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

Abstract

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: Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: 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. García-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: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria.

CXCR4 S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia

“…Moreover, the iNNOVATE study recently evaluated the combination of ibrutinib and rituximab, and updated results demonstrate shorter 36-month PFS among CXCR4 MUT vs CXCR4 WT WM patients (64% vs 84%). 15,21 Preliminary data suggest that the second-generation BTK inhibitor zanubrutinib has some activity in MYD88 WT WM patients, but the impact of CXCR4 mutations is currently unknown. 22 The present study is not without limitations.…”

CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib

“…The recently published INNOVATE study showed lower rates of VGPR (34% vs. 19%, respectively) but similar 30‐month PFS rates (80% vs. 86%, respectively) in CXCR4 ‐mutated versus CXCR4 WT WM patients exposed to the combination of ibrutinib and rituximab (Dimopoulos et al , ). However, at the 36‐month update presented at the 2018 American Society of Hematology Annual Meeting, the PFS rate was lower in CXCR4 mutated than in CXCR4 WT patients (64% vs. 84%, respectively) (Buske et al , ). This finding suggests that CXCR4 mutations can also adversely impact response and PFS rates of WM patients treated with ibrutinib and rituximab.…”

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

“…The median treatment duration for placebo-rituximab was 16 (range, 0.4-37) months; safety data for that arm were previously reported. 2,13 Ibrutinib-rituximab was tolerable regardless of common concomitant medications, including acid-reducing agents (49%), antiplatelet agents (41%), anticoagulants (24%), and antihypertensives (40%) (Data Supplement [Table S3]).…”