Pirtobrutinib Elicits Encouraging Efficacy in CLL, SLL, MCL, & Other Non-Hodgkin Lymphomas

Article

Pirtobrutinib produced promising efficacy in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma, those with mantle cell lymphoma and other non-Hodgkin lymphomas, and those who progressed on Richter transformation–directed therapy.

Pirtobrutinib (LOXO-305) produced promising efficacy in patients with previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), those with mantle cell lymphoma (MCL) and other non-Hodgkin lymphomas, and those who progressed on Richter transformation–directed therapy, according to data from 3 different analyses of the phase 1/2 BRUIN study (NCT03740529) presented during the 2021 EHA Virtual Congress.1-3

The next-generation, highly selective, non-covalent BTK inhibitor elicited an overall response rate (ORR) of 63% (95% CI, 55%-71%) in 139 patients with CLL/SLL, with 50% of patients experiencing a partial response (PR), 14% had a PR with lymphocytosis (PR-L), and 32% achieved stable disease (SD).1

Moreover, among 121 BTK pretreated evaluable patients, pirtobrutinib induced an ORR of 62% (95% CI, 53%-71%); 47% of these patients achieved a PR as their best response to treatment, 15% experienced PR-L, and 34% had SD.

In patients with MCL (n = 56), pirtobrutinib produced an ORR of 52% (95% CI, 38%-65%), with 25% of patients achieving a CR to treatment, 27% experiencing a PR, and 18% having SD. In BTK pretreated patients with MCL (n = 52), the ORR was also 52% (95% CI, 38%-66%); in this subgroup, the CR, PR, and SD rates were 25%, 27%, and 17%, respectively.2

Efficacy with the agent was also observed in patients who previously underwent stem cell transplantation, with an ORR of 64% (n = 9/14), and those who received prior CAR T-cell therapies, with an ORR of 100% (n = 2/2).

In patients with Waldenström macroglobulinemia (n = 19), the ORR produced by pirtobrutinib was higher, at 68% (95% CI, 44%-87%), with 47% of patients experiencing a PR, 21% having a molecular response (MR), and 16% achieving SD. Of the 13 patients who were BTK pretreated, the ORR was 69% (95% CI, 39%-91%) with pirtobrutinib; the rates of PR, MR, and SD were 39%, 31%, and 8%, respectively, in this subset.

The ORRs with pirtobrutinib in patients with follicular lymphoma (n = 8), marginal zone lymphoma (MZL; n = 9), and diffuse large B-cell lymphoma (DLBCL; n = 25) were 50% (95% CI, 16%-84%), 22% (95% CI, 3%-60%), and 24% (95% CI, 9%-45%), respectively.

Among the 15 patients with Richter’s transformation, the BTK inhibitor induced an ORR of 67% (95% CI, 38%-88%), with a CR rate of 13%, a PR rate of 53% and a SD rate of 20%; 7% of patients experienced disease progression and 7% were not evaluable.3

In the phase 1/2 BRUIN trial, investigators set out to examine the safety and efficacy of pirtobrutinib in previously treated patients with advanced B-cell malignancies. The study was comprised of 2 parts; the first phase was the escalation and expansion phase, where the BTK inhibitor was examined at daily doses ranging from 25 mg to 300 mg (n = 203) and the second phase examined pirtobrutinib at a daily dose of 200 mg (n = 120).

Collectively, the trial enrolled a total of 323 patients. The safety population was comprised of 170 patients with CLL/SLL, 61 patients with MCL, 26 with Waldenström macroglobulinemia, and 66 with disease classified as other. The efficacy population consisted of 139 patients with CLL/SLL, 56 patients with MCL, 19 with Waldenström macroglobulinemia, and 55 with other disease.

To be eligible for enrollment, patients needed to be at least 18 years of age, have previously treated CLL or other B-cell non-Hodgkin lymphoma, have active disease that required treatment, and an ECOG performance status of 0 to 2.

Key end points of the trial included safety and tolerability, to determine the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D), pharmacokinetics, and efficacy with regard. To ORR and duration of response (DOR) per disease criteria.

The data cutoff for the analysis performed in patients with CLL/SLL (n = 170) was September 27, 2020. The median age in this subset was 69 years (range, 36-88), 64% were male, 51% had an ECOG performance status of 0, and patients had a median of 3 prior lines of systemic therapy (range, 1-11). In BTK pretreated patients, the median number of prior lines of therapy was 4 (range, 1-11).

Eighty-six percent of patients previously received a BTK inhibitor, 82% received prior chemotherapy, 90% had a CD20-targeted antibody, 34% had a BCL-2 inhibitor, 21% had a PI3K inhibitor, 8% had lenalidomide (Revlimid), 2% had undergone allogeneic stem cell transplant, and 6% had received CAR T-cell therapy. Most patients who discontinued prior BTK treatment (67%) did so because of disease progression.

