Acalabrutinib Plus Venetoclax/Rituximab Yields 100% ORR in Treatment-Naive Mantle Cell Lymphoma

Treatment with the combination of acalabrutinib (Calquence), venetoclax (Venclexta), and rituximab (Rituxan) led to an overall response rate (ORR) of 100% (95% CI, 83.9%-100.0%) per Lugano criteria in previously untreated patients with mantle cell lymphoma (MCL), according to data from a phase 1b trial (NCT02717624) published in Blood Advances.¹

Findings showed that among patients treated with the combination (n = 21), the complete response (CR) rate was 71.4% (95% CI, 47.8%-88.7%) per Lugano criteria. When assessed by PET/CT scan alone, the ORR was 100% (95% CI, 83.9%-100%) and the CR rate was 90.5% (95% CI, 69.6%-98.8%), respectively.

Regarding safety, grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 61.9% of patients, which included neutropenia (33.3%), COVID-19 (9.5%), diarrhea (4.8%), dyspnea (4.8%), and peripheral edema (4.8%). Grade 5 TEAEs occurred in 4 patients (19.0%), and all were COVID-19. Notably, none of these patients received a COVID-19 vaccine; among those who did receive a vaccine (n = 4), only 1 patient had COVID-19 and it was grade 2.

“Acalabrutinib plus venetoclax and rituximab is a promising, highly effective, and well-tolerated chemotherapy-free treatment option for patients with treatment-naive MCL,” lead study author Michael Wang, MD, and colleagues wrote in a publication of the data. “The acalabrutinib, venetoclax, and rituximab combination is being evaluated in [the] phase 2 TrAVeRse study [NCT05951959] for patients with treatment-naive MCL.”

Wang is a professor in the Department of Lymphoma/Myeloma and a professor in the Department of Stem Cell Transplantation of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

The phase 1b trial evaluated acalabrutinib in combination with rituximab and bendamustine (BR) or with venetoclax and rituximab in patients with MCL.² Previous findings from the portion of the study that evaluated acalabrutinib plus BR showed that the ORR per Lugano criteria was 94.4% (95% CI, 72.7%-99.9%) for treatment-naive patients (n = 18) and 85.0% (95% CI, 62.1%-96.8%) for those with relapsed/refractory disease (n = 20).³ The respective CR rates per Lugano criteria were 77.8% and 70.0%.

In the portion of the study evaluating acalabrutinib in combination with venetoclax and rituximab, investigators enrolled patients at least 18 years of age with pathologically confirmed MCL who did not receive prior systemic therapy and had an ECOG performance status of 2 or lower.¹

All patients received continuous acalabrutinib at 100 mg twice per day starting on day 1 of cycle 1. Rituximab was given at 375 mg/m² on day 1 of each 28-day cycle in cycles 1 to 6. Venetoclax was first administered on day 1 of cycle 2 using a 5-week ramp-up schedule. Patients received escalating doses of venetoclax at 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg per day, and the agent was continued at 400 mg per day through cycle 25. Treatment with acalabrutinib continued until disease progression or unacceptable toxicity.

Safety served as the trial’s primary end point. Secondary end points included ORR, progression-free survival (PFS), and duration of response (DOR).

Enrolled patients had a median age of 66 years (range, 51-85); the majority were male (81%) and White (91%). Fifty-two percent of patients had an ECOG performance status of 0, 43% had a performance status of 1, and 5% had a performance status of 2. Bulky lymph nodes of more than 5 cm were observed in 33% of patients at baseline, and 5% of patients had bulky lymph nodes of at least 10 cm. The rates of patients with bone marrow involvement, extranodal disease, and Ann Arbor stage IV disease were 71%, 62%, and 90%, respectively.

Patients had a simplified MCL International Prognostic Index score of low risk (24%), intermediate risk (52%), high risk (19%), missing (5%), or blastoid/pleomorphic MCL (5%). Forty-eight percent of patients had a Ki-67 proliferation index of less than 30%, and 48% had a Ki-67 proliferation index of at least 30%; Ki-67 proliferation index data were missing for 5% of patients.

