In patients with relapsed/refractory acute lymphoblastic leukemia (ALL), the antibody-drug conjugate inotuzumab ozogamicin produced significantly more complete remissions and was a better bridge to transplant than treatment by physician’s choice, according to the final results of a phase III trial reported at the 2016 European Hematology Association Congress in Copenhagen.¹

The results of the INO-VATE ALL trial were simultaneously published online in The New England Journal of Medicine (see Journal Spotlight in this issue of The ASCO Post).² The randomized trial enrolled 326 patients with ALL scheduled to receive their first or second salvage therapy.

“Inotuzumab is part of the new wave of monoclonal antibodies that I think will transform the outcomes of patients with ALL,” lead author Hagop M. Kantarjian, MD, said in an interview with The ASCO Post. Dr. ­Kantarjian is the Samsung Distinguished University Chair in Cancer Medicine, Department of Leukemia, at The University of Texas MD Anderson Cancer Center, Houston.

Hagop M. Kantarjian, MD

Inotuzumab ozogamicin consists of a monoclonal antibody targeting the cell surface antigen CD-22, expressed by 90% of B-cell malignancies, linked to the cytotoxic drug ozogamicin. The U.S. Food and Drug Administration (FDA) put inotuzumab ozogamicin on the fast track to approval last year, granting it Breakthrough Therapy designation. 

The results of this phase III trial of inotuzumab, as well as FDA approval of the bispecific antibody blinatumomab (Blincyto), are changing the treatment landscape for ALL, Dr. Kantarjian said, adding that more antibodies are on the way. When combined with other front-line treatment, these drugs may reduce chemotherapy-associated toxicity and improve survival, he predicted.

“These are very impressive results,” Dr. Kantarjian said, referring to the study he led. “Inotuzumab alone, vs intensive chemotherapy, produced a bone marrow complete response that is close to three times higher [than current standard therapy], and was able to move about twice as many patients to allogeneic transplant.” 

INO-VATE ALL Details

INO-VATE ALL involved 326 patients with relapsed or refractory CD22-positive ALL accrued from 117 sites. The patients were randomized to the investigational agent or to physician’s choice of standard therapy. 

The trial had coprimary endpoints: complete remission with or without complete hematologic recovery and overall survival. Progression-free survival was a secondary endpoint, along with safety, duration of remission, the proportion of patients going to stem cell transplant, and the proportion of complete remissions associated with clearance below the threshold for minimal residual disease.

Inotuzumab is part of the new wave of monoclonal antibodies that I think will transform the outcomes of patients with ALL.

— Hagop M. Kantarjian, MD

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With inotuzumab, significantly more patients attained complete remission (80.7%) compared to the control arm (29.4%, P < .001). However, a 1-month improvement in overall survival (coprimary endpoint) with inotuzumab did not meet the prespecified criteria for statistical significance, Dr. Kantarjian reported.

Median overall survival was 7.7 months with inotuzumab ozogamicin and 6.7 months with standard therapy. The difference translated into a 23% reduction in the survival hazard (P = .04), but the trial design specified a nominal significance level of P < .0208. The 2-year survival rate was 23% in the inotuzumab ozogamicin group and 10% in the control arm.

The novel agent made a strong showing, however, in delaying progression. Median progression-free survival was more than doubled (5.0 months) compared to treatment by physician’s choice (1.8 months)—a 55% reduction in risk (P < .001).

Perspective on the Survival Endpoint

In the interview, Dr. Kantarjian commented on the overall survival endpoint. “In my opinion, survival is significantly different, at P = .04, but it did not meet the statistical endpoint. We had an early look at the data, and the P value had to be .02 for us to meet the endpoint for the proportional-hazards model,” he said.

Since, as the paper described it, “data for overall survival appeared to depart from the proportional-hazards assumption,” the investigators did an exploratory post hoc analysis of restricted mean survival time to alternatively define the clinical benefit. Mean restricted survival time, which calculates the mean average survival time difference, is increasingly being applied in clinical research but was not being used when this study was designed, according to Dr. Kantarjian.

In this analysis, the mean overall survival was longer in the inotuzumab ozogamicin group: 13.9 vs 9.9 months (P = .005). The investigators wrote, “On the basis of the apparent separation of the overall survival curves after approximately 14 months, it may be speculated that the survival benefit occurs at later time points.”

“Here we see a big difference in the space between the curves,” Dr. ­Kantarjian commented. “It’s a more accurate analysis of benefit….”

He added, “The other point is that some treatments may not affect median overall survival, but they do affect long-term survival. We see this with the checkpoint inhibitors.” 

More Patients Underwent Transplant

Among the complete responders, significantly more patients in the inotuzumab ozogamicin arm had results below the threshold for minimal residual disease, defined as 0.01% of marrow blasts (78.4% vs 28.1%, P < .001). The median duration of remission was also significantly longer (4.6 vs 3.1 months, P = .03). 

Finally, significantly more patients proceeded directly to stem cell transplant after treatment with inotuzumab ozogamicin (41% vs 11%, P < .001). Dr. Kantarjian emphasized stem cell transplantation is the best chance for cure at this stage of the disease. 

More Veno-occlusive Disease

Liver enzyme elevations occurred more often with inotuzumab ozogamicin, as did hyperbilirubinemia. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin, with any grade of the disorder occurring in 15 patients (11%) vs 1 patient (1%) receiving standard treatment.

Dr. Kantarjian acknowledged this side effect. “It’s a sizable proportion, but there’s a learning curve. In this randomized study, we found that a couple of geographic areas were using thiotepa in their preparative regimen, and they had a higher incidence of veno-occlusive disease. If we subtract these areas, the incidence goes back to very low levels, close to baseline,” he said.

“With proper measures—avoiding thiotepa in preparative stem cell transplant regimens, avoiding double stem cell transplant, and implementing strategies to prevent veno-occlusive disease—the incidence is less than 5%.… Our recommendation is not to use this regimen with bulsulfan and other alkylators,” he added. 

Grade ≥ 3 cytopenias occurred less frequently with inotuzumab ozogamicin. The most frequent nonhematologic adverse events in that arm, of any grade, were nausea (32%), headache (28%), and pyrexia (27%); they were grade ≥ 3 in ≤ 5% of patients. The most common nonhematologic adverse events with standard therapy were nausea (47%), pyrexia (43%), and diarrhea (40%), which were also grade ≥ 3 in ≤ 5%. ■

Disclosure: The trial was supported by Pfizer. Dr. Kantarjian disclosed relevant relationships with Amgen, ARIAD, Pfizer, Novartis, and Bristol-Myers Squibb. 

References

1. Kantarjian HM, DeAngelo DJ, Advani AS, et al: Overall survival in relapsed/refractory B-cell acute lymphoblastic leukemia patients receiving inotuzumab ozogamicin vs standard care in the phase 3 INO-VATE study. 2016 Congress of the European Hematology Association Congress. Abstract LB2233. Presented June 12, 2016.

2. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. June 12, 2016 (early release online).