Hagop M. Kantarjian, MD
The anti–CD22 antibody-drug conjugate inotuzumab ozogamicin demonstrated significantly improved progression-free survival (PFS) and complete remission (CR) rates compared with chemotherapy for patients with relapsed or refractory acute lymphoblastic leukemia (ALL), according to updated findings from the INO-VATE ALL study presented at the 2016 European Hematology Association (EHA) congress and simultaneously published in the New England Journal of Medicine
In the phase III trial, inotuzumab ozogamicin demonstrated a median PFS of 5.0 months (95% CI, 3.7-5.6) compared with 1.8 months (95% CI, 1.5-2.2) with standard chemotherapy (HR, 0.45; 97.5% CI, 0.34-0.61; P
<.001). The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 80.7% with inotuzumab ozogamicin (95% CI, 72.1-88.7) compared with 29.4% of those who received standard chemotherapy (95% CI, 21.0-38.8; P
The 2-year overall survival (OS) rate for inotuzumab ozogamicin was 23% (95% CI, 16-30) compared with 10% for chemotherapy (95% CI, 5-16). There was a 23% advantage seen in the median OS with inotuzumab ozogamicin versus chemotherapy; however this did not pass the bar for statistical significance (HR, 0.77; 97.5% CI, 0.58-1.03; P
These results are exciting for a patient population with few options, said Hagop Kantarjian, MD, the lead investigator on INO-VATE who presented the findings at EHA.
“Refractory/relapsed acute lymphoblastic leukemia has a very poor prognosis with a 5-year survival rate of less than 10%,” said Kantarjian, professor, department of Leukemia, division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “There is an unmet medical need.”
The study included 326 patients, randomized at 117 sites in 18 countries. All patients were 18 years or older and had relapsed or refractory disease, CD-22-positivity, and were scheduled to receive their first or second salvage treatment. Philadelphia chromosome (Ph)-positive and Ph-negative ALL patients were both included.
Patients were randomized in a 1:1 ratio to receive either inotuzumab ozogamicin or investigator’s choice of standard chemotherapy regimens. No crossover between groups was allowed. Patients were stratified based on whether their first remission was greater or less than 12 months, salvage-treatment phase, and age. Patients who achieved complete remission were permitted to undergo stem cell transplantation at the investigator’s discretion.
The study had duel primary endpoints. The first, achievement of CR or CRi was assessed in the first 218 patients randomized. The second, OS, occurred at the prespecified boundary of the P
value 0.01 assessed in all 326 randomized patients after more than 248 events occurred, which happened in March 2016. Secondary endpoints included safety, MRD-negativity in patients that achieved CR or CRi, remission duration, PFS, and transition to stem cell transplant.
Patients treated with inotuzumab ozogamicin achieved a minimal residual disease-negativity rate of 78.4% (95% CI, 68-87) versus 28.1% (95% CI, 14-47) with chemotherapy (P
<.001). The median duration of response was 4.6 months with the anti–CD22 agent (95% CI, 3.9-5.4) versus 3.1 months (95% CI, 1.4-4.9) for chemotherapy (HR, 0.55; 95% CI, 0.31-0.96; P
Significantly more patients proceeded to stem cell transplant with inotuzumab ozogamicin compared with standard chemotherapy (41% vs. 11%; P
The study demonstrated a strong trend toward longer median OS for patients treated with inotuzumab ozogamicin compared with chemotherapy. The lack of statistical significance did not suggest that a benefit was not seen, said Kantarjian.
“Looking at the curve it is important to note that a proportion of the hazard ratio was not met after 14 months so there is a portion of this curve that favors inotuzumab ozogamicin, similar to what we see with checkpoint inhibitors,” he said.
Investigators felt that OS appeared to depart from the proportional-hazards assumption, and conducted a post hoc analysis of restricted mean survival time. This is a statistical analysis commonly used across solid tumors, said Kantarjian. In this analysis, the restricted mean survival time was determined to be 13.9 months (±1.10) with inotuzumab ozogamicin compared with 9.9 months (±0.85) with chemotherapy (P
“This statistic analysis is an alternative that measures the average survival from the start of the study up to a specific part,” he said. “What you are looking at is the number of years under the curve of both the two curves, and the difference in the later outcome with the two curves.”