Additional findings in this subset of patients showed that the ORR achieved with pirtobrutinib increased over time. The agent was also found to be effective, irrespective of BTK experience and other previous therapy received.

The data cutoff for the analysis performed in patients with MCL (n = 61), Waldenström macroglobulinemia (n = 26), and other disease (n = 66) was also September 27, 2020. Across these subgroups, the median age was 68.3 years. Moreover, 50% had an ECOG performance status of 0, 44% had a status of 1, and 3% had a status of 2. The median number of prior lines of systemic therapy was 3 lines (range, 1-11). Additionally, 66.3% of patients received prior BTK inhibition and 74.3% discontinued because of disease progression.

Additional data demonstrated that at a median follow-up of 6 months, 83% (n = 24/29) of responders who had MCL continued to experience a response to treatment with pirtobrutinib. Only 5 responders with MCL discontinued treatment; 4 did so because of disease progression and 1 who experienced a CR discontinued to undergo allogeneic stem cell transplantation.

Seventy-seven percent (n = 10/13) of patients with Waldenström macroglobulinemia are still in response to the BTK inhibitor.

Among those with Richter transformation (n = 17), 15 were determined to be efficacy evaluable. For this subgroup, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, have active Richter transformation, arising in the setting of previous CLL, and have received prior treatment. Notably, patients were allowed to have received previous covalent BTK inhibitors and there was no limit on the number of prior lines of treatment.

Of these patients, 16 were given pirtobrutinib at a daily dose of 200 mg as their initial dose, and 1 patient received the BTK inhibitor at a daily dose of 150 mg. In this group of patients, the data cutoff was March 29, 2021.

Among the 17 patients in this subset, the median age was 64 years (range, 33-84), 82% were male, 47% had an ECOG performance status of 0, 59% had BTK wild-type disease, 59% had bulky disease that was less than 5 cm, all had DLBCL Richter transformation histology, and the median number of prior lines of system therapy was 6 (range, 2-10). Moreover, 82% received a prior BTK inhibitor and 59% received a prior BCL-2 inhibitor.

All patients received prior chemotherapy and a CD20-targeted antibody, 35% received a prior BTK inhibitor, 29% had PD-1/PD-L1 immunotherapies, 24% had a mTOR inhibitor, 19% had a PI3K inhibitor, 18% had lenalidomide, 18% had a BCL-2 inhibitor, and 6% had CAR T-cell therapy. The median time to treatment was 3.4 months (range, 1.6-13.1+), and the time to best response was 1.9 months (range, 1.6-2.1).

Additional findings showed that the median DOR had not yet been reached in this subset at a median follow-up of 1.87 months. The median PFS had also not been reached at a median follow-up of 3.71 months. The 6-month PFS rate was estimated to be 52% with pirtobrutinib. Notably, the BTK inhibitor demonstrated activity in patients who previously received BTK inhibitors and chemoimmunotherapy for CLL.

No dose-limiting toxicities were reported and the MTD had not been reached. Five of 323 patients discontinued treatment because of treatment-related adverse effects. Here, a daily dose of 200 mg was selected to be the RP2D.

Notable covalent BTK inhibitor–associated toxicities were rarely observed, but longer follow-up is needed to understand the safety profile linked with chronic administration of the agent.

The safety profile of the BTK inhibitor among the 17 patients with Richter transformation proved to be consistent to what had been observed in the overall population. The most common treatment-emergent toxicities in this subset included decreased neutrophil count and diarrhea. None of the patients discontinued treatment because of an AE. The dose of pirtobrutinib was reduced from once-daily 200 mg to 100 mg in 1 patient because of grade 2 lipase increase.

References

  1. Roeker L, Pagel JM, Coombs CC, et al. Pirtobrutinib (LOXO-305): a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Presented at: 2021 EHA Virtual Congress; June 9-17, 2021; Virtual. Poster EP633.
  2. Shah NN, Alencar AJ, Gerson JN, et al. Pirtobrutinib (LOXO-305), a next generation highly selective non-covalent Bruton’s tyrosine kinase inhibitor in previously treated mantle cell lymphoma and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study. Presented at: 2021 EHA Virtual Congress; June 9-17, 2021; Virtual. Poster EP500.
  3. Mato AR, Shah NN, Lamanna N, et al. Pirtobrutinib (LOXO-305), a next generation, highly selective, non-covalent BTK inhibitor in previously treated Richter transformation: results from the phase 1/2 BRUIN study. Presented at: 2021 EHA Virtual Congress; June 9-17, 2021; Virtual. Poster EP524.
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