Nemtabrutinib Generates Responses, Displays Manageable Safety in CLL/SLL

Nemtabrutinib (ARQ-53), a potent, non-covalent BTK inhibitor, continued to demonstrate antitumor activity with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to data from the dose-expansion phase 2 BELLWAVE-001 trial (NCT03162536) presented at the 2022 EHA Congress.¹

At a median follow-up of 7.1 months (range, 0.1-33.9) in patients with CLL/SLL who received the recommended phase 2 dose (RP2D) of nemtabrutinib (n = 57), the overall response rate (ORR) was 53% (95% CI, 39%-66%), which included a complete response (CR) rate of 4%, a partial response (PR) rate of 26%, and a PR with residual lymphocytosis (PR-L) rate of 23%. Thirty percent of patients had stable disease and 4% experienced disease progression.

Patients in cohort A had relapsed/refractory CLL/SLL and received 2 or more prior therapies, including treatment with a covalent BTK inhibitor, and harbored C481S mutations (n = 25); these patients achieved an ORR of 60% (95% CI, 39%-79%), which comprised a 20% PR rate, a 40% PR-L rate, and a 32% stable disease rate. In cohort B, which included patients with relapsed/refractory CLL/SLL who received 2 or more prior therapies, were intolerant of BTK inhibitors and did not harbor C481S mutations (n = 10), the ORR with nemtabrutinib was 40%; this included a 10% CR rate, a 20% PR rate, a 10% PR-L rate, and a 30% stable disease rate.

“Responses [with nemtabrutinib] were seen in very heavily pretreated patients and those progressing on prior covalent BTK inhibitors,” Jennifer A. Woyach, MD, lead study author, hematologist oncologist, and professor in the Division of Hematology at The Ohio State University, and colleagues, wrote in a poster on the findings.

The development of covalent BTK inhibitors, such as ibrutinib (Imbruvica), altered the treatment landscape for patients with CLL and SLL. However, resistance to these agents has been found to primarily develop through select mutations, such as C481, at the cysteine binding site on BTK. Nemtabrutinib is an inhibitor of wild-type and ibrutinib-resistant, C481S-mutated BTK.

BELLWAVE-001 enrolled patients who were at least 18 years of age who had symptomatic CLL/SLL or B-cell non-Hodgkin lymphoma with measurable disease. Patients were required to have relapsed/refractory disease following at least 2 lines of prior treatment and an ECOG performance status of 2 or less.

In total, 74 patients with CLL/SLL received treatment with nemtabrutinib, including 57 patients who received the agent at the RP2D of 65 mg once daily. Those with CLL or SLL were further divided into those whose tumors harbored a C481S mutation and those who did not. Those with B-cell NHL could have had Richter transformation, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, high-grade B-cell lymphoma, or Waldenström macroglobulinemia.

Patients in the expansion cohorts received nemtabrutinib at 65 mg once daily. Treatment was continued until intolerable toxicity, disease progression, or withdrawal.

The primary end point of the trial was ORR per International Workshop on CLL criteria in patients with CLL/SLL. Secondary end points included duration of response (DOR), safety, and tolerability. Progression-free survival (PFS) served as an exploratory end point of the trial.

Prior data from the trial, which had a data cutoff of April 7, 2021, and a median follow-up of 6.18 months, indicated that nemtabrutinib given at the RP2D resulted in encouraging antitumor activity with manageable safety in those with CLL or SLL. At the 2022 EHA Congress, investigators shared updated data, which had a data cutoff of January 25, 2022.

Of all patients with CLL or SLL who received nemtabrutinib (n = 74), 56 discontinued the agent; 8 patients did so because of adverse effects (AEs), 18 due to clinical progression, 6 because of radiographic progression, 1 due to withdrawn consent, 5 because of physician decision, 15 due to another unspecified reason, and 3 due to death.

In this subset, the median age was 66 years (range, 45-86). Most patients were male (73%), White (88%), received 65 mg of nemtabrutinib (77%), received prior BTK inhibitor therapy (96%), and had an ECOG performance status of 0 or 1 (91%). Moreover, 58% of patients had IGHV-unmutated disease and 68% did not harbor a 17p deletion (68%). More than half of patients, or 68%, had a tumor that harbored a C481S mutation. The population of patients was heavily pretreated, with a median of 4 prior lines of therapy received (range, 1-18).

Additional data showed that the median DOR in all patients with CLL/SLL was not estimable (NE; 95% CI, 13.9-NE). In cohorts A and B, the median DOR with nemtabrutinib was 13.9 months (95% CI, 5.5-NE) and NE (95% CI, NE-NE), respectively.

In all patients with CLL/SLL, the median PFS was NE (95% CI, 10.6-NE). In cohorts A and B, the median PFS was 15.7 months (95% CI, 7.6-NE) and NE (95% CI, 5.0-NE), respectively.

Regarding safety, all patients experienced at least 1 treatment-emergent AE (TEAE) of any grade, and 74% experienced a grade 3 or higher TEAE. Sixty-nine percent of patients reported a TEAE that was related to the study drug, and in 30% of these patients, that effect was grade 3 or higher. Twelve percent of patients discontinued treatment due to a nemtabrutinib-related TEAE.

Common TEAEs that were reported in 20% or more of patients included dysgeusia (any-grade, 36%; grade 3 or higher, 0%), hypertension (35%; 14%); peripheral edema (34%; 1%), cough (32%; 0%), fatigue (32%; 3%), constipation (31%, 1%), decreased neutrophil count (31%; 27%), dizziness (30%; 0%), nausea (30%; 3%), pyrexia (30%; 4%), diarrhea (28%; 3%), dyspnea (28%, 7%); arthralgia (24%; 1%), decreased platelet count (24%; 14%); upper respiratory tract infection (23%; 1%), chills (22%; 0%), pneumonia (22%; 14%), and anemia (20%; 12%).

Notably, 2 patients experienced atrial fibrillation, and 1 of these cases was grade 3 in severity. No grade 5 nemtabrutinib-related TEAEs were reported.

“Investigation of nemtabrutinib at doses 65 mg and higher for the treatment of [patients] with B-cell malignancies continues,” the study authors concluded.

Reference

Woyach J, Flinn IW, Awan FT, et al. Nemtabrutinib (MK-1026), a non-covalent inhibitor of wild-type and C481S mutated Bruton Tyrosine Kinase for B-cell malignancies: efficacy and safety of the phase 2 dose-expansion BELLWAVE-001 study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P682. https://bit.ly/3HDw2fC