months of therapy, 79% of those receiving Imbruvica were alive and progression-free, compared with 31% of those in the control group. This represented a 77% reduction in the risk of cancer progression or death.

This combo therapy also benefited the high-risk population, leading to an 85% lower risk of disease progression or death.

Over the 31.3 months of median follow-up, only a minority of those on Imbruvica (4%) had to initiate a second-line treatment, whereas nearly half of those who took chlorambucil (44%) had to do so.

The percentage of patients responding to treatment was also higher with Imbruvica — 88% versus 73% — as was the proportion of patients experiencing total tumor clearance — 19% versus 8%.

However, survival rates were similar in both groups, with 86% patients in the Imbruvica and 85% of control groups being alive at the time of the analysis.

The safety profile of Imbruvica-Gazyva therapy was consistent with that already known for each medicine. The most common serious side effects were pneumonia, abnormal heart beat, low number of neutrophils in the blood, and fever. Adverse reactions related to intravenous administration of medicine were less frequent (25%) with Imbruvica, than with chlorambucil (58%).

After three years, 70% of the patients on Imbruvica-Gazyva remained on Imbruvica alone.

The data shows that using Imbruvica when treating CLL/SLL patients for the first time results in superior progression-free survival over using chlorambucil, even if patients carry mutations that predispose them to poorer outcomes.

The Imbruvica-Gazyva combo “represents an effective chemotherapy-free treatment option for first-line CLL/SLL including the high-risk population,” the researchers wrote.

In October 2018, the U.S. Food and Drug Administration (FDA) granted priority review to AbbVie‘s application seeking the approval of the Imbruvica-Gazyva combo as a first-line therapy for CLL/SLL. This application was based on the iLLUMINATE trial results.

In a priority review, the FDA expedites an application faster, taking action within 6 months, compared with 10 months under a standard review. It’s given to therapies with the potential to significantly improve the treatment of serious conditions.

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