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Clinical Trial
. 2020 Nov 24;4(22):5773-5784.
doi: 10.1182/bloodadvances.2020003121.

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

Ariela Noy  1   2 , Sven de Vos  3 , Morton Coleman  2 , Peter Martin  2 , Christopher R Flowers  4 , Catherine Thieblemont  5 , Franck Morschhauser  6 , Graham P Collins  7 , Shuo Ma  8 , Shachar Peles  9 , Stephen D Smith  10 , Jacqueline C Barrientos  11 , Elizabeth Chong  12 , Shiquan Wu  12 , Leo W-K Cheung  12 , Kevin Kwei  12 , Bernhard Hauns  12 , Israel Arango-Hisijara  12 , Robert Chen  13
Affiliations
Clinical Trial

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

Ariela Noy et al. Blood Adv. .

Abstract

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

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Conflict of interest statement

Conflict-of-interest disclosure: A.N. reports employment with Memorial Sloan Kettering Cancer Center; has received honoraria from Janssen, Medscape, Prime Oncology, and Pharmacyclics LLC, an AbbVie Company; has a consulting role with MorphoSys and Janssen; has received research funding from Rafael and Pharmacyclics LLC, an AbbVie Company; reports patent pending at Rafael; and has received travel expenses from Janssen and Pharmacyclics LLC, an AbbVie Company. S.d.V. has a consulting role with Bayer and Verastem. M.C. has stock ownership in Immunomedics; a consulting role with Pharmacyclics LLC, an AbbVie Company; has received research funding from AbbVie, Celgene, Genentech, BeiGene, and Pharmacyclics LLC, an AbbVie Company; and has received speaker fees from Celgene, Janssen, and Gilead. P.M. has consulting roles with AstraZeneca, Bayer, BeiGene, Cellectar, Celgene, I-MAB, Janssen, Karyopharm, Kite, MorphoSys, Sandoz, and TeneoBio; has received research funding from Karyopharm; and has received travel expenses from Janssen, MorphoSys and Bayer. C.R.F. has consulting roles with AbbVie, Spectrum, Celgene, Denovo Biopharma, OptumRx, Karyopharm, Pharmacyclics LLC, an AbbVie Company, Janssen, Gilead, and Bayer; has received research funding from AbbVie, Acerta, Celgene, Gilead, Genentech/Roche, Janssen, Millennium/Takeda, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics; and has received travel expenses from Genentech/Roche. C.T. has received honoraria from Gilead and Novartis; has consulting roles with Roche, Janssen, Celgene, Gilead, Kite, Novartis, Bayer, and Cellectis; has received research funding from Roche and Hospira; and has received travel expenses from Novartis, Roche, Janssen, Celgene, Novartis, and Cellectis. F.M. has received honoraria from Celgene, Roche, Bristol-Myers Squibb, and Gilead; and has consulting roles with Celgene, Roche, Epizyme, Gilead, and Bayer. G.P.C. has received honoraria from Takeda, Roche, Gilead, Bristol Myers Squibb, Merck, Celleron, ADC Therapeutics, Novartis, and Pfizer; has consulting roles with Takeda, Roche, Gilead, Bristol Myers Squibb, Merck, Celleron, and ADC Therapeutics; has received research funding from Bristol Myers Squibb, Celleron, Merck, Amgen, and Celgene; has received speaker fees from Takeda, Roche, Gilead, Novartis, and Bristol Myers Squibb; and has received travel expenses from Takeda and Roche; and has received support from NIHR Oxford Biomedical Research Centre. S.M. has consulting roles with AbbVie, AstraZeneca, Bioverativ, Genentech, Gilead, Janssen, Kite, Verastem, and Pharmacyclics LLC, an AbbVie Company; has received research funding from AbbVie, AstraZeneca, BeiGene, Janssen, Juno, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; and has received speaker fees from AstraZeneca, BeiGene, Janssen, and Pharmacyclics LLC, an AbbVie Company. S.P. has received research funding from AbbVie, Acerta Pharma, Amgen, BeiGene, Bristol Myers Squibb, Celgene, CTI Biopharma, Epizyme, Genentech, Gilead, GlaxoSmithKline, Janssen, Karyopharm, Merck, Rhizen, Seattle Genetics, TG Therapeutics, Verastem, and Pharmacyclics, an AbbVie Company; and has received speaker fees and travel expenses from