Christian Buske, MD – Medical Director Comprehensive Cancer Center and Institute of Experimental Cancer Research of the University Hospital of Ulm discusses ASH 2020 abstract – 336 Five-Year Follow-Up of Ibrutinib Plus Rituximab Vs Placebo Plus Rituximab for Waldenstrom’s Macroglobulinemia: Final Analysis From the Randomized Phase 3 iNNOVATETM Study.
Context:
Ibrutinib is an inhibitor of Bruton tyrosine kinase approved once daily in the US and EU, either as a single agent therapy or in conjunction with rituximab (R) for the treatment of patients (pts) with Waldenström macroglobulinemia (WM) across all treatment lines. In the iNNOVATE (PCYC-1127; NCT02165397) phase 3 trial, ibrutinib demonstrated superior progression-free survival (PFS) in combination with R(IR) vs placebo plus R in WM pts after a median follow-up of 26.5 months in the primary review (Dimopoulos, N Engl J Med 2018). IR continued to demonstrate dominance over R in treatment-naive (TN) and previously treated WM pts after a 30.4 mo median follow-up, independent of genomic factors (Buske, ASH 2018). Here, we present findings from the final study of iNNOVATE’s randomized weapons.
Methodology:
Randomized to once-daily ibrutinib 420 mg or placebo plus R (375 mg/m2/week IV at weeks 1-4 and 17-20) were Pts with reported symptomatic WM needing treatment. Pts maybe TN or previously treated; pts had to have obtained at least a mild response (MR) to their last R-based regimen with prior R therapy. PFS and response rates per Independent Review Committee (IRC), overall survival (OS), change in hemoglobin (Hgb), time to next treatment (TTNT), and protection were included in the endpoints.
Outcomes:
Of the randomized 150 pts (75 per arm), the baseline features were well balanced between the arms. The median follow-up period was 50 mo (range between 0.5+ and 63). Median PFS with IR vs 20.3 mo (95 percent CI 13.0–27.6) with R (hazard ratio [HR] 0.25 [0.15–0.42]; P<0.0001) was not achieved (NR; 95 percent CI 57.7 mo to unestimated) with IR vs 20.3 mo (95 percent CI 13.0–27.6) with R (hazard ratio [HR] 0.25 [0.15–0.42]; P<00001) (Figure 1A). PFS values at the 54-mo landmark timepoint were 68 percent vs. 25 percent. Regardless of their prior care status (HR [95% CI]: TN, 0.32 [0.14–0.70]; previously treated, 0.22 [0.11–0.43]) or genotype (HR [95% CI]: MYD88L265P/CXCR4WT, 0.18 [0.08–0.43]; MYD88L265P/CXCR4WHIM, 0.27 [0.12–0.62]; MYD88WT/CXCR4WT, 0.29 [0.07–1.19]), Patients treated with IR also had a PFS benefit over those treated with R (Figure 1B). Across prespecified subgroups including baseline age, sex, serum immunoglobulin, Hgb, and IPSSWM, PFS advantage of IR over R was also observed. The main response rate (almost partial response) was 76% with IR vs. 31% with R (P<0.0001), and the total response rate (almost MR) was 92% vs. 44% (P<0.0001). High response rates were observed for IR irrespective of prior care (91% [31/34] for TN; 93% [38/41] for previous treatment) and for genotypes (94% [30/32] for MYD88L265P/CXCR4WT; 100% [26/26] for MYD88L265P/CXCR4WHIM; 82% [9/11] for MYD88WT/CXCR4WT). Hgb progress was sustained by a greater proportion of pts receiving IR vs R (77 percent vs 43 percent; P<0.0001). Median OS was NR in either treatment arm; the OS rate was 86 percent with IR at the 54 mo landmark timepoint vs 84 percent with R. After IRC-confirmed progressive disorder, 35 pts (47 percent) on R crossed over to single-agent ibrutinib. The median TTNT was NR with IR and 18 mo with R; at 54 mo, 87% of pts receiving IR, and 29% receiving R were not subsequently viewed. Treatment for the R arm was terminated; the median period of treatment was 16 months and safety findings were previously recorded (Buske, ASH 2018). The median period of treatment for IR was 48 mo. Overall, IR’s safety profile is consistent with previous reports; after 24 months of additional follow-up since the primary study, minor variations (1–4 percent) in common (about 10 percent) adverse event (AE) rates were observed. Atrial fibrillation (16 percent [4 percent]), hypertension (15 percent [1 percent]), neutropenia (13 percent [4 percent]), and anemia were the most common grade 3–4 AEs (percent in final analysis [difference from primary analysis]) (12 percent [1 percent ]). Of 12 pts with grade 4 atrial fibrillation, 9 (75 percent) stayed on treatment; no other discontinuations of ibrutinib occurred due to typical grade 4 AEs (about 10 percent). 68 pts (45 percent) remained on medication after the conclusion of the study (32 enrolled in a treatment extension study and 36 continued to receive ibrutinib in a non-trial setting).
Findings:
IR demonstrated continuing dominance across clinical results in pts for WM with up to 5 years of follow-up independent of genotype, previous treatment, and main pt characteristics. Answer trends with IR for both TN and previously treated pts were identical. IR retained a manageable safety profile, with no new safety signals detected and after an additional 24 months of follow-up, modest rises in common AEs.