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149 Ibrutinib Treatment in Waldenström’s Macroglobulinemia: Follow-up Efficacy and Safety from the iNNOVATETM Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Prognostic Markers and Therapies in Mantle Cell Lymphoma and Waldenstrom's Macroglobulinemia
Hematology Disease Topics & Pathways:
Diseases, Adult, Study Population, Lymphoid Malignancies
Saturday, December 1, 2018: 1:00 PM
Pacific Ballroom 20 (Marriott Marquis San Diego Marina)

Christian Buske, MD1, Alessandra Tedeschi, MD2*, Judith Trotman, FRACP3, Ramon Garcia-Sanz, MD, PhD4, David MacDonald, MD5, Véronique Leblond, MD, PhD6, Beatrice Mahe, MD7*, Charles Herbaux, MD8*, Constantine S. Tam, MBBS, MD, FRACP, FRCPA9, M. Lia Palomba, MD10, Jeffrey V Matous, MD11, Chaim Shustik, MD12, Eftathios Kastritis, MD13*, Steven P Treon, MD, PhD, FRCP14, Chih-Jian Lih, PhD15*, Jianling Li, MS15*, Zeena Salman, BS15*, Thorsten Graef, MD, PhD15* and Meletios A Dimopoulos, MD16

1Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm, Ulm, Germany
2ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
3Concord Hospital, University of Sydney, Concord, Australia
4Hospital Universitario de Salamanca, Salamanca, Spain
5The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
6Département d’ Hématologie Hôpital Pitié-Salpêtrière APHP, UPMC Université Paris, Paris, France
7Centre Hospitalier Universitaire de Nantes, Nantes, France
8Centre Hospitalier Régional Universitaire de Lille, Institute of Hematolog-Tranfusion, Lille, France
9Peter MacCallum Cancer Centre & St. Vincent's Hospital and the University of Melbourne, Melbourne, Australia
10Memorial Sloan Kettering Cancer Center, New York, NY
11Colorado Blood Cancer Institute, Denver, CO
12Royal Victoria Hospital at McGill University Health Centre, Montreal, QC, Canada
13National and Kapodistrian University of Athens School of Medicine, Athens, Greece
14Dana-Farber Cancer Institute, Boston, MA
15Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA
16Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

Background: Rituximab (RTX) is commonly used to treat Waldenström’s macroglobulinemia (WM). Treatment options are limited for patients (pts) who fail rituximab therapy. Single-agent ibrutinib (ibr) is highly active in WM and is approved in the United States and Europe for WM. In the phase 3 iNNOVATE study, ibr plus RTX resulted in significantly longer PFS and higher response rates vs RTX alone, both among TN and previously treated pts with WM (Dimopoulos MA, et al. N Engl J Med. 2018). Previous reports from the open-label, single-agent substudy showed sustained responses and a manageable toxicity profile in RTX-refractory WM, with a median follow-up of 18.1 mo (Dimopoulos MA, et al. Lancet Oncol. 2016). Follow-up data from both the randomized portion (median follow-up of 30.4 mo) and substudy (median follow-up of 38.7 mo) of iNNOVATE are presented.

Methods: Pts had confirmed, symptomatic WM requiring treatment. Pts in the randomized portion (Arms A and B) with prior RTX therapy required a response (≥MR) to their last RTX-based regimen. Pts were randomized to daily 420 mg ibr (Arm A; IR) or placebo (Arm B; R) plus RTX (375 mg/m2/week IV at weeks 1–4 and 17–20). In Arm C, pts who failed to achieve ≥MR or relapsed <12 mo of their last RTX-containing therapy received daily 420 mg ibr until PD/unacceptable toxicity. Endpoints included PFS, response rates, OS, hemoglobin (Hb) improvement, time to next treatment (TTnT), pt-reported outcomes (PROs) and safety.

