Ibrutinib Plus Obinutuzumab Elicits Intriguing Survival Benefits in Relapsed/Refractory CLL

The combination of ibrutinib (Imbruvica) and obinutuzumab (Gazyva) could represent a promising treatment option for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including those with high-risk features and disease progression on venetoclax (Venclexta), according to Christine Ryan, MD.

Notably, treatment with the combination resulted in high 4-year progression-free survival (PFS) and overall survival (OS) rates, according to data from a phase 1b trial (NCT02537613) presented at the 2022 EHA Annual Congress.

“[The study] provided support for the combination regimen of ibrutinib plus obinutuzumab in relapsed/refractory disease,” Ryan said. “This regimen is safe and tolerable with no new safety concerns, and it achieved a very high rate of clinical efficacy with durable responses.”

In an interview with OncLive^®, Ryan, a Hematology/Oncology fellow at Dana-Farber Cancer Institute, discussed the evaluation of safety and efficacy of ibrutinib plus obinutuzumab in patients with relapsed/refractory CLL in the trial and how the results could result in another treatment option for patients with relapsed/refractory CLL.

OncLive^®: Could you share the importance of investigating ibrutinib plus obinutuzumab in patients with relapsed/refractory CLL?

Ryan: By way of background, we know that the combination regimen of ibrutinib plus obinutuzumab is an FDA-approved frontline therapy for CLL. But minimal data exists about this regimen in the relapsed/refractory setting. We know that ibrutinib monotherapy rarely leads to a complete response in relapsed/refractory CLL.

The rationale for this study and the hypothesis that we were investigating were whether the combination of ibrutinib plus obinutuzumab would lead to improved efficacy in the relapsed/refractory setting and whether it would improve the efficacy of ibrutinib monotherapy. We also sought to investigate 3 sequencing regimens of ibrutinib plus obinutuzumab and the overall efficacy of that combination regimen.

How was this study designed?

The primary end point of this study was safety of the 3 sequencing regimens. Key secondary end points were overall clinical efficacy and clinical outcomes. We also looked at rates of undetectable minimal residual disease in the peripheral blood and the bone marrow.

In terms of overall study design, patients were initially randomized to 1 of 3 ibrutinib plus obinutuzumab sequencing arms. Then ibrutinib and obinutuzumab were dosed at the standard-of-care doses, and ibrutinib was continued until disease progression or unacceptable toxicity.

Could you expand on the patient population that was enrolled?

There were 52 patients enrolled, and the median age at enrollment was 67 years. Just over half of patients had IGHV-unmutated disease, and just over one-third of patients had TP53-aberrant disease.

This relapsed/refractory patient population was slightly enriched for these high-risk disease features. Moreover, another notable aspect of the patients included were that 3 patients had progressed on venetoclax.

How effective was the combination treatment in patients who had previously progressed on venetoclax?

[Although it was a small number of patients], all 3 patients did respond, and they all achieved a partial response by International Workshop on Chronic Lymphocytic Leukemia [iwCLL] criteria.

What were the efficacy results of this phase 1b study?

This regimen produced a high overall response rate of 96%. [Specifically], 40% of patients achieved a complete response by iwCLL criteria. We had very high rates of 4-year PFS and OS. The 4-year PFS rate was 74%, and the 4-year OS rate was 93%.

Another important aspect to highlight is that there were no significant differences in PFS or OS when the results were stratified by those high-risk disease features. When we looked at patients by IGHV mutational status, or by presence or absence of TP53-aberrant disease, there were no significant differences in the clinical outcomes.

Were there any notable safety data with the combination treatment?

With regard to safety, the toxicity profile of this regimen was relatively consistent with what has been reported previously. We saw hematological adverse effects [AEs] such as anemia, thrombocytopenia, and neutropenia, plus some cardiovascular toxicity [such as] hypertension and atrial fibrillation. All AEs were within range of what has been established and reported previously with ibrutinib and the combination regimen, which has been reported in the frontline setting.

Were there any surprising data that stood out to you?

It is important to highlight that there were no significant differences in the PFS and OS, even in the high-risk disease population. This was really an encouraging aspect of this study, along with the, overall, very durable responses. A 4-year PFS rate of 74% was very encouraging.

What next steps will be taken with this research?

Our study provides an important foundation for further exploration of this regimen in relapsed/refractory CLL, especially given that all 3 patients who had [previously] progressed on venetoclax did respond. This is a particular area that would be good for future focus and research.

Reference

1. Ryan CE, Brander DM, Barr PM, et al. Updated results of a phase 1b study of ibrutinib plus obinutuzumab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P674.