Background

CD22 is expressed in most (>90%) cases of B-cell acute lymphoblastic leukemia (ALL) and is an attractive target for the treatment of B-cell malignancies. Inotuzumab ozogamicin (InO), a humanized anti-CD22 antibody conjugated to calicheamicin, has demonstrated significantly superior response vs standard care (SC) in the first 218 randomized patients with relapsed/refractory (R/R) ALL in the phase 3 INO-VATE trial.

Aims

To assess overall survival (OS) and progression free survival (PFS) of adults with R/R ALL receiving InO vs SC.

Methods

In this ongoing global, 2-arm, randomized phase 3 trial (NCT01564784), patients with R/R ALL (including ~15% of patients in each arm with Philadelphia-positive ALL) due to receive salvage (S) 1 or 2 therapy were randomized to InO (starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15 of a 21–28 day cycle (≤6 cycles)]) or SC (either fludarabine/cytarabine [ara-C]/granulocyte colony-stimulating factor [FLAG], ara-C plus mitoxantrone, or high-dose ara-C). Study was designed with two primary endpoints: 1) OS and 2) complete remission (CR)/CR with incomplete hematologic recovery (CRi) assessed in first 218 patients randomized (results previously presented). Overall study-wise type-I error was controlled by splitting 1-sided α to 0.0125 for each endpoint. Safety was assessed in all patients who received ≥1 dose of study drug. Per protocol, the final OS analysis was to occur upon observing ~248 events; 252 events (122 with InO and 130 with SC) were observed on March 8, 2016; data as of this date are presented.

Results

The ITT analysis population included 326 patients with both arms being well balanced for baseline stratification factors. The OS hazard ratio (HR) between InO and SC was 0.77 (97.5% CI, 0.58‒1.03) with 1-sided P=0.0203 and median OS 7.7 [95% CI, 6.0‒9.2] vs 6.7 [95% CI, 4.9‒8.3] months. The second primary objective of demonstrating a statistically significant improvement in final OS with InO vs SC was not met at prespecified significance level of 0.0104. The 2-year OS rate for InO vs SC was 23% (95% CI, 16‒30%) vs 10% (95% CI, 5‒16%). It was noted, however, that the OS departed from the proportional hazards assumption. Given this, a restricted mean survival time (RMST) analysis was applied and showed: mean OS was 13.9 months for InO vs 9.9 months for SC, a difference that met statistical significance. PFS was significantly longer with InO vs SC (HR, 0.45 [97.5% CI, 0.34‒0.61]; 1-sided P<0.0001), with median PFS 5.0 [95% CI, 3.7‒5.6] vs 1.8 [95% CI, 1.5‒2.2] months. Follow-up of previously reported endpoints, including objective response, MRD-negativity, and SCT rates were all superior in the InO arm compared to the SC arm by protocol-specified criteria. Updated safety results demonstrate a tolerability and toxicity profile consistent with that reported previously.

Conclusion

Compared with SC, InO provided evidence of longer OS and significantly prolonged PFS in adult patients with R/R ALL.