Results: A total of 150 pts were randomized to Arms A and B (n=75/arm; Table 1). Median age was 69 y. High IPSSWM was reported in 38% of pts; 45% of pts were treatment naïve. With prolonged follow-up and a median duration of treatment of 29.5 mo with IR and 15.5 mo with R, investigator-assessed major response rates (≥PR) were 77% with IR vs 33% with R (P<0.0001); ORRs (≥MR) were 95% vs 48% (P<0.0001), respectively. With continued IR treatment, 27% of pts achieved a VGPR compared to only 3% in the R arm. Major responses with IR stayed robust independent of MYD88/CXCR genotype, with time to major response of 1.8, 2.9, and 5.7 mo for MYD88L265P/CXCR4WT, MYD88L265P/CXCR4WHIM, and MYD88WT/CXCR4WT, respectively. Median investigator-assessed PFS was not reached (NR) with IR vs 20.3 mo (95% CI: 11.6–31.3) with R (HR=0.219 [0.122–0.393]; P<0.0001); estimated 30-mo PFS was 79% vs 41%. Importantly, among pts receiving IR, 30-mo PFS estimates did not show any major differences among the different genotypes. The 30-mo OS estimate was 93% with IR vs 90% with R; 31 pts on R crossed over to IR after IRC-confirmed PD. Treatment with IR was ongoing in 73% of pts; the most common reasons for discontinuation of ibr were disease progression and pt withdrawal of consent (9% each); 35% of pts who received R were in response follow-up after the interim analysis. The AE profile in the IR arm was consistent with previous reports. Overall, grade ≥3 AEs occurred in 61% of pts in both arms. Incidence of grade ≥3 AEs was 53% during the first 12 months of treatment in the IR arm and increased 8% with longer follow up. Serious AEs occurred in 43% of IR pts vs 33% of R pts. Similarly, incidence of serious AEs was 39% during the first 12 months of treatment with IR and increased 4% with longer follow up.

In Arm C, 31 pts received single-agent ibr (Table 1). Median age was 67 y. Most (71%) pts had ≥3 prior therapies; all patients were RTX-refractory and 90% had prior treatment with cyclophosphamide. High IPSSWM was reported in 42% of pts. With longer follow-up, median investigator-assessed PFS was NR (95% CI: 27.6–NR); estimated 36-mo PFS was 61%. Major response rate by investigator assessment was 77% and ORR was 90%. The estimated 36-mo OS was 84%. Improved Hb level was seen in 71% of pts. Treatment was ongoing in 52% of pts. Median duration of ibr treatment was 37.0 mo, with no major hemorrhagic or atrial fibrillation events reported. Grade ≥3 AEs occurred in 74% of pts and 39% had serious AEs. No fatal AEs were reported.

Conclusions: IR showed continued superiority over R, in treatment-naïve and previously treated pts with WM, regardless of genotypic factors. Similarly, in heavily pretreated, RTX-refractory pts with follow-up >3 y, single-agent ibr was highly active and response improved over time. Alone or in combination, ibr had a manageable safety profile and no new safety signals were identified with longer follow-up.

Disclosures: Buske: Pfizer: Honoraria; Bayer: Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding. Tedeschi: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Trotman: Beigene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; PCYC: Research Funding; Roche: Research Funding; Jassen: Research Funding. Garcia-Sanz: Spanish Government: Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy, Honoraria; Hospira: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. MacDonald: Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Seattle Genetics: Honoraria. Leblond: Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sandoz: Honoraria; Gilead: Honoraria, Speakers Bureau. Herbaux: Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Tam: Beigene: Honoraria, Other: Travel funding; Roche: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Janssen: Honoraria, Research Funding. Palomba: Seres: Honoraria, Patents & Royalties; Juno: Honoraria, Patents & Royalties; Merck: Consultancy; Pharmacyclics: Consultancy; Therakos: Consultancy. Matous: Celgene: Consultancy, Honoraria, Speakers Bureau. Shustik: Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Kastritis: Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Genesis Pharma: Consultancy; Prothena: Consultancy. Treon: Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Lih: Abbvie: Employment, Equity Ownership; Abbvie/Pharmacyclics: Other: Travel, Accommodations, Expenses. Li: Pharmacyclics: Employment; Abbvie: Equity Ownership; BMS: Equity Ownership; Pfizer: Equity Ownership; Abbott: Equity Ownership; Amgen: Equity Ownership; Gilead: Equity Ownership; Biogen: Equity Ownership; Celgene: Equity Ownership; Medivation: Equity Ownership; Merck: Equity Ownership; Exelixis: Equity Ownership; Juno: Equity Ownership; Isis: Equity Ownership; Aduro: Equity Ownership; Merrimack: Equity Ownership. Salman: Pharmacyclics LLC: Employment, Equity Ownership; Abbvie: Equity Ownership. Graef: Abbvie: Equity Ownership, Patents & Royalties; Pharmacyclics: Employment, Other: Leadership, Patents & Royalties. Dimopoulos: Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

*signifies non-member of ASH