Among patients with relapsed chronic lymphocytic leukemia (CLL) who expressed frequent baseline BTKmutations, responses on the non-covalent BTK inhibitor Jaypirca (pirtobrutinib) remained high, according to a genomic analysis of the phase 1/2 BRUIN trial.
Additional data presented at the 2023 ASH Annual Meeting show that the majority of patients acquired non-BTK mutations or no resistance mutations at the time of progression, suggesting that alternative mechanisms may be responsible for the development of resistance.
Assessment of baseline genomics in patients who experienced progressive disease (PD) during Jaypirca treatment showed that the most frequently observed mutations at baseline were BTK, TP52, SF3B1, ATM, NOTCH1, PLCG2 and BCL2. These mutations were present in 53%, 49%, 34%, 23%, 20%, 14% and 9% of patients, respectively. Notably, baseline genomic features were not found to predict responses with Jaypirca.
LEARN MORE: Jaypirca, ‘Much-Needed’ Treatment for CLL and SLL, Approved by FDA
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 of these acquired BTKmutations at PD, 64% also displayed a BTKmutation at baseline. Fourteen percent and 30% percent of patients had multiple versus one acquired BTK mutation, respectively, while 51% of patients had clearance of BTKmutations.
The most common acquired mutation other than BTK was TP53 (14%). Patients also expressed acquired PLCG2(7%), PIK3CA (7%) and BCL2 (3%) mutations.
“Thirty-two percent of patients who progressed on Jaypirca did acquire any mutations (at the time of PD) in this targeted panel, suggesting alternative resistance mechanisms,” lead author Dr. Jennifer Brown, director of chronic lymphocytic leukemia at Dana-Farber Cancer Institute, said in an oral presentation of the data. “However, the panel only included 74 genes, so it is possible that they have alternate genomic resistance mechanisms.”
Objective response rates (ORRs; patients who responded partially or completely to treatment) 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 BTKmutations 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 PBMCs, 18 (37%) were pre-existing at low VAF at baseline. Once again, ORRs were similar in patients with both pre-existing T474xmutations andL528W mutations, at 93% and 75%, respectively.
“Importantly, these subclonal BTK mutations did not preclude (Jaypirca) efficacy,” Brown noted.
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 C481substitutions, followed by gatekeeper TP53 and kinase impaired L528 mutations. A limited number of patients treated with (Jaypirca) exhibit these acquired mutations.
Research shows that the non-covalent BTK inhibitor Jaypirca 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. This makes it necessary to characterize the genomic evolution and development of resistance during Jaypirca treatment.
Accordingly, investigators conducted the largest systematic evaluation of genomic evolution to date in CLL, featuring a larger cohort of patients treated with Jaypirca and longer follow-up from the BRUIN trial. BRUIN was a dose escalation and expansion study of Jaypirca monotherapy in 317 adult patients with MCL, CLL/small lymphocytic lymphoma (SLL), and other histologic subtypes.
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 Jaypirca.
Seventy-two of these patients were excluded from this analysis due to missing next-generation sequencing (NGS) results at baseline, no prior exposure to covalent BTK inhibitors (35 patients) and a missing reason for BTK discontinuation (one patient). Of the remaining 245 patients, 139 developed PD during Jaypirca treatment; another 51 patients were subsequently excluded from the analysis due to missing NGS data at or near the time of PD.
A total of 88 paired baseline and progression peripheral blood mononuclear cell (PBMC) samples were obtained from the remaining patients through NGS. NGS-targeted 74 exons, including BTK, PLCG2 and TP53. To identify the presence of pre-existing BTK mutations, 79 baseline PBMC samples were re-sequenced using a more sensitive procedure.
Within the final study population of 88 patients with PD and longitudinal samples, the median age was 69 and 36% of patients were female. Regarding ECOG performance status, 49%, 47% and 5% of patients had a score of 0, 1 and 2, respectively, meaning most participants would perform daily tasks with little or no assistance.
The median time on treatment was 16 months, the median number of prior lines of systemic therapy was four and the median number of prior covalent BTK inhibitors was one. Eighty-five percent of patients discontinued treatment with their prior covalent BTK inhibitor due to disease progression.
“Many patients were on therapy for more than 24 months, including six with ongoing treatment past progression as allowed by protocol,” Brown detailed.
Prior covalent BTK inhibitors received included Imbruvica (ibrutinib; 90%), Calquence (acalabrutinib; 17%) and Brukinsa (zanubrutinib; 2%); other prior therapies in this population included chemotherapy (85%), an anti–CD20 monoclonal antibody (90%), a BCL-2 inhibitor (48%), a PI3K inhibitor (24%) and CAR-T cell therapy (9%).
The overall response rate with Jaypirca in this subgroup was 83% and consisted of two complete responses, 63 partial responses (PRs), and eight PRs with lymphocytosis. Ten patients achieved stable disease and five experienced PD.
“The ORR in this cohort…was comparable to the ORR in the entire cohort, at 82%,” Brown noted during the presentation.
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