Acalabrutinib Triplet Shows Early Signals of Activity, Safety in R/R Mantle Cell Lymphoma

Austin I. Kim, MD

The combination regimen comprised of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) proved to be safe and feasible and to elicit responses in patients with high-risk, relapsed or refractory mantle cell lymphoma (MCL), according to data from a small phase 1/2 trial (NCT04855695) shared during the 2023 ASH Annual Meeting.¹

No dose-limiting toxicities (DLTs) or serious adverse effects (SAEs) were observed. The recommended phase 2 dose (RP2D) was determined at the full FDA-approved dosage of all 3 drugs.

The triplet induced a best overall response rate (ORR) of 78% in evaluable patients (n = 9); this included a complete response (CR) rate of 67% and a partial response (PR) rate of 11%; 22% of patients experienced progressive disease (PD). In the 2 patients who had TP53-mutated disease, the CR rate was 100%. In the 3 patients who had blastoid variant, the CR rate was 67% and the PR rate was 33%.

“Preliminary efficacy is encouraging in this high-risk R/R MCL population,” Austin I. Kim, MD, of the Department of Medical Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues, wrote in a poster. “Phase 1 R/R MCL expansion cohort and phase 2 treatment-naive transplant ineligible/TP53-aberrant MCL cohort are now open and enrolling.”

In October 2017, the FDA granted accelerated approval to acalabrutinib for adult patients with mantle cell lymphoma after at least 1 previous therapy.² The second-generation BTK inhibitor has been shown to have improved toxicity vs ibrutinib (Imbruvica). The BCL-2 inhibitor venetoclax is used off label in patients with relapsed or refractory MCL as a single agent or paired with ibrutinib. Lastly, preclinical data have indicated that the type II anti-CD20 antibody obinutuzumab helped suppress resistance to venetoclax in this disease.

Previously, the combination of ibrutinib, venetoclax, and obinutuzumab showed early safety and efficacy in patients with relapsed/refractory or treatment-naive MCL.

The phase 1 study, which utilizes a 3+3 dose-finding schema, enrolled patients with relapsed/refractory MCL following at least 1 prior anti-CD20 monoclonal antibody. They were required to be at least 18 years of age, have an ECOG performance status of 0 to 2, and acceptable renal and hepatic function. Patients needed to meet select hematologic criteria. Previous transplant and CAR T-cell therapy were permitted.

If patients experienced disease progression or relapse after exposure to a BTK or BCL-2 inhibitor, confirmed central nervous system involvement, human immunodeficiency virus positivity, or active hepatitis B or C virus, they were excluded. Other key exclusion criteria included uncontrolled arrhythmia; acute coronary syndrome, myocardial infarction, stroke, or intracranial hemorrhage in the past 6 months; or warfarin or Vit K antagonists.

The study was designed to examine up to 2 dose levels of acalabrutinib, beginning with the FDA-approved dose of 100 mg twice daily (DL0) followed by a lower dose of 100 mg daily (DL1) if DLTs happened in more than 1 of 6 patients in DL0 in the first 4 cycles. Participants received treatment as part of 28-day cycles, with acalabrutinib started in cycle 1; followed by obinutuzumab in cycle 2 at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15, and on day 1 of cycles 3 through 7; and venetoclax given at a weekly dose ramp-up beginning in cycle 3 to a target dose of 400 mg daily. Acalabrutinib and venetoclax were continued indefinitely. Maintenance treatment with obinutuzumab was administered every 2 cycles beginning with cycle 9 for a total of 12 doses.

The primary end points were establishing RP2D and to evaluate safety and tolerability of the triplet. A key secondary end point was CR rate following 7 cycles of the combination regimen.

In the total patients, the median age was 67 years (range, 63-79). Most of patients were male (78%), 33% had relapsed after autologous stem cell transplant, and 22% were primary refractory. The majority of patients had stage IV disease (89%). Regarding Mantle Cell Lymphoma International Prognostic Index score, 22% had high-risk disease, 56% had intermediate-risk disease, and 22% had low-risk disease.

Moreover, 33% of patients had blastoid variant, 44% had a Ki67 of at least 50%, 22% had TP53 mutations, 33% had p53 immunohistochemistry expression greater than 50%, and 33% had complex karyotype defined as at least 3 cytogenetic abnormalities. The median number of prior therapies received was 1 (range 1-2).

DL0 was determined to be the RP2D, and 9 patients received treatment at this level. A total of 3 patients were replaced before the DLT window was reached; 2 patients had PD before received venetoclax on day 1 of cycle 3, and 1 patient was not able to receive more than 80% of acalabrutinib plus venetoclax doses because of grade 4 thrombocytopenia. The latter patient had achieved a CR but was not efficacy evaluable on day 1 of cycle 8.

The median follow-up was 6 months (range, 1-21). At the time of the data cutoff date of July 26, 2023, 56% of patients continued to receive treatment. The median progression-free survival and overall survival had not yet been reached.

The most common adverse effects included headache (78%), bruising (67%), decreased neutrophil count (67%), decreased platelet count (56%), diarrhea (44%), dizziness (33%), fatigue (33%), decreased white blood cell count (33%), anemia (22%), bloating (22%), increased creatinine (22%), dyspnea (22%), nausea (22%), palpitations (22%), and upper respiratory infection (22%).

Grade 3 neutropenia occurred in 33% of patients and they received growth factor support; 22% of patients experienced grade 3 anemia. Grade 3 or 4 thrombocytopenia occurred in 22% of patients. One patient had a severe infection in the form of grade 3 COVID-19.

No patients experienced febrile neutropenia, laboratory or clinical tumor lysis syndrome, or atrial fibrillation.

References

1. Kim AI, Armand P, Redd RA, et al. Phase I safety and preliminary efficacy of acalabrutinib, venetoclax, and obinutuzumab (AVO) in patients with relapsed/refractory mantle cell lymphoma. Blood. 2023;142(suppl 1):3031. doi:10.1182/blood-2023-173103
2. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. FDA. October 31, 2017. Accessed December 18, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma