Ibrutinib-Venetoclax Combo Elicits Durable Complete Responses in TP53+ MCL

Treatment with ibrutinib (Imbruvica) and venetoclax (Venclexta) resulted in durable responses in newly diagnosed and relapsed/refractory mantle cell lymphoma (MCL) harboring TP53 mutations, according to data from the phase 3 SYMPATICO trial (NCT03112174) presented at the 2024 ASCO Annual Meeting.¹

Findings showed that in the pooled population of patients treated in the first-line or relapsed/refractory setting (n = 74), ibrutinib plus venetoclax elicited an overall response rate (ORR) of 84% (95% CI, 73%-91%) and a complete response (CR) rate of 57% (95% CI, 45%-68%). In patients treated in the first-line setting (n = 29), the ORR and CR rate were 90% (95% CI, 73%-98%) and 55% (95% CI, 36%-74%), respectively. These respective rates were 80% (95% CI, 65%-90%) and 58% (95% CI, 42%-72%) in patients treated in the relapsed/refractory setting (n = 45).

Additionally, the median duration of response was 26.0 months (95% CI, 16.8-32.2) in the overall population, 26.5 months (95% CI, 16.8-not evaluable [NE]) in the relapsed/refractory population, and 20.5 months (95% CI, 12.0-NE) in the treatment-naive population. The respective median durations of CR were 32.2 months (95% CI, 18.7-NE), not reached (NR; 95% CI, 18.7-NE), and 20.5 months (95% CI, 5.4-NE).

“This study represents the largest single-study cohort of patients with MCL and TP53 mutations reported to date,” lead study author Michael Wang, MD, said in a presentation of the data. “These results are encouraging in light of the poor responses and shorter survival outcomes with standard chemoimmunotherapy in patients with MCL and TP53 mutations.”

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

SYMPATICO was an international, randomized, double-blinded, placebo-controlled study that evaluated ibrutinib plus venetoclax vs placebo plus ibrutinib in patients with relapsed/refractory MCL, and the study also included an open-label cohort where patients with newly diagnosed disease received ibrutinib plus venetoclax.

Prior data from the study presented at the 2023 ASH Annual Meeting showed that in the randomized portion of the trial, ibrutinib plus venetoclax reduced the risk of disease progression or death by 35% compared with placebo plus ibrutinib in patients with relapsed/refractory MCL (HR, 0.65; 95% CI, 0.47-0.88; long-rank P = .0052). Patients treated with ibrutinib plus venetoclax (n = 134) achieved a median progression-free survival (PFS) of 31.9 months per investigator assessment compared with 22.1 months for placebo plus ibrutinib (n = 133).²

In a presentation at the 2024 ASCO Annual Meeting, investigators presented an analysis of patients with TP53-mutated MCL treated during SYMPATICO.¹

The study featured a safety-run in phase where patients with relapsed/refractory MCL (n = 21) all received oral ibrutinib at 560 mg once per day plus oral venetoclax at 400 mg once per day after doses were ramped up over 5 weeks. Treatment continued for 2 years and was followed by maintenance ibrutinib at 560 mg once per day until progressive disease or unacceptable toxicity. In the randomized phase, patients with relapsed/refractory disease were randomly assigned 1:1 to receive 2 years of ibrutinib plus venetoclax, followed by ibrutinib maintenance (n = 134), or ibrutinib plus placebo for 2 years, followed by maintenance ibrutinib (n = 133). Previously untreated patients in the open-label cohort (n = 78) received ibrutinib plus venetoclax for 2 years, followed by ibrutinib maintenance.

In the pooled population of patients whose disease harbored TP53 mutations, the median age was 67 years (range, 41-82), and 62% of patients were at least 65 years of age. Patients had an ECOG performance status of 0 (54%) or 1 to 2 (46%). MCL histology included typical (64%), blastoid (11%), pleomorphic (11%), or other (15%). Simplified MCL International Prognostic Index score included low risk (16%), intermediate risk (38%), high risk (43%), or missing (3%). Thirty-six percent of patients had bulky disease measuring at least 5 cm, and 8% had bulky disease measuring at least 10 cm. At baseline, extranodal disease was observed in half of patients, bone marrow involvement was reported in 64% of patients, and splenomegaly was noted in 39% of patients.

Thirty-one percent of patients in the pooled population completed 2 years of venetoclax. Treatment with ibrutinib was ongoing in 24% of patients, and venetoclax treatment was ongoing in 4% of patients. The median time on study was 40.0 months, and the median treatment duration was 15.9 months.

Sixty-five percent of patients discontinued venetoclax due to progressive disease (39%), adverse effects (AEs; 12%), or death (7%). Seventy-six percent of patients discontinued ibrutinib due to progressive disease (43%), AEs (18%), or death (7%).

