Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

William G Wierda, John N Allan, Tanya Siddiqi, Thomas J Kipps, Stephen Opat, Alessandra Tedeschi, Xavier C Badoux, Bryone J Kuss, Sharon Jackson, Carol Moreno, Ryan Jacobs, John M Pagel, Ian Flinn, Yvonne Pak, Cathy Zhou, Edith Szafer-Glusman, Joi Ninomoto, James P Dean, Danelle F James, Paolo Ghia, Constantine S Tam, William G Wierda, John N Allan, Tanya Siddiqi, Thomas J Kipps, Stephen Opat, Alessandra Tedeschi, Xavier C Badoux, Bryone J Kuss, Sharon Jackson, Carol Moreno, Ryan Jacobs, John M Pagel, Ian Flinn, Yvonne Pak, Cathy Zhou, Edith Szafer-Glusman, Joi Ninomoto, James P Dean, Danelle F James, Paolo Ghia, Constantine S Tam

Abstract

Purpose: CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL).

Methods: Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety.

Results: One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time.

Conclusion: The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

Conflict of interest statement

William G. WierdaConsulting or Advisory Role: SanofiResearch Funding: GlaxoSmithKline/Novartis, AbbVie, Genentech, Pharmacyclics, Acerta Pharma, Gilead Sciences, Janssen, Juno Therapeutics, Kite, a Gilead Company, Oncternal Therapeutics, Loxo, Xencor, miRagen, Sunesis Pharmaceuticals, Cyclacel John N. AllanHonoraria: AstraZeneca, AbbVie, Pharmacyclics/Janssen, BeiGeneConsulting/Advisory Role: AbbVie/Genentech, Pharmacyclics, Ascentage Pharma, BeiGene, Janssen Oncology, Epizyme, AstraZeneca, TG Therapeutics, ADC TherapeuticsResearch Funding: Genentech, Janssen, Celgene, TG Therapeutics Tanya SiddiqiConsulting/Advisory Role: Juno Therapeutics, AstraZeneca, BeiGene, Celgene, Pharmacyclics, Bristol Myers Squibb/Celgene, Pharmacyclics/JanssenSpeakers Bureau: Pharmacyclics/Janssen, AstraZeneca, BeiGene, Bristol Myers Squibb/CelgeneResearch Funding: Juno Therapeutics (Inst), Kite, a Gilead Company (Inst), Acerta Pharma (Inst), TG Therapeutics (Inst), BeiGene (Inst), Pharmacyclics (Inst), Celgene (Inst), Oncternal Therapeutics (Inst) Thomas J. KippsEmployment: Moores Cancer CenterStock and Other Ownership Interests: Oncternal TherapeuticsHonoraria: Pharmacyclics, AbbVie, Janssen, Genentech, Gilead Sciences, DAVAOncology, AstraZenecaConsulting/Advisory Role: AbbVie, Pharmacyclics, Genentech, Janssen, DAVAOncologySpeakers Bureau: Verastem/Pharmacyclics, Pharmacyclics/Janssen, AbbVie/Genentech, Gilead Sciences, DAVA PharmaceuticalsResearch Funding: Pharmacyclics/Janssen (Inst), Breast Cancer Research Foundation (Inst), Oncternal Therapeutics (Inst), Leukemia and Lymphoma Society (Inst), California Institute for Regenerative Medicine (CIRM) (Inst), National Cancer Institute (Inst), NIH (Inst)Patents, Royalties, Other Intellectual Property: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc, which provided stock options and research funding to the Thomas J. Kipps laboratory. (Inst)Travel, Accommodations, Expenses: AbbVie/Pharmacyclics, Genentech/Roche, Janssen, Gilead Sciences, Celgene, DAVAOncology, Breast Cancer Research Foundation, TG Therapeutics, Verastem, AstraZeneca Stephen OpatHonoraria: AbbVie, AstraZeneca, Janssen, Roche, Gilead Sciences, Mundipharma, Takeda, Merck, and CSL BehringConsulting/Advisory Role: AbbVie, AstraZeneca, Janssen, Celgene, Novartis, Gilead Sciences, Takeda, Merck, Mundipharma, CSL BehringResearch Funding: AstraZeneca (Inst), BeiGene (Inst), Roche (Inst), AbbVie (Inst), Gilead Sciences (Inst), Takeda (Inst), Pharmacyclics (Inst), Janssen (Inst), Celgene (Inst), Merck (Inst), Epizyme (Inst)Travel, Accommodations, Expenses: Roche Alessandra TedeschiConsulting/Advisory Role: Janssen, BeiGene, AstraZeneca, AbbVieSpeakers Bureau: AbbVie, AstraZeneca, Janssen, BeiGene Xavier C. BadouxHonoraria: Janssen/Pharmacyclics, AbbVie Bryone J. KussStock and Other Ownership Interests: Commonwealth Serum Laboratories (CSL)Honoraria: Roche, Janssen Oncology, AstraZeneca, AbbVie, Merck, Mundipharma, Takeda, SandozConsulting/Advisory Role: AbbVie, Janssen Oncology, Kyowa Kirin International, AstraZenecaSpeakers Bureau: AstraZeneca, Janssen-Ortho Sharon JacksonHonoraria: AbbVie NZ LtdConsulting/Advisory Role: AbbVie NZSpeakers Bureau: AbbVie NZTravel, Accommodations, Expenses: Roche NZ Carol MorenoConsulting/Advisory Role: Janssen Oncology, Abbott/AbbVie, AstraZeneca, BieGeneSpeakers Bureau: Janssen OncologyResearch Funding: AbbVie Ryan JacobsConsulting/Advisory Role: AstraZeneca, Janssen Oncology, Secura Bio, Genentech, Adaptive Biotechnologies, ADC Therapeutics, TG TherapeuticsSpeakers Bureau: Pharmacyclics, Janssen Oncology, AbbVie, TG Therapeutics, AstraZenecaResearch Funding: TeneoBio (Inst), Pharmacyclics (Inst), TG Therapeutics (Inst), MEI Pharma (Inst) John M. PagelConsulting/Advisory Role: Gilead Sciences, AstraZeneca, Actinium Pharmaceuticals, BeiGene, Loxo, MEI Pharma, TG Therapeutics, MorphoSys, Epizyme Ian FlinnConsulting/advisory role: AbbVie (Inst), Seattle Genetics (Inst), TG Therapeutics (Inst), Verastem (Inst), Roche (Inst), Gilead Sciences (Inst), Kite, a Gilead Company (Inst), Janssen (Inst), BeiGene (Inst), Takeda (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Nurix (Inst), Shanghai Yingli Pharmaceuticals (Inst), Genentech (Inst), Great Point Partners (Inst), Iksuda Therapeutics (Inst), Novartis (Inst), Pharmacyclics (Inst), Century Therapeutics (Inst), Hutchison MediPharma (Inst), Servier (Inst), Vincerx (Inst)Research Funding: Acerta Pharma (Inst), Agios (Inst), Calithera Biosciences (Inst), Celgene (Inst), Constellation Pharmaceuticals (Inst), Genentech (Inst), Gilead Sciences (Inst), Incyte (Inst), Infinity Pharmaceuticals (Inst), Janssen (Inst), Karyopharm Therapeutics (Inst), Kite, a Gilead Company (Inst), Novartis (Inst), Pharmacyclics (Inst), Portola Pharmaceuticals (Inst), Roche (Inst), TG Therapeutics (Inst), Trillium Therapeutics (Inst), AbbVie (Inst), ArQule (Inst), BeiGene (Inst), Curis (Inst), Forma Therapeutics (Inst), Forty Seven (Inst), Merck (Inst), Pfizer (Inst), Takeda (Inst), Teva (Inst), Verastem (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Seattle Genetics (Inst), IGM Biosciences (Inst), Loxo (Inst), Rhizen Pharmaceuticals (Inst), Triact Therapeutics (Inst) Yvonne PakEmployment: BridgeBio Pharma, AbbVieStock and Other Ownership Interests: BridgeBio Pharma, AbbVie Cathy ZhouEmployment: Abbvie/PharmacyclicsStock and Other Ownership Interests: Abbvie/Pharmacyclics Edith Szafer-GlusmanStock and Other Ownership Interests: AbbVie Joi NinomotoEmployment: AbbVieStock and Other Ownership Interests: AbbVie James P. DeanEmployment: PharmacyclicsStock and Other Ownership Interests: AbbVie Danelle F. JamesEmployment: Abbvie/PharmacyclicsLeadership: Abbvie/PharmacyclicsStock and Other Ownership Interests: AbbVie/PharmacyclicsPatents, Royalties, Other Intellectual Property: AbbVie/PharmacyclicsTravel, Accommodations, Expenses: Abbvie/Pharmacyclics Paolo