Article

Examining Safety, Efficacy of Pirtobrutinib in CLL/SLL, MCL, and WM; Results Seen for Patients With Intolerance to Covalent BTK Inhibitors

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In abstracts presented at the 64th American Society of Hematology Annual Meeting and Exposition, the investigational BTK inhibitor pirtobrutinib showed promising efficacy and safety in several types of B-cell lymphoma.

Pirtobrutinib, an investigational, highly selective Bruton tyrosine kinase (BTK) inhibitor, demonstrated promising efficacy and safety across multiple types of B-cell lymphoma in abstracts presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition.1-4

The reversible, noncovalent BTK inhibitor is being studied in patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), and other conditions including Richter syndrome.5 Starting with ibrutinib in 2014, covalent BTK inhibitors have transformed treatment of CLL and other B-cell hematologic malignancies, but resistance and intolerance cause problems for many patients. Although off-target effects have been reduced with second-generation BTK inhibitors, some patients still experience adverse events (AEs) that lead to discontinuation. For these patients, pirtobrutinib may offer a treatment option.

“One striking property of this drug is there is really low toxicity,” said M. Lia Palomba, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, who presented data on WM in an oral session. When asked what the ultimate role of pirtobrutinib would be relative to existing BTK inhibitors, she said this was not yet clear but noted that a study for use in first-line CLL is already approved.

The phase 1/2 BRUIN study (NCT03740529), a wide-ranging study that has tested pirtobrutinib in 773 patients,5 featured coauthors from Strategic Alliance Partners of The American Journal of Managed Care®. Manish R. Patel, MD, director of drug development at Florida Cancer Specialists and Research Institute; and Ian W. Flinn, MD, PhD, a medical oncologist with the Center for Blood Cancers, Tennessee Oncology, and director of lymphoma research, Sarah Cannon Research Institute, both in Nashville, were coauthors on abstracts detailing extended follow-up in CLL/SLL and results for patients previously intolerant of BTK inhibitors1-2; in addition, Patel was the second author on an abstract detailing results on a cohort with WM,3 and Flinn was a coauthor on an abstract focusing on MCL.4

Extended Follow-up in CLL/SLL

BRUIN was a phase 1 dose escalation study followed by a phase 2 expansion cohort study, which tested a recommended phase 2 oral dose of 200 mg/d. At the data cutoff of January 31, 2022, the expansion cohort consisted of 276 patients with CLL/SLL who had enrolled in phase 1 or 2 who had prior covalent BTK inhibitor treatment and had been assessed following treatment or discontinuation.1 Key end points were overall response rate (ORR), progression-free survival (PFS), and safety. Patients had received several other therapies, including anti-CD20 therapy (89%) and chimeric antigen receptor T-cell therapy (6%). Many patients had high-risk features, including 85% with unmutated immunoglobulin heavy chain variable region gene (IGHV); 75% of the group discontinued prior BTK inhibitor therapy due to disease progression.

RESULTS. In this group with relapsed/refractory CLL/SLL, the ORR by investigator assessment was 74% (95% CI, 69-79), with 3 complete responses (CR, 1%), 174 partial responses (PR, 64%), 23 PRs with lymphocytosis (8%), and 1 nodular PR (< 1%). After a median follow-up of 13.9 months, estimated PFS was 68% (95% CI, 62-74) for 12 months and 54% (95% CI, 46-61) for 18 months. The most common treatment-emergent AEs (TEAEs) were fatigue (26%), diarrhea (22%), and contusion (18%); grade 3 or higher neutropenia was seen in 20% of patients. Investigators found low rates of grade 3 or higher cardiac related TEAEs, including hyper- tension (3%), hemorrhage (2%), and atrial fibrillation/flutter (1%); 2% of patients stopped taking the drug due to TEAEs.

Results for Those Previously Intolerant to Covalent BTK Inhibitor

Nirav N. Shah, MD, an associate professor at Medical College of Wisconsin, presented data for an abstract that evaluated responses to pirtobrutinib among patients across multiple disease types who had stopped taking covalent BTK inhibitors.2 Shah explained that although second-generation BTK inhibitors are more selective than ibrutinib, “the frequency of cytopenias, infections, and diarrhea have not technically decreased.” Any interruption of treatment can adversely affect outcomes, he said.

