Earlier-Line Pirtobrutinib Investigation May Alter BTK Inhibitor Sequencing in CLL and MCL


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Prioty Islam, MD, MSc, discusses findings from the BRUIN trial, highlights the potential benefits of using noncovalent BTK inhibitors instead of or before covalent BTK inhibitors in patients with MCL or CLL, and previewed ongoing clinical trials investigating this class of agents in earlier treatment lines in these populations.

Prioty Islam, MD, MSc

Prioty Islam, MD, MSc

Pirtobrutinib (Jaypirca), as well as other noncovalent BTK inhibitors in development, may play a role in earlier treatment settings for patients with mantle cell lymphoma (MCL) and/or chronic lymphocytic leukemia (CLL), although further research is needed to confirm the efficacy of this agent in the frontline setting or after progression on a prior covalent BTK inhibitor, according to Prioty Islam, MD, MSc.

On January 27, 2023, the FDA approved pirtobrutinib for adult patients with relapsed/refractory MCL who have received at least 2 prior lines of systemic therapy, including a BTK inhibitor. This regulatory decision was supported by findings from a subset of patients with MCL enrolled in the single-arm, phase 1/2 BRUIN trial (NCT03740529), who achieved an overall response rate (ORR) of 50% (95% CI, 41%-59%).1 Currently, the randomized phase 3 BRUIN-MCL-321 trial (NCT04662255) is investigating pirtobrutinib vs investigator’s choice of BTK inhibitor in patients with pretreated, BTK inhibitor–naïve MCL.2

Additionally, in the relapsed/refractory CLL/small lymphocytic lymphoma cohort of BRUIN, pirtobrutinib elicited an ORR of 73.3% (95% CI, 67.3%-78.7%) and an ORR of 82.2% (95% CI, 76.8%-86.7%) when patients with partial response with lymphocytosis were included.3

“It’s possible that a patient progressing on a noncovalent BTK inhibitor may then respond to a covalent BTK inhibitor because there are no overlapping resistance mechanisms between the 2 [classes of agents],” Islam said.

In an interview with OncLive®, Islam discussed findings from the BRUIN trial, highlighted the potential benefits of using noncovalent BTK inhibitors instead of or before covalent BTK inhibitors in patients with MCL or CLL, and previewed ongoing clinical trials investigating this class of agents in earlier treatment lines in these populations.

Islam is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What data have been reported with the noncovalent BTK inhibitor pirtobrutinib in patients with CLL, and what is the potential role for this class of agents in the CLL treatment paradigm?

Islam: Of the noncovalent BTK inhibitors, pirtobrutinib is 1 of the furthest along in development. A couple other [noncovalent BTK inhibitors] are in earlier-phase trials as well. The main role [of noncovalent BTK inhibitors in CLL] will be overcoming the resistance mechanisms we’ve seen with covalent BTK inhibitors.

In the BRUIN trial, we demonstrated that patients had responses to pirtobrutinib, even those who had previously progressed on a covalent BTK inhibitor because of a resistance mutation [on sites such as] the binding site of the BTK protein. [Pirtobrutinib] restored BTK dependency and induced another response in those patients, which is exciting.

Regarding bringing pirtobrutinib to the frontline setting as a first choice of BTK inhibitor in CLL, more [research will need] to be done to help us make that decision. Right now, that may not be where it will have the biggest effect. Its biggest effect [may be its ability to] overcome resistance to covalent BTK inhibitors, but we’ll see. We may conduct a trial in the frontline setting and see durable, long-term remissions [showing] patients do better with the noncovalent BTK inhibitor up front. Those data remain to be seen.

Since the FDA approval of pirtobrutinib in patients with MCL after 2 prior lines of therapy, including a BTK inhibitor, how has this agent fit into the MCL treatment landscape?

BTK inhibitors have transformed how we approach relapsed/refractory MCL. Traditionally, these patients had poor prognoses and didn’t respond well to traditional chemoimmunotherapy combinations. Now, however, we’re inducing robust overall responses and some reasonable durations of response [DORs] with single-agent, oral targeted therapies, which greatly improve quality of life and efficacy. In general, the introduction of BTK inhibitors to MCL has transformed this entire treatment paradigm and was a true paradigm shift in how we approached this disease, starting with first-generation ibrutinib [Imbruvica] approximately 10 years ago when it was first under investigation.

Regarding where pirtobrutinib falls into this paradigm, as in the CLL cohort of BRUIN, [where] we demonstrated that patients who were previously progressing on a BTK inhibitor can respond to pirtobrutinib, [in MCL], we’re seeing that same pattern. [Pirtobrutinib can] restore BTK inhibitor dependency and induce another response in patients [with MCL]. [However, like in CLL], we’re not sure how to bring pirtobrutinib to the frontline [setting].

In MCL, a clinical trial is currently underway, BRUIN-MCL-321, which uses pirtobrutinib as the first BTK inhibitor of choice. Currently, the FDA indication [for pirtobrutinib] is after progression on or intolerance to a prior covalent BTK inhibitor. That ongoing clinical trial, once results are out, will be extremely illuminating and informative.

I have some reservations about bringing pirtobrutinib to the forefront when we don’t know what the responses or DOR will be if patients progress on it. That remains to be seen, but [there is] still important work being done, and I’m excited to see the results from that trial.

How would moving pirtobrutinib up to the frontline setting in MCL or CLL affect treatment sequencing with the available covalent BTK inhibitors?

Pirtobrutinib resistance mechanisms are still an emerging area. Memorial Sloan Kettering Cancer Center has led some of this research, doing deep sequencing to investigate patients who have progressed on pirtobrutinib and evaluating their resistance mechanisms. While there is some overlap between covalent BTK inhibitor and noncovalent BTK inhibitor resistance mechanisms, there are also some unique mutation profiles.

[Using a covalent BTK inhibitor after a noncovalent BTK inhibitor] hasn’t been done in clinical practice, so we won’t know until we try. Bringing pirtobrutinib up as our first noncovalent BTK inhibitor of choice may not necessarily take away the possibility of using a covalent BTK inhibitor as a next line of therapy. We’d need to see the data.

Disclosures: Dr Islam reports consulting roles with AbbVie, AstraZeneca, BeiGene, DAVA Oncology, and LOXO Oncology; as well as speaking roles with Targeted Oncology and The Video Journal of Hematologic Oncology (VJHemOnc).


  1. US FDA approves Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor, for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. News release. Loxo@Lilly. January 27, 2023. Accessed July 31, 2023. https://investor.lilly.com
  2. Wang M, Eyre TA, Shah NN, et al. BRUIN MCL-321: a phase 3, open-label, randomized study of pirtobrutinib versus investigator choice of BTK inhibitor in patients with previously treated, BTK inhibitor naïve mantle cell lymphoma. J Clin Oncol. 2023;41(suppl 16):TPS7587. doi:10.1200/JCO.2023.41.16_suppl.TPS7587
  3. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
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