Evaluating the Addition of Ibrutinib to Standard Chemotherapy for Follicular Lymphoma or MZL

Results from the SELENE Study

Gilles Salles, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York, highlights the findings from the phase 3 SELENE trial, which aimed to assess the potential value of adding Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib to bendamustine and rituximab (BR) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy among patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). 

Although the addition of ibrutinib to standard chemotherapy did not yield improved survival, Dr Salles speaks on how these findings imply that, at the very least, there are options for patients who failed first-line therapy with this indolent disease. He notes that more research is needed. 

Transcript:

My name is Dr Gilles Salles. I am from Memorial Sloan Kettering Cancer Center in New York. I'm happy to discuss with you the results of the SELENE study, which is a study aiming to assess the value of ibrutinib combined with chemotherapy in previously treated patients with follicular and marginal zone lymphoma. This paper and this work result from the collaboration of many investigators, including the first author, Dr Nastoupil [Loretta J Nastoupil, MD, UT MD Anderson Cancer Center, Houston, Texas] from MD Anderson. I'm happy to discuss it in [the] name of all my colleagues. 

The bottom line of the study is, as you may remember, years ago, when ibrutinib was developed, which [is] a first-in-line and first-in-class [Bruton’s tyrosine kinase] (BTK) inhibitor, we saw that this drug was efficient and has single-agent activity in some patients with both follicular lymphoma, but also marginal zone lymphoma, where actually this drug was approved as a single agent in the relapsed/refractory setting. 

But, because in many countries and in many instances, the second line of therapy for patients with this indolent lymphoma [is] chemotherapy, either [cyclophosphamide, doxorubicin, vincristine, and prednisone] (CHOP) or bendamustine, the [aim] of this study [was] to establish whether adding ibrutinib to bendamustine-rituximab or CHOP-rituximab in patients who have experienced the first line of therapy with follicular lymphomas or marginal zone lymphoma will improve the outcome of these patients. So, that was the objective of the study. 

The way it was designed is a randomized blind study where patients who were to receive either CHOP or [bendamustine-rituximab] (BR) were randomized to receive either in combination [with] that, ibrutinib at the standard dose during the whole time of chemotherapy and as maintenance until progression, or a placebo [in the] control arm. In order to show a benefit, we aim[ed] to randomize 400 patients. 

The results that are presented here are the results obtained after more than almost 7 years of follow-up, [or] 84 months, and the primary endpoint of the study was unmet. But, the median [progression-free survival] (PFS) in those patients [who] received ibrutinib plus chemoimmunotherapy was 44.5 months versus 23 months for the placebo arm. In other words, almost 3 and a half years or a little bit more than 3 years versus 2 years. However, this was not a significant difference. More importantly, the median overall survival was not reach[ed] [in] either arm. 

The adverse events that were encountered were those that we know are associated with ibrutinib, including some rashes, some bruising or bleeding, and some cardiac events. They were more frequent in the ibrutinib arm as compared to the placebo arm. The number of deaths or treatment-emergent adverse events leading to death was identical in both arms. When we look a little bit more [at] the characteristics of these patients, most of the patients actually received, as a second line of therapy, bendamustine-rituximab. This was a lot of European patients who have been treated with [rituximab-CHOP] (R-CHOP) as [the] first line of therapy. And 90% of them, as I said, were receiving BR as a backbone. 

We also explore whether there was a different effect in patients treated with follicular lymphomas, the majority of patients, versus those treated for marginal zone lymphoma, given the activity of ibrutinib in those. Interestingly, the median duration of response was not reached in the ibrutinib-chemotherapy arm, but was 89 months in the placebo-chemotherapy arm. There was also maybe a little [of a] trend numerically for higher overall survival rate for those [patients]. 

Overall, we missed the primary endpoints. There is no statistical benefit of ibrutinib plus chemotherapy in these patients. There is a significant burden of side effects associated with the use of this drug, which basically, was not approved by health authorit[ies] in this situation. 

There was another [piece of] information brought by this trial, which is a very good outcome [for] these patients in [the] second line of therapy. If we take all patients at 7 years, the overall survival was 67% in the ibrutinib-chemo [arm] and 68% in the placebo-chemo arm. So, two-thirds of the patients were alive 7 years after having progressed. Obviously, the number of patients with [progression of disease within 2 years] (POD24) was limited in this population. Although, some of them were still POD24—actually, half of them. But, this indicates that we have options to offer for patients who failed first-line therapy with this indolent disease. 

So again, [this was] an important study that was expected and we were hoping to get positive results, but [results show] that ibrutinib does not add to chemoimmunotherapy.

Source: 

Nastoupil LJ, Hess G, Pavlovsky MA, et al. Phase 3 SELENE study: ibrutinib plus BR/R-CHOP in previously treated patients with follicular or marginal zone lymphoma. Blood Advances. Published online: September 18, 2023. doi: 10.1182/bloodadvances.2023010298