Pirtobrutinib Provides Promising Results in Richter Transformation

Pirtobrutinib (formerly LOXO-305)—a highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor—induced a 67% response rate in patients with Richter transformation, according to findings from the phase 1/2 dose-escalation and- expansion BRUIN study (NCT03740529). Study co-author Meghan Thompson, MD, said that response rate compares favorably with historical results in this patient population.

Richter transformation is a serious and life-threatening complication that arises in patients with aggressive lymphoma. Overall survival (OS) ranges from 3 to 11 months for patients with the condition, according to Thompson.

“Richter transformation is a relatively rare, but very serious complication that can arise in patients with chronic lymphocytic leukemia [CLL],” she added. “In a small subgroup of patients with CLL, the disease can transform into a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma [DLBCL], although other histologies such as Hodgkin lymphoma are possible.”

In an interview with OncLive, Thompson, a third-year fellow in hematology and medical oncology at Memorial Sloan Kettering Cancer Center, discusses the results of the phase 1/2 BRUIN study, as well as upcoming research efforts in the population of patients with Richter transformation.

OncLive: What was the rationale for this study, particularly for evaluating the Richter transformation population?

Thompson: This subgroup of patients is very high risk. Currently, the therapies that are available lead to very poor outcomes for these patients, with estimates of OS, once a patient has a diagnosis of Richter transformation, around 3 to 11 months. There isn't an agreement on what the standard-of-care therapy for these patients should be. [We’re] discussing a novel way to approach Richter transformation, and that's with pirtobrutinib, formerly known as LOXO-305, because Richter patients were included in the larger BRUIN study of pirtobrutinib monotherapy in patients with non-Hodgkin lymphoma [NHL].

What was the design of the study?

The BRUIN study is a multicenter phase 1/2 dose-escalation and -expansion study examining pirtobrutinib in patients with advanced B-cell malignancies. [The majority of patients had] previously treated NHL, or patients with CLL, though there were other non-Hodgkin histologies. This included mantle cell lymphoma, Waldenstrom’s macroglobulinemia, and the [patients with] Richter transformation, among others.

The primary objective of this study was to look at the safety of pirtobrutinib and establish the recommended phase 2 dose, which has now been established at 200 mg daily. The dose-expansion study gave a preliminary look at efficacy, as well. As a part of this, we reported on 17 patients with Richter transformation, and those patients had no limit on the prior lines of therapy that were allowed. They had to have Richter arising in the setting of a prior diagnosis of CLL.

How did the agent perform in terms of safety in this subgroup of patients? Were there any unexpected toxicities observed?

We present in whole the safety data from the BRUIN study, which is overall quite remarkable. The agent is an oral therapy [and] it’s very well tolerated. For the 17 patients with Richter transformation, we see a similar safety profile compared with the overall cohort. The most common treatment-emergent adverse events in the Richter subgroup were decreased neutrophil count and diarrhea. Notably, none of the 17 patients with Richter discontinued treatment due to a drug toxicity. There was 1 patient who had a dose reduction, but overall, pirtobrutinib is very well tolerated.

What did you observe in terms of efficacy?

There is a very promising response rate in these patients. Any patient with Richter transformation is extraordinarily high risk and outcomes are poor right now. These 17 patients had a median of 4 lines of CLL therapy prior to Richter transformation and 2 prior lines of Richter transformation–directed therapy, so this is the sickest of the sick that we have reported on.

Overall, 15 of the 17 patients were included in evaluation, and of those 15 patients, 10 had a partial or complete response, including 2 complete responses, for an overall response rate of 67%. Using historical comparisons, that is a pretty good response rate in Richter transformation. The time to best response was just around 2 months at median, and while we would like to see longer follow-up and a greater number of patients treated for Richter transformation, this is really a promising strategy.

Are there any next steps with this research underway, particularly in this subgroup of patients?

Yes. There are some patients who, at the time of the data cutoff, are remaining on therapy. It will be important to see in terms of duration of response, with longer follow-up, whether these responses are maintained. Longer follow-up will inform how pirtobrutinib may fit into care in the future [for] Richter transformation, but certainly, these are very promising results here.

Is there anything else you would like to highlight?

A lot of these patients have received prior covalent BTK inhibitors like ibrutinib (Imbruvica) or acalabrutinib (Calquence). We saw that when these data from the BRUIN study were published. We see that the prior covalent BTK exposure is reflected in the Richter transformation subgroup, and there were responses in patients who had prior covalent BTK inhibitors for CLL or Richter transformation. That’s an important point in this study and the BRUIN study as a whole. This drug has activity following ibrutinib and acalabrutinib.