Ibrutinib Plus Venetoclax in Patients With Relapsed/Refractory Mantle Cell Lymphoma: Results From the Safety Run-In Period of the Phase 3 Sympatico Study

Autor: Frederic Peyrade, Geoffrey Chong, Michael Wang, Lionel Karlin, Jutta K. Neuenburg, Ka Lung Wu, Mark Bishton, Wojciech Jurczak, Robert T. Chen, Edith Szafer-Glusman, Paul Eliadis, Constantine S. Tam, Graham P. Collins, Yihua Lee, Radhakrishnan Ramchandren, Karl Eckert
Rok vydání: 2020
Předmět:
Zdroj: Blood. 136:39-41
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2020-134392
Popis: Background : Ibrutinib (ibr) is a once-daily Bruton's tyrosine kinase (BTK) inhibitor approved in the US for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (ven) is a BCL-2 inhibitor approved for pts with CLL or previously untreated AML. Ibr + ven have shown synergistic antitumor activity in preclinical models and complementary clinical activity in early phase studies (Zhao Br J Haematol 2015; Tam NEJM 2018; Jain NEJM 2019). The ongoing phase 3 SYMPATICO study (PCYC-1143-CA, NCT03112174) evaluates the safety and efficacy of ibr + ven in pts with relapsed/refractory (R/R) MCL. A safety run-in (SRI) was conducted to inform whether a 1-month (mo) ibr lead-in would be implemented for the randomized portion of the study; initial data from the SRI evaluating tumor lysis syndrome (TLS) events and dose-limiting toxicities (DLTs) concluded that the study would proceed with concurrent ibr + ven, with no ibr lead-in (Wang ICML 2019). Updated safety and efficacy from the SRI are presented. Methods : The phase 3 SYMPATICO study is comprised of an open-label SRI and a double-blind randomized period. Key eligibility criteria were pathologically confirmed MCL with measurable disease, 1-5 prior therapies, and no prior treatment with BTK or BCL inhibitors. In the SRI, pts received oral, once-daily 560 mg ibr + ven in a 5-week ramp-up to 400 mg ven. Ibr + ven are dosed concurrently for 2 years; thereafter, ven is discontinued in all pts and ibr is continued until progressive disease (PD) or unacceptable toxicity. The primary endpoint of the SRI was occurrence of TLS events and DLTs. Secondary endpoints included complete response (CR) and partial response (PR) per the 2014 Lugano criteria, progression-free survival (PFS), and duration of response (DOR). Rates of undetectable minimal residual disease (MRD) were assessed in bone marrow and peripheral blood. Efficacy and safety were analyzed by TLS risk (low or high). TP53 mutational status was determined by next-generation sequencing. Results: Twenty-one pts were enrolled in the SRI, with a median time on study of 22 (range, 2-31) mo. The median age was 68 (range, 53-84) years, and the median number of prior therapies was 2 (range, 1-4); 6 pts were considered at low risk for TLS and 15 pts were considered at high risk for TLS. All pts had at least 1 lesion >2 cm at baseline; 11/21 (52%) had baseline detectable MRD in peripheral blood or bone marrow. Of the 11 pts with available TP53 mutation data, 4 (36%) had mutated TP53. Median time on treatment was 18 (range, Conclusions : Ibr + ven is an all-oral, once-daily, chemotherapy-free regimen being studied for treatment of pts with R/R MCL. With a median of 22 mo on study, no new safety signals were observed; TLS events and DLTs were rare. Ibr + ven had sustained efficacy, with an ORR of 81%, CR rate of 62%, and the median PFS not reached. All MRD-assessable pts achieved undetectable MRD. The ongoing randomized portion of the SYMPATICO study is evaluating the efficacy and safety of ibr + ven compared with ibr + placebo in pts with R/R MCL; additionally, a single-arm, open-label cohort in previously untreated pts, including pts with TP53 mutations, is ongoing. Disclosures Tam: AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria. Ramchandren:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Research Funding. Chen:Autolus Therapeutics: Current Employment. Karlin:Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Other: Personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Chong:Hutchison Medipharma: Research Funding; Bayer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Servier: Research Funding; Isofol: Research Funding; Merck Serono: Research Funding; Bristol-Myers Squibb: Research Funding. Jurczak:AstraZeneca, Epizyme: Consultancy; BeiGene: Consultancy, Research Funding; Sandoz Novartis: Consultancy; Janssen: Consultancy, Research Funding; Acerta: Consultancy; Loxo: Consultancy; TG Therapeutics, Acerta, Bayer, MeiPharma: Research Funding; Merck: Research Funding; Pharmacyclics LLC, an AbbVie Company,: Research Funding; Roche: Research Funding; Takeda: Research Funding. Bishton:AbbVie: Research Funding; Gilead: Other: Travel/accomodations/expenses, Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding; Takeda: Other: Travel/accommodations/expenses, Research Funding; Janssen: Consultancy. Collins:Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Amgen: Research Funding; Celgene: Research Funding; MSD: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; BeiGene: Consultancy. Szafer-Glusman:Pharmacyclics LLC, an AbbVie Company: Current Employment. Lee:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Neuenburg:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Wang:Targeted Oncology: Honoraria; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Acerta Pharma: Research Funding; Verastem: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Molecular Templates: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; MoreHealth: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; VelosBio: Research Funding; BioInvent: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication
Databáze: OpenAIRE
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