A genomic analysis of the phase 1/2 BRUIN trial (NCT03740529) has revealed that the non-covalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca) maintains high response rates in patients with relapsed chronic lymphocytic leukemia (CLL) who have baseline BTK mutations. The findings, presented at the 2023 American Society of Hematology (ASH) Annual Meeting, suggest that alternative mechanisms may be responsible for resistance development, as most patients acquired non-BTK mutations or no resistance mutations at the time of progression.
The study represents the largest systematic evaluation of genomic evolution to date in CLL, featuring an extensive cohort of patients treated with pirtobrutinib with extended follow-up from the BRUIN trial.
High Response Rates Despite Baseline Mutations
The overall response rate (ORR) with pirtobrutinib in the analyzed subgroup was 83% (95% CI, 73%-90%), consisting of 2 complete responses, 63 partial responses (PRs), and 8 PRs with lymphocytosis. This response rate was comparable to the 82% ORR observed in the entire BRUIN cohort.
"Importantly, these subclonal BTK mutations did not preclude pirtobrutinib efficacy," noted lead author Jennifer Brown, MD, PhD, the director of Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, during her presentation.
Assessment of baseline genomics in patients who experienced progressive disease (PD) during pirtobrutinib treatment showed that the most frequently observed mutations at baseline were BTK (53%), TP52 (49%), SF3B1 (34%), ATM (23%), NOTCH1 (20%), PLCG2 (14%), and BCL2 (9%). Notably, baseline genomic features were not found to predict responses to pirtobrutinib.
Patterns of Resistance Development
A total of 138 acquired resistance mutations were detected in 68% of patients at the time of PD. Multiple acquired mutations were seen in 40% of these patients, while 28% harbored a single acquired resistance mutation.
Of the 44% of patients who had one or more acquired BTK mutations at PD, 64% also displayed a BTK mutation at baseline. Fourteen percent of patients had multiple acquired BTK mutations, while 30% had a single acquired BTK mutation. The percentage of patients who had clearance of BTK mutations was 51%.
"Thirty-two percent of patients who progressed on pirtobrutinib did not acquire any mutations in this targeted panel, suggesting alternative resistance mechanisms," Dr. Brown explained. "However, the panel only included 74 genes, so it is possible that they have alternate genomic resistance mechanisms."
The most common acquired mutation other than BTK was TP53 (14%). Patients also expressed acquired PLCG2 (7%), PIK3CA (7%), and BCL2 (3%) mutations.
Mutation Patterns and Response Rates
Most acquired BTK mutations were in T474x (n = 23) and L528W (n = 14). At the time of PD, 85% of patients experienced a decrease in C481x clones, and 53% experienced clearance. The 55 mutations arising at or near the time of PD comprised BTK C481S/Y/R, T474x, L528W, and other kinase mutations with variant allele frequency (VAF) ranges of 3%-86%.
ORRs were comparable across subgroups regardless of the type of acquired BTK mutation, at 96% for those with T474x mutations and 79% for those with L528W mutations. A change in VAF of 120 BTK mutations was detected at baseline and/or the time of PD. Thirty-six were cleared, 29 shared, and 55 were acquired.
Of the 49 acquired BTK mutations among patients with re-sequenced baseline peripheral blood mononuclear cells (PBMCs), 18 (37%) were pre-existing at low VAF at baseline (VAF range, 0.2%-5.6%). Once again, ORRs were similar in patients with both pre-existing T474x mutations and L528W mutations, at 93% and 75%, respectively.
Study Design and Patient Characteristics
The BRUIN trial was a dose escalation and expansion study of pirtobrutinib monotherapy in adult patients with mantle cell lymphoma (MCL), CLL/small lymphocytic lymphoma (SLL), and other histologic subtypes (n = 317).
The study included pretreated patients from the CLL/SLL cohort who had relapsed on a covalent BTK inhibitor and subsequently experienced PD on single-agent pirtobrutinib. After excluding patients with missing next-generation sequencing (NGS) results and other criteria, a total of 88 paired baseline and progression PBMC samples were analyzed.
Within the final study population, the median age was 69 years (range, 36-86), and 36% of patients were female. The median time on treatment was 16 months (range, 1.2-39), the median number of prior lines of systemic therapy was 4 (range, 1-10), and the median number of prior covalent BTK inhibitors was 1 (range, 1-4). Most patients (85%) discontinued treatment with their prior covalent BTK inhibitor due to disease progression.
"Many patients were on therapy for more than 24 months, including 6 with ongoing treatment past progression as allowed by protocol," Dr. Brown noted.
Clinical Implications
Many patients with CLL discontinue treatment with covalent BTK inhibitors due to the development of intolerance or PD. The most common resistance mechanisms to covalent BTK inhibitors are C481 substitutions, followed by gatekeeper TP53 and kinase impaired L528 mutations.
Research shows that pirtobrutinib is effective in heavily pretreated patients with both wild-type and C481-mutated CLL. The agent may stabilize the BTK protein in its inactive conformation, thereby potentially inhibiting kinase-independent BTK signaling.
These findings highlight pirtobrutinib's potential as an effective treatment option for patients with relapsed CLL, particularly those who have developed resistance to covalent BTK inhibitors. The high response rates observed despite baseline BTK mutations suggest that pirtobrutinib could address an important unmet need in this patient population.
