Neil Kay, MD, Discusses Ibrutinib–Rituximab Combo for CLL, SLL

On April 21, 2020, the FDA expanded its approval of ibrutinib (Imbruvica; Pharmacyclics) 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 spoke to Neil Kay, MD, Mayo Clinic, Rochester, Minnesota, about the data that led to this approval and the benefits of this new treatment option for this patient population.

Can you discuss some of the existing data that led to the evaluation of ibrutinib in combination with rituximab for patients with CLL and SLL?

The genesis of this trial came from early data over several years that ibrutinib-based regimens were very powerful for induction of responses in relapsed/refractory CLL. Thanks to other phase 2 trials, there was enough evidence that ibrutinib could be approved as a single agent for previously untreated CLL.

Additionally, more data also led to its approval for high-risk CLL. In particular, CLL patients with a 17p-minus defect; that is where our technical fluorescence in situ hybridization, or FISH, or mutation sequencing, showed a defect in chromosomes 17p or a mutation at the p53 gene.

With these significant advances, we saw overall responses that were very, very high, up in the 90% range, but the complete response rate was not so high. There were complete responses, particularly as single agent ibrutinib was used over several years and in untreated patients we saw this in as high as in 30% of patients. Nevertheless, it was very impressive as an oral agent.

Importantly, ibrutinib didn't depress the immune system like chemoimmunotherapy did. The toxicities with ibrutinib were much more tolerable. The momentum over several years ultimately led to the design of the treatment regimen seen in E1912.

Tait Shanafelt, MD, the principal investigator of the E1912 trial, in consultation with the ECOG Leukemia Steering Committee, came up with a trail design which would evaluate single-agent ibrutinib in combination with rituximab for patients with upfront progressive CLL, meeting International Workshop, 2008 criteria for need for therapy

Reasoning that that combination would potentially give us a better chance at having more better responses or perhaps even more durable responses. This was compared to fludarabine-cyclophosphamide-rituximab, or standard chemoimmunotherapy (FCR), which had been the gold standard treatment approach for previously untreated, progressive CLL up to that point.

Can you describe the E1912 trial and the findings that led to the recent expanded approval of ibrutinib?

The E1912 study compared ibrutinib and rituximab with FCR for patients with previously untreated, progressive CLL. Patients received ibrutinib-rituximab for approximately 6 cycles. Rituximab was then dropped and ibrutinib continued indefinitely for as long as the patient was responding.

FCR was given for the usual 6 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 small lymphocytic lymphoma (SLL).

This approval was based on the positive results from the phase 3 trial design E1912 study and was conducted by ECOG-ACRIN and supported by the National Cancer Institute, of course, it's 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, 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.

Were any of the outcomes of the E1912 study particularly surprising?

That is a good question. I'm not a betting person, but we knew that ibrutinib-rituximab was potentially going to be less toxic than chemoimmunotherapy because of its known impact on bone marrow function and immunosuppression, as well as immune-deficiencies and more prolonged lower blood counts and infections.

I think that the toxicity profile with ibrutinib-rituximab as we expected, was different and potentially more tolerable. The progression-free survivorship differences were very obvious as well, which we expected based on the 2 interim analyses that continue to look quite solid as an advantage for ibrutinib-rituximab.

The most dramatic finding was that in the initial interim analysis, the overall survivorship was distinctly significantly better for the ibrutinib-based therapy. I think there was skepticism at a lot of people felt that the first interim analysis was too soon, and that there were too few events.

At the 49th-month interim analysis, that difference continues to hold up. If the root question was what was surprising, perhaps it was the overall survivorship data.

What is the significance of this approval? How will this new treatment option impact treatment of patients with CLL and SLL in clinical practice?

It's complicated but let me be succinct. We have used the term "game-changing." It's 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. Although there is continuing conversation about another chemoimmunotherapy, bendamustine-rituximab, which has been used more in the elderly CLL patient because it's 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 be support the use of ibrutinib-rituximab instead of FCR.

That's the most dramatic clinical discussion. I think FCR or chemoimmunotherapy is not completely eliminated from the conversation, but it's probably going to be much less used because of this clinical trial and the efficacy outcomes.

Is there anything else of note you would like to add?

A couple of things I would like to add. One is that there will likely be an update in the next 12 months in regard to both the progression-free and overall survivorship for this trial. The second is that there is a derivative of this trial that's ongoing, EA9161, which is ECOG-led, North American Intergroup trial. This trial is comparing ibrutinib plus obinutuzumab to ibrutinib plus obinutuzumab and venetoclax for previously untreated CLL.