Takeda, Celgene, and Johnson & Johnson. S.D.S. has consulting roles with AstraZeneca, Millennium/Takeda, and BeiGene; has received research funding from Acerta Pharma BV, AstraZeneca, Bayer, BeiGene, Denovo Biopharma, Genentech, Incyte Corporation, Merck, Portola Pharmaceuticals, Seattle Genetics, and Pharmacyclics LLC, an AbbVie Company; and reports spouse research funding from Ayala, Bristol Myers Squibb, and Ignyta. J.C.B. has received honoraria from Janssen; has consulting roles with Genentech, Gilead, Bayer, AstraZeneca, and Sandoz; and has received research funding from Oncternal Therapeutics. E.C. reports employment with Pharmacyclics LLC, an AbbVie Company, and stock ownership in AbbVie. S.W. reports employment, patents, royalties, and intellectual property with Pharmacyclics LLC, an AbbVie Company, and stock ownership in AbbVie. L.W.-K.C. reports employment, patents, royalties, and intellectual property with Pharmacyclics LLC, an AbbVie Company, and stock ownership in AbbVie and Eli Lilly. K.K. reports employment with Pharmacyclics LLC, an AbbVie Company, and stock ownership in AbbVie and Gilead. B.H. reports employment with Pharmacyclics LLC, an AbbVie Company, and stock ownership in AbbVie. I.A.-H. reports employment with Pharmacyclics LLC, an AbbVie Company, and stock ownership in AbbVie and Bristol Meyers Squibb. R.C. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
ORR and reduction in lymph node SPD with single-agent ibrutinib treatment. (A) Response rates for total efficacy population and by prior line of therapy. (B) Best response over time in the total efficacy population (n = 60). (C) Change in tumor size by prior line of therapy in the ITT population. *Patients in the “Other” category had prior treatment with both single-agent RTX and chemotherapy or investigational therapies. †Four patients who discontinued before the first response assessment were excluded. PD, progression of disease; SD, stable disease.
Figure 2.
Figure 2.
PFS and OS with single-agent ibrutinib treatment. (A) PFS in the total efficacy population and by prior line of therapy. (B) OS in the total efficacy population and by prior line of therapy.
Figure 3.
Figure 3.
Most common AEs. (A) Prevalence of most common TEAEs* of any grade over time† in the total safety population. (B) Most common TEAEs* in the total safety population and by prior line of therapy. URTI, upper respiratory tract infection. *Occurring in ≥20% of patients overall in the total safety population. †Prevalences of TEAEs beyond 3 years have been excluded because of small sample size (n = 7).
Figure 4.
Figure 4.
Gene-level mutational analyses correlate to clinical outcomes. Mutations in A20 (A) and MYD88 (B) correlate to favorable prognosis. Mutations in KMT2D (C) and CARD11 (D) correlate to poor prognosis. BOR, best overall response; mDOR, median DOR; mPFS, median PFS; NED, no evidence of disease.
Figure 5.
Figure 5.
Extranodal subgroup and gene variant analyses. (A) Gene-level analysis for A20 in patients with extranodal MZL. (B) Analysis of the MYD88 L265P variant for all MZL subtypes combined. (C) Gene-level analysis for KMT2D in patients with extranodal MZL. (D) Gene-level analysis for CARD11 in patients with extranodal MZL.
See this image and copyright information in PMC

Comment in

  • Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.
    Epperla N, Zhao Q, Chowdhury SM, Shea L, Moyo TK, Reddy N, Sheets J, Weiner DM, Geethakumari PR, Kandarpa M, Bruno XJ, Thomas C, Churnetski MC, Hsu A, Zurbriggen L, Tan C, Lindsey K, Maakaron J, Caimi PF, Torka P, Bello C, Ayyappan S, Karmali R, Kim SH, Kress A, Kothari S, Sawalha Y, Christian B, David KA, Greenwell IB, Janakiram M, Kenkre VP, Olszewski AJ, Cohen JB, Palmisiano N, Umyarova E, Wilcox RA, Awan FT, Alderuccio JP, Barta SK, Grover NS, Ghosh N, Bartlett NL, Herrera AF, Shouse G. Epperla N, et al. J Hematol Oncol. 2022 Jul 16;15(1):96. doi: 10.1186/s13045-022-01316-1. J Hematol Oncol. 2022. PMID: 35842643 Free PMC article.

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