Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study

Abstract

Background: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate used for adults with relapsed/refractory B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy (INO-VATE) previously reported improved outcomes with InO versus standard-of-care (SoC) chemotherapy. This article reports the final INO-VATE results (≥2 years of follow-up) and additional analyses of patient characteristics associated with improved outcomes.

Methods: Between August 27, 2012, and January 4, 2015, this multicenter, parallel, open-label, phase 3 trial randomized 326 adults with relapsed/refractory ALL to InO (n = 164) or SoC (n = 162); 307 received 1 or more doses of the study drug (164 in the InO arm and 143 in the SoC arm).

Results: The complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate was higher with InO versus SoC (73.8% vs 30.9%; 1-sided P < .0001), with consistent CR/CRi rates across patient subgroups. The median overall survival (OS) was 7.7 months with InO and 6.2 months with SoC, with 2-year OS rates of 22.8% and 10.0%, respectively (overall hazard ratio, 0.75; 97.5% confidence interval [CI], 0.57-0.99; 1-sided P = .0105). The predictors of OS with InO were the best minimal residual disease status, baseline platelet count, duration of first remission, achievement of CR/CRi, and follow-up hematopoietic stem cell transplantation (HSCT; all 2-sided P values < .05). More InO arm patients proceeded directly to HSCT after achieving CR/CRi before any follow-up induction therapy (39.6% [95% CI, 32.1%-47.6%] vs 10.5% [6.2%-16.3%]; 1-sided P < .0001). The most frequent all-grade and grade 3 or higher adverse events in both arms were hematologic. Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) was more frequent with InO (23 of 164 [14.0%] vs 3 of 143 [2.1%]).

Conclusions: In patients with relapsed/refractory BCP ALL in INO-VATE, InO was associated with a greater likelihood of CR/CRi across key patient subgroups, and it served as a bridge to HSCT. Potential VOD/SOS risk factors must be considered when InO treatment decisions are being made.

Trial registration: ClinicalTrials.gov NCT01564784.

Keywords: acute lymphoblastic leukemia; adults; hematopoietic stem cell transplantation; hepatic veno-occlusive disease; inotuzumab ozogamicin; remission induction.

Figure 1

Trial profile. Completing the study was defined as completing follow‐up for 5 years from the individual patient’s randomization or for 2 years from randomization of the last patient (January 4, 2015), whichever occurred first. On the date of the last visit by the last patient to be randomized (January 4, 2017), all patients discontinued the study. In the InO arm, patients received InO intravenously at 1.8 mg/m² per cycle, 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15 of a 21‐ to 28‐day cycle, for a maximum of 6 cycles. Patients who achieved CR/CRi had their InO dose adjusted to 1.5 mg/m² per cycle, with 0.5 mg/m² administered on days 1, 8, and 15. Patients in the standard‐of‐care arm received a regimen of the investigator’s choice: 1) FLAG for up to four 28‐day cycles, which consisted of cytarabine at 2.0 g/m²/d on days 1 to 6, fludarabine at 30 mg/m²/d on days 2 to 6, and granulocyte colony‐stimulating factor at 5 μg/kg/d (or at the standard dose of the institute); 2) MXN/Ara‐C for up to four 15‐ to 20‐day cycles, which consisted of cytarabine at 200 mg/m²/d on days 1 to 7 and mitoxantrone at 12 mg/m²/d on days 1 to 3 (with dose reductions to 8 mg/m² allowed on the basis of age, coexisting conditions, and previous anthracycline exposure); or 3) HIDAC for up to two 12‐dose cycles at 3.0 g/m² every 12 hours (the dose could be reduced up to 1.5 g/m² for patients aged 55 years or older and was reduced to 1.5 g/m² for patients older than 60 years). CR indicates complete remission; CRi, complete remission with incomplete hematologic recovery; FLAG, fludarabine, cytarabine, and granulocyte colony‐stimulating factor; HIDAC, high‐dose cytarabine; InO, inotuzumab ozogamicin; ITT, intent‐to‐treat; mITT, modified intent‐to‐treat; MXN/Ara‐C, mitoxantrone and cytarabine.

Figure 2

Stratified comparison of CR/CRi rates. Stratification factors (duration of first remission, salvage status, and age at randomization) were based on information provided for the interactive voice response system at randomization. †One‐sided P values. BMA indicates bone marrow aspirate; CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; InO, inotuzumab ozogamicin; NA, not applicable; Ph–, Philadelphia chromosome–negative; Ph+, Philadelphia chromosome–positive; SoC, standard of care (intensive chemotherapy).

Figure 3

PFS. For INO‐VATE, PFS was defined as the time from randomization to the earliest of the following: disease progression (including objective progression, relapse after CR/CRi, or treatment discontinuation due to a global deterioration of health status), the start of new induction therapy or post‐therapy HSCT without the achievement of CR/CRi, or death from any cause. It was censored at the last valid disease assessment. †One‐sided log‐rank test. CI indicates confidence interval; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; InO, inotuzumab ozogamicin; INO‐VATE, INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy; PFS, progression‐free survival; SoC, standard of care (intensive chemotherapy).

Figure 4

OS. For 2‐ and 3‐year survival, the 1‐sided P value was based on the chi‐square test or the Fisher exact test (if any cell count was <5). †One‐sided log‐rank test. CI indicates confidence interval; HR, hazard ratio; InO, inotuzumab ozogamicin; OS, overall survival; SoC, standard of care (intensive chemotherapy).

Figure 5

OS according to subgroups. BMA indicates bone marrow aspirate; CI, confidence interval; InO, inotuzumab ozogamicin; OS, overall survival; Ph–, Philadelphia chromosome–negative; Ph+, Philadelphia chromosome–positive; SoC, standard of care (intensive chemotherapy).

Figure 6

OS censored at the time of blinatumomab, a tyrosine kinase inhibitor, chimeric antigen receptor T‐cell therapy, or InO. †One‐sided log‐rank test. CI indicates confidence interval; HR, hazard ratio; InO, inotuzumab ozogamicin; OS, overall survival; SoC, standard of care (intensive chemotherapy).

Figure 7

OS of InO‐treated patients who achieved CR/CRi according to follow‐up HSCT. The graph shows the time from randomization to the date of death due to any cause. Patients whose date of death could not be verified were censored at the date of last contact. †One‐sided log‐rank test. CI indicates confidence interval; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; InO, inotuzumab ozogamicin; OS, overall survival.

Figure 8

OS censored at the date of any HSCT. Patients were censored at the time of any HSCT, regardless of whether they were in continuous first complete remission. CI indicates confidence interval; HSCT, hematopoietic stem cell transplantation; InO, inotuzumab ozogamicin; OS, overall survival; SoC, standard of care (intensive chemotherapy).