Pirtobrutinib Expands MCL Armamentarium, Although Sequencing Questions Remain

The addition of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) to the mantle cell lymphoma (MCL) treatment paradigm provides an effective treatment option for patients with MCL and resistance to prior covalent BTK inhibitors, according to William B. Pearse, MD.

In an interview with OncLive®, Pearse, an assistant professor of medicine at the UC San Diego School of Medicine, discussed how the 2023 FDA approval of pirtobrutinib for patients with MCL that is relapsed or refractory to at least 2 prior therapies has led to advances in the use of BTK inhibitors in this patient population. He also noted unanswered questions about BTK inhibitor sequencing and spotlighted research that may support the use of BTK inhibitors in earlier lines of therapy. Pearse provided further insights from this interview in another article.

OncLive: Since the FDA approval of pirtobrutinib, how has this agent changed the later-line MCL treatment setting?

Pearse: [Pirtobrutinib] provides a meaningful alternative treatment option, perhaps a third-line option, for patients who have progressed on a prior BTK inhibitor. BTK inhibitors in general have changed the treatment paradigm for MCL over the past 5 or 7 years. However, invariably, almost all patients will progress on a BTK inhibitor.

Now that we have tools available to us to assess specific mechanisms of BTK inhibitor resistance, [pirtobrutinib] is an important clinical option to restore BTK inhibitor sensitivity [in patients] who have progressed on a prior BTK inhibitor. Using a noncovalent BTK inhibitor, such as pirtobrutinib, is important. [In] the [phase 1/2] BRUIN trial [NCT03740529], we [saw] encouraging long-term follow-up data that prove the efficacy [of pirtobrutinib and show] a favorable safety profile, as well. This is meaningful for patients.

What questions remain regarding the optimal sequencing of pirtobrutinib and other BTK inhibitors? Do you foresee a potential shift of pirtobrutinib to earlier lines for patients with MCL?

The MCL 135 study [NCT04662255] is in progress. This is a phase 3, open-label, randomized study investigating pirtobrutinib vs investigator’s choice of BTK inhibitor for patients with previously treated, BTK inhibitor–naive MCL. Clinical trials are currently investigating moving pirtobrutinib further up in the sequencing to determine whether [the agent] may have an improved safety or efficacy profile relative to an investigator’s choice of acalabrutinib [Calquence] or zanubrutinib [Brukinsa] in the second-line relapsed/refractory setting. This [investigation] may also give us interesting phase 3 data when comparing acalabrutinib vs zanubrutinib in the second-line setting.

We don’t have a lot of that prospective data comparing 2 different BTK inhibitors in the second-line relapsed/refractory setting. This next iteration of the BRUIN trial has the potential to answer a couple questions about pirtobrutinib’s role in treating [patients with MCL as a whole and] in head-to-head assessments evaluating other BTK inhibitors in patients who’ve never been exposed to those drugs before.

What is your main message for colleagues regarding the current state of BTK inhibitors in patients with MCL?

The incorporation of BTK inhibition in the up-front setting is an important step forward in treating patients. The [phase 3] TRIANGLE study [NCT02858258] gives us useful and meaningful information. Although those data have not fully matured, [the data that have] been published thus far are encouraging [and support moving] BTK inhibition into the up-front setting, particularly when used in combination with traditional, more aggressive induction regimens for patients who can tolerate it, like rituximab [Rituxan] and cytarabine backbone.

We need to think critically about incorporating these drugs in the frontline setting. MCL is a rarer disease, and it has a wide heterogeneous clinical presentation, which in part is driven by genetics and in part driven by molecular mechanisms that [lead to] lymphomagenesis in this disease. I encourage you to consider early [patient] referral to an academic medical center when [determining] optimal [disease] management strategies for this complex group of patients. We are fortunate to have access to certain clinical trials in multiple different stages of the disease, [including] presentation and prior drug exposures. It is important to try and identify academic partnerships with community practice colleagues to consider partnering in the treatment of these patients and to ensure they have access to clinical trials, particularly those with TP53-mutated disease.