Shah explained the mechanism of action for pirtobrutinib, which he noted had been previously shown to be well tolerated with “promising efficacy in poor-prognosis B-cell malignancies,” in patients who had received prior treatments.

“It’s highly selective for BTK; it inhibits both wild-type and C41 mutant BTK,” he said, adding that the “favorable oral pharmacology allows continuous BTK inhibitor inhibition regardless of the intrinsic rate of BTK turnover.”

He presented results for 127 patients who had been BTK intolerant coming into BRUIN. The median time on treatment was 10 months for the overall study population (773 patients) compared with 15 months for the 127 patients who were BTK intolerant. The ORR was 76.9% in CLL/SLL (95% CI, 66.9-85.7) and 81.0 (58.1-94.6) with a 42.9% CR rate in MCL. Discontinuations due to treatment-related AEs occurred in 2.6% of the overall study population (20 patients) compared with 6% of the BTK-intolerant population (7 patients).

AEs of any grade were similar between the overall study population and the BTK-intolerant population except for neutropenia; 14.7% of the overall population had neutropenia compared with 21.3% of the BTK-intolerant population. For grade 3 or higher events, BTK-intolerant patients were more likely to have neutropenia (17.3% for the BTK-intolerant group vs 11.5% for the overall group) and fatigue (1.6% vs 0.8%).

The other AE of grade 3 or higher reported was anemia, 2.4% in the BTK-intolerant group vs 2.1% in the overall population. AEs of special interest in grade 1-2 were bruising (15.1% overall vs 26.8% BTK intolerant), rash (6.0% overall vs 8.7% BTK intolerant), arthralgia (3.5% overall vs 4.7% BTK intolerant), hypertension (3.4% overall vs 3.1% BTK intolerant), and atrial fibrillation 0.8% both overall and BTK intolerant). No AEs or higher were reported in more than 0.1% of the study population.

First “Sizable Cohort” in WM

Palomba reported on a cohort of 80 patients treated prior to the data cutoff on July 29, 2022; 63 had previously been treated with a covalent BTK inhibitor; the median number of overall prior therapies was 3. Investigators described this as the first time results for pirtobrutinib had been reported in a “sizable cohort” of patients with WM.

The major response rate (MRR) was 67% (95% CI, 53.7-78.0); of the group, 15 (23.8%) had a very good PR and 27 (42.9%) had a PR. For patients previously treated with both covalent BTK inhibitor and chemoimmunotherapy, MRR was 68% (95% CI, 53.3-80.5). Among patients previously treated with a covalent BTK inhibitor, median PFS was 19.4 months (95% CI, 15.1- 22.1); median overall survival was not reached. WM safety profiles were consistent with the overall treatment population.

Results in Mantle Cell Lymphoma

Results reported at ASH evaluated 90 patients with MCL before the January 31, 2022, cutoff date; all had been treated with a BTK inhibitor. Patients had received a median of 3 prior treatments. Pirtobrutinib produced ORR of 58% (95% CI, 4. 46.0-68.`) and a median duration of response of 21.6 months (95% CI, 7.5-not evaluable), as well as a median PFS of 7.4 months (95% CI, 5.3-12.5). Response rates were not affected by the number of prior lines of therapy or classes of therapy used previously.

References

1. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed / refractory CLL/SLL: additional patients and extended follow-up from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 961. https://ash.confex.com/ash/2022/webprogram/Paper159497.html

2. Shah NN, Wang ML, Brown JR, et al. Safety and tolerability of pirtobrutinib monotherapy in patients with B-cell malignancies who were previously intolerant to a covalent BTK inhibitor: results from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 1797. https://ash.confex.com/ash/2022/webprogram/Paper159035.html

3. Palomba ML, Patel MR, Eyre TA, et al. Efficacy of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor in relapsed/refractory Waldenström macroglobulinemia: results from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meet- ing and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 229. https://ash.confex.com/ash/2022/webprogram/Paper159123.html

4. Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pretreated relapsed/refractory mantle cell lymphoma; additional patients and extended follow-up from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 4218. https://ash.confex.com/ash/2022/webprogram/Paper159425.html

5. Loxo@Lilly presents updated pirtobrutinib data from the phase 1/2 BRUIN clinical trial at the 2022 American Society of Hematology Annual Meeting. News release. Eli Lilly. December 12, 2022. https://investor.lilly.com/news-releases/news-release-details/loxolilly-presents-updat- ed-pirtobrutinib-data-phase-12-bruin

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