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

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