On April 21, 2020, the FDA expanded its approval of ibrutinib to include its use in combination with rituximab for the primary treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Oncology Learning Network published an interview with Neil Kay, MD, Mayo Clinic, (Rochester, MN), about the data that led to this approval and how it is likely to change the treatment landscape for patients with CLL/SLL.
Can you describe the E1912 trial and the findings that led to the recent expanded FDA approval of ibrutinib?
Dr Kay: The E1912 study compared ibrutinib and rituximab with fludarabine plus cyclophosphamide and rituximab (FCR) for patients with previously untreated, progressive CLL. Patients received ibrutinib plus rituximab for approximately six cycles. Rituximab was then dropped and ibrutinib continued indefinitely for as long as the patient was responding.
FCR was given for the usual six cycles, which equates to about 4.5 months. Roughly 2 months later, patients were assessed for response and responding patients are continuing to be observed over several years.
The data from this trial has been analyzed a few times. The data we are discussing today is what led the FDA to approve the use of ibrutinib and rituximab for the treatment of previously untreated patients with CLL or SLL.
This approval was based on the positive results from the phase III trial design E1912 study and was conducted by ECOG‑ACRIN and supported by the National Cancer Institute, of course, it is a part of the National Institutes of Health.
The main clinical findings that generated the approval was the ibrutinib‑rituximab combination demonstrating superior progression‑free survival compared to FCR.
With respect to the overall survival (OS), the first interim analysis, which was a few years ago, demonstrated a hint toward more favorable OS for the ibrutinib‑rituximab combination. At the time of the FDA approval, which was median follow‑up time of 49 months, and median OS was not reached, with a total of 23 deaths. There was 11% or 3% in the ibrutinib‑rituximab arm, and 12% or 7% in the FCR treatment arms.
Additionally, there is a very convincing continuing data showing an advantage for progression‑free survivorship with ibrutinib-rituximab as well as an improvement in overall survivorship with the combination.
I think it is also very important to note that because FCR is considered inappropriate therapy for CLL patients with 17p or p53 mutation. They were excluded from the study.
What is the significance of this approval? How will this new treatment option impact treatment of patients with CLL and SLL in clinical practice?
Dr Kay: It is complicated but let me be succinct. We have used the term "game‑changing." It is a new order in how a CLL caregiver would have a conversation with a previously untreated patient who does meet criteria for treatment.
Before this trial, likely there would have been more discussion about the use of chemoimmunotherapy or particularly FCR. There is continuing conversation about another chemoimmunotherapy, bendamustine plus rituximab, which has been used more in the elderly CLL patient because it is more tolerable than FCR.
The essence of the new conversation is that off of the clinical trial, everything else being equal, with a patient being in relatively good health, there is more reason to support the use of ibrutinib plus rituximab instead of FCR.
That is the most dramatic clinical discussion. I think FCR or chemoimmunotherapy is not completely eliminated from the conversation, but it is probably going to be much less used because of this clinical trial and the efficacy outcomes.