Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study

Abstract

Ibrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://ichgcp.net/clinical-trials-registry/NCT03112174 .

Keywords: Hematological cancers/lymphomas; Ibrutinib; Safety; Small molecule agents/kinase inhibitors; Venetoclax.

Conflict of interest statement

MW: honoraria from Janssen, AstraZeneca, OMI, Targeted Oncology, OncLive, Dava Oncology, Beijing Medical Award Foundation, Lu Daopei Medical Group, and Pharmacyclics LLC, an AbbVie Company; consulting or advisory role with Celgene, Janssen, AstraZeneca, MORE Health, Pulse Biosciences, Nobel Insights, Guidepoint Global, Kite Pharma, Juno Therapeutics, Loxo Oncology, InnoCare, Oncternal, and Pharmacyclics LLC, an AbbVie Company; research funding from Janssen, AstraZeneca, Acerta Pharma, Kite Pharma, Juno Therapeutics, Celgene, Loxo Oncology, VelosBio, Verastem, Molecular Templates, BioInvent, Oncternal, and Pharmacyclics LLC, an AbbVie Company; and travel accommodations from Janssen, Celgene, Juno Therapeutics, Kite Pharma, Loxo Oncology, VelosBio, Verastem, Molecular Templates, BioInvent, Oncternal, AstraZeneca, Acerta Pharma, and Pharmacyclics LLC, an AbbVie Company. RR: consulting or advisory role with Pharmacyclics LLC, an AbbVie Company; and research funding from Janssen and Pharmacyclics LLC, an AbbVie Company. RC: nothing to disclose. LK: employment with Aguettant; honoraria from Amgen, AbbVie, Celgene, Janssen, Takeda, and Sanofi; consulting or advisory role with Amgen, Celgene, Janssen, and Takeda; and travel accommodations from Amgen, Janssen, and Takeda. GC: consulting or advisory role with Bristol Myers Squibb; research funding from Merck Serono, Bristol Myers Squibb, Hutchison MediPharma, Regeneron, Isofol, AstraZeneca, Servier, and Pharmacyclics LLC, an AbbVie Company. WJ: consulting or advisory role with Sandoz Novartis, BeiGene, Janssen, Acerta, AstraZeneca, Loxo, and Epizyme; research funding from AbbVie, Acerta, Bayer, BeiGene, Janssen, MEI Pharma, Takeda, Telios, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company. KLW: consulting or advisory role with Amgen, Janssen, and AbbVie. MB: honoraria from Teva Pharma, Celltrion, and Roche Pharmaceuticals; consulting or advisory role with Celltrion, and Roche Pharmaceuticals; travel accommodations from Celltrion, Roche Pharmaceuticals, Takeda, and Gilead. GPC: honoraria from Roche, Takeda, Gilead, Pfizer, Bristol Myers Squibb, Merck Sharp & Dohme, Celleron, ADC Therapeutics, and Novartis; consulting or advisory role with Roche, Takeda, Gilead, Bristol Myers Squibb, Merck Sharp & Dohme, Celleron, and ADC Therapeutics; research funding from Bristol Myers Squibb, Celleron, Merck Sharp & Dohme, Celgene, and Amgen; speakers bureau with Roche, Takeda, Bristol Myers Squibb, Novartis, and Gilead; travel accommodations from Roche and Takeda. PE: nothing to disclose. FP: nothing to disclose. YL, KE, and JKN: employment with Pharmacyclics LLC, an AbbVie Company; and stock ownership in AbbVie. CST: honoraria from AbbVie, Janssen, Loxo, and BeiGene; consulting or advisory role with Janssen, Loxo, Roche, BeiGene, and AbbVie; and research funding from BeiGene, Janssen, and AbbVie.

© 2021. The Author(s).

Figures

Fig. 1

Most common adverse events by grade. A Any-grade treatment-emergent adverse events occurring in > 20% of all patients. B Grade 3/4 adverse events occurring in > 5% of all patients. Patient numbers are shown within the bars. aAEs of infection were bronchitis (n = 1), candida infection (n = 1), cellulitis (n = 1), fungal abscess central nervous system (n = 1, recovered), infection (not specified, n = 1), pneumonia (n = 2), sepsis (n = 1), staphylococcal bacteremia (n = 1), upper respiratory tract infection (n = 1), and urinary tract infection (n = 1)

Fig. 2

Investigator-assessed efficacy outcomes. A Overall response by TLS-risk group. B PFS by Kaplan–Meier estimates. Tick marks indicate patients with censored data. Abbreviations: CI, confidence interval; CR, complete response; CT, computed tomography; NE, not estimable; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TLS, tumor lysis syndrome.aTwo patients with a CR by CT scan are missing confirmatory bone marrow examinations and therefore are considered to have PR. bOne patient was not evaluable