GhiaHonoraria: AbbVie, BeiGene, Janssen Oncology, Gilead Sciences, Juno Therapeutics, Sunesis Pharmaceuticals, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, Juno/Celgene/Bristol Myers Squibb, MSD, Lilly, RocheConsulting/Advisory Role: AbbVie, BieGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, MSD, Lilly, RocheResearch Funding: AbbVie, Janssen Oncology, Gilead Sciences, Sunesis Pharmaceuticals, Novartis, AstraZeneca Constantine S. TamHonoraria: Janssen-Cilag, AbbVie, Novartis, BeiGene, PharmacyclicsConsulting/Advisory Role: Janssen, Loxo, Roche, BeiGene, AbbVieResearch Funding: Janssen-Cilag, AbbVieNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Patient flow and disposition. AEs, adverse events; MRD, minimal residual disease; PD, progressive disease; uMRD, undetectable minimal residual disease.
FIG 2.
FIG 2.
MRD response during the prerandomization phase. (A) MRD levels serially over time in PB and best MRD response in PB and BM. (B) Forest plot of undetectable MRD in BM across patient subgroups by baseline characteristics. (C) Best MRD response of the prerandomization phase in all-treated patients and according to Confirmed uMRD status in patients eligible for random assignment. aBM MRD assessment was scheduled after completion of 12 cycles of combination treatment (cycle 16). bPer Dohner hierarchy. cPatients without available samples (PB, n = 1; BM, n = 8) were counted as having detectable MRD. BM, bone marrow; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy variable; MRD, minimal residual disease; PB, peripheral blood; uMRD, undetectable minimal residual disease.
FIG 3.
FIG 3.
Impact of single-agent ibrutinib lead-in on TLS risk category. Shown are TLS risk categories at baseline and after ibrutinib lead-in in the prerandomization phase. TLS, tumor lysis syndrome.
FIG 4.
FIG 4.
Disease-free survival. Kaplan-Meier estimates of DFS by randomized treatment arm in the Confirmed uMRD population. Tick marks indicate patients with censored data. Patients who did not experience a DFS event were censored by the last MRD sample date with a valid result or the date of last adequate disease assessment after random assignment, whichever occurred earlier. aThe three DFS events in the placebo arm were disease progression in two patients and MRD relapse in one patient; of the two patients with disease progression, after primary analysis one was confirmed to have partial response (not progression), for a total of two DFS events. bAt 12 cycles after random assignment. DFS, disease-free survival; MRD, minimal residual disease; uMRD, undetectable minimal residual disease.
FIG 5.
FIG 5.
Rates over time of AEs of clinical interest. (A) Prevalence of AEs of clinical interest over time by randomized treatment arm for any-grade AEs and (B) grade ≥ 3 AEs. aAt postrandomization 7-12 months, Confirmed uMRD population: placebo (n = 42), ibrutinib (n = 42); uMRD Not Confirmed population: ibrutinib (n = 30), ibrutinib plus venetoclax (n = 29). bGrade 3 menorrhagia in one patient. cGrade 3 retroperitoneal hemorrhage in one patient. AEs, adverse events; uMRD, undetectable minimal residual disease.
FIG 6.
FIG 6.
Best overall uMRD rates by randomized treatment arm in the uMRD Not Confirmed population. BM, bone marrow; PB, peripheral blood; uMRD, undetectable minimal residual disease.

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Source: PubMed

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