Responses With Pirtobrutinib Remain High Despite Acquired Resistance in Relapsed CLL/SLL

Jennifer Brown, MD, PhD

Responses on the non-covalent BTK inhibitor pirtobrutinib (Jaypirca) remained high in patients with relapsed chronic lymphocytic leukemia (CLL) who expressed frequent baseline BTK mutations, according to a genomic analysis of the phase 1/2 BRUIN trial (NCT03740529). 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 pirtobrutinib 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 pirtobrutinib.

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 1 or more of these acquired BTK mutations at PD, 64% also displayed a BTK mutation at baseline. Fourteen and 30% percent of patients had multiple vs 1 acquired BTK mutation, respectively. The percentage of patients who had clearance of BTK mutations was 51%.

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 pirtobrutinib did acquire any mutations [at the time of PD.] in this targeted panel, suggesting alternative resistance mechanisms,” lead author Jennifer Brown, MD, PhD, the 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.”

Most acquired mutations in BTK mutations were inT474x (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 (n = 39, variant allele frequency [VAF] range, 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 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 T474xmutations andL528W mutations, at 93% and 75%, respectively.

“Importantly, these subclonal BTK mutations did not preclude pirtobrutinib 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 C481 substitutions, followed by gatekeeper TP53 and kinase impaired L528 mutations. A limited number of patients treated with pirtobrutinib exhibit these acquired mutations.

Research shows that the non-covalent BTK inhibitor 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. This makes it necessary characterize the genomic evolution and development of resistance during pirtobrutinib treatment.

Accordingly, investigators conducted the largest systematic evaluation of genomic evolution to date in CLL, featuring a larger cohort of patients treated with pirtobrutinib and longer follow-up from the BRUIN trial. BRUIN was a dose escalation and expansion study of pirtobrutinib monotherapy in adult patients with 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.

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 (n = 35), and a missing reason for BTK discontinuation (n = 1). Of the remaining 245 patients, 139 developed PD during pirtobrutinib 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 assay.

Within the final study population of patients with PD and longitudinal samples (n = 88), the median age was 69 years old (range, 36-86) 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. 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 discontinued treatment with their prior covalent BTK inhibitor due to disease progression (85%).

“Many patients were on therapy for more than 24 months, including 6 with ongoing treatment past progression as allowed by protocol,” Brown detailed.

Prior covalent BTK inhibitors received included ibrutinib (Imbruvica; 90%), acalabrutinib (Calquence; 17%), and zanubrutinib (Brukinsa; 2%); other prior therapies in this population included chemotherapy (85%), an anti–CD20 monoclonal antibody (90%), a BCL-2 inhibitor (485), a PI3K inhibitor (24%), and CAR T-cell therapy (9%).

The overall response rate (ORR) with pirtobrutinib in this subgroup was 83% (95% CI, 73%-90%), and consisted of 2 complete responses, 63 partial responses (PRs), and 8 PRs with lymphocytosis. Ten patients achieved stable disease, and 5 experienced PD.

“The ORR in this cohort…was comparable to the ORR in the entire cohort, at 82%,” Brown noted during the presentation.

Dr Brown reports receiving research funding from Gilead, BeiGene, MEI Pharma, Loxo/Lilly, iOnctura, SecuraBio, TG Therapeutics; she served as a consultant for Alloplex Biotherapeutics, Genentech/Roche, BeiGene, Abbvie, Acerta, AstraZeneca, Pharmacyclics, Pfizer, Numab Therapeutics, Merck, Loxo/Lilly, Kite, iOnctura, hutchmed, Grifols Worldwide Operations.

Reference

Brown JR, Desikan SP, Nguyen B, et al. Genomic evolution and resistance during pirtobrutinib therapy in covalent BTK-inhibitor (cBTKi) pre-treated chronic lymphocytic leukemia patients: updated analysis from the BRUIN study. Presented at the 2023 ASH Annual Meeting; December 9-12, 2023; San Diego, CA; abstract 326.