Additional data showed all patients with TP53-mutated MCL experienced a median PFS of 20.9 months (95% CI, 14.7-30.6). In the relapsed/refractory setting for patients with TP53-mutated disease, the median PFS was 20.9 months (95% CI, 13.0-33.1) for ibrutinib plus venetoclax (n = 45) vs 10.9 months (95% CI, 4.5-17.9) for ibrutinib plus placebo (n = 37). Patients with MCL harboring TP53 mutations treated with ibrutinib plus venetoclax in the frontline setting (n = 29) achieved a median PFS of 22.0 months (95% CI, 9.2-NE).

In patients whose disease did not harbor TP53 mutations, the median PFS in the relapsed/refractory setting was 46.9 months (95% CI, 31.5-NE) for ibrutinib plus venetoclax (n = 75) and 22.2 months (95% CI, 12.0-34.9) for ibrutinib plus placebo (n = 57). Ibrutinib plus venetoclax produced a median PFS that was NR (95% CI, NE-NE) in patients with treatment-naive MCL absent of TP53 mutations (n = 44).

The median overall survival (OS) in the pooled TP53-mutated population treated with ibrutinib plus venetoclax was 47.1 months (95% CI, 30.6-NE). In the relapsed/refractory setting, the median OS was 35.0 months (95% CI, 14.1-NE) for ibrutinib plus venetoclax vs 15.4 months (95% CI, 10.9-38.5) for ibrutinib plus placebo. Patients given ibrutinib plus venetoclax in the frontline setting had a median OS that was NE (95% CI, 30.6-NE).

In the TP53-unmutated population, patients treated with ibrutinib plus venetoclax in the relapsed/refractory setting experienced a median OS that was NE (95% CI, 34.5-NE) vs 52.6 months (95% CI, 24.6-NE) for those given ibrutinib plus placebo. In the frontline setting, ibrutinib plus venetoclax elicited a median OS that was NE (95% CI, NE-NE).

An analysis of minimal residual disease (MRD) showed high MRD-negative remission rates were reported in patients achieving a CR with ibrutinib plus venetoclax, irrespective of TP53 mutation status. In the pooled population evaluable for MRD in peripheral blood, the MRD-negative remission rate was 73% (95% CI, 50%-89%) for patients with TP53-mutated disease (n = 22) and 79% (95% CI, 63%-90%) for those with TP53-unmutated disease (n = 38). In those evaluable for MRD in the bone marrow, the MRD-negative remission rate was 63% (95% CI, 35%-85%) for patients with TP53-mutated disease (n = 16) and 63% (95% CI, 42%-81%) for those with TP53-unmutated disease (n = 27).

Wang noted that safety findings for the TP53-mutated population were consistent with the known safety profiles of ibrutinib and venetoclax. In the pooled population of patients with TP53-mutated MCL treated in the frontline or relapsed/refractory settings, grade 3 or higher AEs occurred in 80% of patients, and 55% had serious AEs. AEs led to treatment discontinuation in 30% of patients, including ibrutinib only in 9% of patients, venetoclax only in 3% of patients, and both agents in 18% of patients. AEs led to dose reductions in 46% of patients, including ibrutinib only in 19% of patients, venetoclax only in 12% of patients, and both agents in 15% of patients.

AEs led to death in 15% of patients. Notably, 1% of patients died due to AEs related to ibrutinib, and venetoclax-related AEs did not lead to any deaths.

The most common any-grade AEs included diarrhea (66%), neutropenia (36%), fatigue (34%), nausea (34%), thrombocytopenia (30%), anemia (28%), COVID-19 (24%), vomiting (23%), hypomagnesemia (20%), and pyrexia (20%). The most common grade 3 or higher AEs consisted of neutropenia (32%), anemia (15%), and thrombocytopenia (15%).

Laboratory tumor lysis syndrome (TLS) was reported in 7% of patients; however, no patients had clinical TLS.

References

1. Wang M, Jurczak W, Trneny M, et al. Efficacy and safety of ibrutinib plus venetoclax in patients with mantle cell lymphoma (MCL) and TP53 mutations in the SYMPATICO study. J Clin Oncol. 2024;42(suppl 16):7007. doi:10.1200/JCO.2024.42.16_suppl.7007
2. Wang M, Jurczak W, Trneny M, et al. Ibrutinib combined with venetoclax in patients with relapsed/refractory mantle cell lymphoma: primary analysis results from the randomized phase 3 SYMPATICO study. Blood. 2023;142(suppl 2):LBA2. doi:10.1182/blood-2023-191921