During the study. 95.2% of patients completed the first 6 cycles of induction therapy. Venetoclax was discontinued in 1 patient between cycles 1 and 6 due to COVID-19. At data cutoff, 57.1% of patients remained on the study; 42.9% of patients discontinued treatment due to death (n = 6), unspecified reasons (n = 2), and investigator decision (n = 1). Among the 6 deaths, 1 was due to progressive disease, and 5 were attributed to other causes.

Additional data showed that 90.5% of patients achieved a response after the first 6 cycles. Two patients who missed their assessment on the first day of cycle 7 achieved a confirmed partial response at cycle 10.

The median time to response was 2.8 months (range, 0.7-3.7), and the median time to best response was 3.0 months (range, 0.7-18.3). The median DOR was not reached (NR), and the estimated 12- and 36-month DOR rates were 90.5% (95% CI, 67.0%-97.5%) and 53.3% (95% CI, 24.0%-75.8%), respectively.

When censoring for the 5 patients who died due to COVID-19, the median DOR was NR. The estimated 12-month DOR rate was 95% (95% CI, 69.5%-99.3%), and the estimated 36-month DOR rate was 79.2% (95% CI, 31.8%-95.4%).

At a median follow-up of 27.8 months (range, 8.0-39.8), patients achieved a median PFS and overall survival (OS) that were both NR. The 1- and 2-year PFS rates were 90.5% (95% CI, 67.0%-97.5%) and 63.2% (95% CI, 34.7%-82.0%), respectively. The respective 1- and 2-year OS rates were 95.2% (95% CI, 70.7%-99.3%) and 75.2% (95% CI, 50.3%-88.9%).

When censoring for COVID-19 deaths, the 1- and 2-year PFS rates were both 95% (95% CI, 69.5%-99.3%). The 1- and 2-year OS rates were both 100% after censoring for COVID-19 deaths.

Among patients evaluable for minimal residual disease (MRD; n = 16), the best MRD-negative ORR was 87.5% at a 10-6 sensitivity. The MRD-negativity rates among evaluable patients at cycle 6 (n = 12) and cycle 12 (n = 14) were 100% and 78.6%, respectively.

Additional safety data showed that serious AEs of any grade were reported in 57.1% of patients, and 52.4% of patients had grade 3 or higher serious AEs. The most common serious AE was COVID-19 (33.3%), and other serious AEs reported in at least 2 patients were pneumonia (9.5%) and seizures (9.5%).

Any-grade TEAEs occurred in all patients. The most common consisted of diarrhea (71.4%), headache (52.4%), fatigue (47.6%), neutropenia (38.1%), COVID-19 (33.3%), dizziness (33.3%), cough (28.6%), paresthesia (28.6%), dyspnea (23.8%), hypoesthesia (23.8%), myalgia (23.8%), memory impairment (19.0%), peripheral edema (19.0%), pruritus (19.0%), upper respiratory tract infection (19.0%), and blurred vision (19.0%).

AEs led to temporary withholding of any study drug in 71.4% of patients; AEs led to temporary withholding of acalabrutinib in 66.7% of patients, venetoclax in 52.4% of patients, and rituximab in 14.3% of patients.

Most TEAEs of clinical interest were grade 1 to 2. Grade 3 or higher TEAEs of clinical interest reported in at least 20% of patients included leukopenia (42.9%) and infections (38.1%). Notably, no grade 3 or higher cardiac TEAEs occurred, and there were no instances of atrial fibrillation or ventricular tachyarrhythmia. Major hemorrhage or tumor lysis syndrome did not occur in any patients.

References

1. Wang M, Robak T, Maddocks KJ, et al. Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis. Blood Adv. 2024;8(17):4539-4548. doi:10.1182/bloodadvances.2023012424
2. A study of acalabrutinib in combination with rituximab + (bendamustine or venetoclax) in subjects with MCL. ClinicalTrials.gov. Updated August 26, 2024. Accessed October 22, 2024. https://clinicaltrials.gov/study/NCT02717624
3. Phillips TJ, Wang M, Robak T, et al. Safety and efficacy of ABR in pts with TN or R/R MCL: Ph Ib trial. J Clin Oncol. 2023;41(suppl 16):7546. doi:10.1200/JCO.2023.41.16_suppl.7546