ANTI-CD22 ANTIBODY FOR ALL

COPENHAGEN, Denmark -- Final results are now out for a pivotal study of the new anti-CD22 antibody conjugate inotuzumab ozogamicin (Pfizer, Inc) in acute lymphoblastic leukemia (ALL). When compared with chemotherapy, the drug significantly improved progression-free survival and other measures, but it just failed to reach statistical significance for overall survival.

"There are clear responses here. Thus, beyond doubt, this is a very effective drug, yet obviously as a single drug, the activity is limited -- this is reflected by the (mere) few months of life gained by therapy with this drug," commented Shai Izraeli, MD, professor and head of functional genomics and the Childhood Leukemia Research Center at the Sheba Medical Center, Israel.

He was not involved in the study but was comoderator the session here at the European Hematology Association (EHA) 2016 Congress at which the new results were presented. The results were simultaneously published online in the New England Journal of Medicine.

Commenting on the study for Medscape Medical News, Dr Izraeli said: "These are very significant findings.

"Clearly inotuzumab is a very effective drug," he continued. He emphasized that any improvement in the treatment of this disease is important, because patients with ALL have very poor prognoses. The 5-year survival rate for R/R ALL [relapsed or refractory B-cell acute lymphoblastic leukemia] is less than 10%. "Pediatric patients have basically no chances for survival and rarely respond to any chemotherapy," he commented.

Study Details

The study, known as the INO-VATE ALL trial, was conducted at 117 sites in 19 countries. It enrolled 326 adult patients with R/R ALL and CD22-positive diseasePatients were randomly assigned to treatment with inotuzumab or standard chemotherapy. Treating physicians had a choice of using one of the following three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine.

The results were presented at the meeting by Hagop P. Kantarjian, MD, professor, Division of Cancer Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston.

The study met its first primary endpoint of complete response, which was significantly improved with inotuzumab compared with chemotherapy (80.7% vs 29.4%; P < 0.001).

However, inotuzumab failed to meet the second primary endpoint of overall survival, falling short of the level of statistical significance (ie, P < .0104) set for the trial (hazard ratio, 0.77; P = 0.0203; median overall survival, 7.7 months vs 6.7 months).

With regard to the 2-year overall survival rate, the difference in favor of inotuzumab was better -- 23% compared with 10% with chemotherapy. Using a restricted mean survival time analysis, which Dr Kantarjian explained is now commonly used with solid tumors, the mean overall survival was 13.9 months with inotuzumab, compared with 9.9 months with the standard of care (P = .0023)

Patients receiving inotuzumab did have significantly longer median progression-free survival compared with those receiving standard care (5.0 months vs 1.8 months; P < .0001). In an intent-to-treat (ITT) analysis of 218 patients, the complete response/complete response with incomplete hematologic recovery rate was also significantly higher for patients receiving inotuzumab than for those receiving chemotherapy (80.7% vs 29.4%; P < .0001).

In that ITT analysis, four times as many patients in the inotuzumab group were able to proceed to stem cell replacement compared with the chemotherapy group (41 vs 10; P < .0001). Ultimately, however, 47% of patients receiving inotuzumab in the phase 3 trial went on to post-study stem cell transplant, compared with 20% in the chemotherapy group.

The most common adverse events observed in the trial were cytopenias, including febrile neutropenia (16% with inotuzumab vs 22% with chemotherapy). Nonhematologic treatment-emergent adverse events included nausea (32% in both groups), headache (28%), and pyrexia (27%).

The incidence of veno-occlusive liver disease (VOD) was significantly higher in the inotuzumab group than in the chemotherapy group (13% vs 1%). The incidences of grade 3 liver function abnormalities were similar in the two groups.

Dr Kantarjian noted that at his center, they have reduced the incidence of VOD to less than 5% by avoiding the use of agents that damage the liver and by using measures to prevent VOD.

"In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent but in combination with chemotherapy or with other antibodies (e.g., targeting CD19), and this will hopefully improve the outcomes of people with RR/ALL and with newly diagnosed ALL significantly compared to what we see today," Dr Kantarjian commented.

"My vision and hope is that 5 years from now, instead of treating RR/ALL and newly diagnosed patients with 2½ to 3 years of intensive chemotherapy, we may be able to treat them with 2 to 3 months of induction–consolidation therapy, then a monoclonal therapy or a cocktail of monoclonal antibodies for another 3 to 6 months, allowing for better compliance, much shorter time of therapy, less short- and long-term chemotherapy-related tocixities, and, hopefully, better survival," he added.

"Clearly inotuzumab is a very effective drug. R/R ALL adult but also pediatric patients have basically no chances for survival and rarely respond to any chemotherapy."

Dr Izraeli echoed Dr Kantarjian's suggestion that use of inotuzumab in combination with other treatments may lead to substantial improvements in outcomes.

"I think the challenge is to conduct two types of clinical trials: combining inotuzumab with chemotherapy, and combining and comparing different types of immunotherapies to achieve a combined targeting of CD19 and CD22," he said.

The study was sponsored by Pfizer. Dr Kantarjian has received research support from Pfizer, Amgen, Astex, Bristol-Myers Squibb, and Novartis. Dr Izraeli has disclosed no relevant financial relationships.

European Hematology Association (EHA) 2016 Congress: Abstract LB2233. Presented June 12, 2016.

N Engl J Med. Published online June 12, 2016.