In an open-label, randomized Phase III INO-VATE ALL study, also known as study 1022, of the investigational drug inotuzumab ozogamicin, also known as CMC-544 (Pfizer), a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.
Acute lymphoblastic leukemia is an aggressive type of leukemia with a poor prognosis in adults. The current foundational treatment is intensive, long-term chemotherapy. In 2016, it is estimated that 6,590 cases of ALL will be diagnosed in the United States, with about 2 in 5 cases in adults. Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens. For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.
The study evaluated the safety and efficacy of inotuzumab ozogamicin as compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL. Results showed improvement over chemotherapy on a number of measures including complete hematologic remission and progression-free survival (PFS). Updated results and newly available overall survival (OS) data were also presented as a late-breaking oral presentation (#LB2233) at the 21st Congress of the European Hematology Association (EHA) 2016 Annual Meeting in Copenhagen, Denmark.
Inotuzumab ozogamicin is an antibody-drug conjugate linking an antibody that targets CD22, a protein found on the surface of more than 90% of ALL cells, conjugated to the cytotoxin calecheamicin. Once the agent binds to CD22, it is thought to be internalized into the cell, where the cytotoxic agent is released to destroy the cell. 
The study, which revealed complete remission rates of nearly 81% and significantly longer progression-free and higher overall survival rates than with standard therapies, was conducted at The University of Texas MD Anderson Cancer Center. Study findings were reported in the June 12 online issue of the New England Journal of Medicine. 
“Relapsed or refractory ALL is an aggressive leukemia in urgent need of new treatment options as about half of adult patients will not respond to chemotherapy or will see their disease return,” noted Hagop Kantarjian, MD, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
“Forty-one percent of all patients with acute lymphoblastic leukemia participating in the study were able to proceed to transplant after receiving inotuzumab ozogamicin compared with the 11% we have seen qualify through standard chemotherapy,” he said.
“Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging,” Kantarjian explained.
“The efficacy results seen in patients treated with inotuzumab ozogamicin in this study are impressive, particularly median progression-free survival, high rates of hematological remission and absence of minimal residual disease. These results suggest inotuzumab ozogamicin, if approved, could be a valuable new addition to currently available treatment options.”
Stem cell transplants
Donor stem cell transplants generally are considered curative for this aggressive form of leukemia with more than 6,500 American adults expected to be diagnosed with the disease in 2016. However, patients must be in complete remission before they are eligible for transplant.
Current therapies for adults with newly diagnosed B-cell ALL result in complete remission rates (CR) of 60 to 90%. However, many of those patients will relapse and only about 30 to 50% will achieve long-term, disease-free survival lasting more than three years.
“Standard chemotherapy regimens result in complete remission in 31 to 41% of patients who relapse earlier, and just 18 to 25% in those who relapse later,” said Kantarjian. “Patients in the inotuzumab ozogamicin study had remission rates of 58%, higher than previously reported, possibly due to patients being treated later in the disease course.”
The INO-VATE ALL study had two independent primary endpoints, complete response with or without hematologic remission and OS. INO-VATE ALL met its first primary endpoint of complete response, which was significantly better with inotuzumab ozogamicin compared to chemotherapy (80.7% [95% CI, 72%-88%] vs. 29.4% [95% CI, 21%-39%], P<0.001).
Inotuzumab ozogamicin also significantly extended PFS compared to chemotherapy (HR: 0.45 [97.5% CI, 0.34-0.61], P<0.001; median PFS, 5.0 vs. 1.8 months, in their respective arms). The second primary endpoint of OS showed a strong trend toward longer OS for patients treated with inotuzumab ozogamicin compared to chemotherapy, but did not reach the level of statistical significance (p < 0.0104) for the trial (HR: 0.77 [97.5% CI, 0.58-1.03], one-sided P=0.0203; median OS, 7.7 months [95% CI, 6.0-9.2] vs. 6.7 months [95% CI, 4.9-8.3]). The two-year OS rate for inotuzumab ozogamicin was 23 percent (95% CI, 16%‒30%) compared to chemotherapy at 10 percent (95% CI, 5%‒16%).
“Adult patients with relapsed or refractory ALL have a five-year survival rate of less than 10 percent, making these patients particularly difficult to treat. To see remission rates and two-year survival rates that are more than doubled compared to standard of care chemotherapy is very gratifying,” said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.
“We believe these data add to the growing body of evidence that supports inotuzumab ozogamicin as an important potential treatment option in adults with relapsed or refractory ALL,” Rothenberg added.
Results from INO-VATE ALL also showed patients treated with inotuzumab ozogamicin achieved high rates of minimal residual disease (MRD) negativity (78.4% [95% CI, 68%-87%; P<0.001]), and experienced a duration of response (DOR) of 4.6 months (95% CI, 3.9-5.4; HR: 0.55; P<0.034).
In comparison, 28.1 percent (95% CI, 14%-47%; P<0.001) of patients treated with chemotherapy achieved MRD negativity and median DOR was 3.1 months (95% CI, 1.4-4.9; HR: 0.55; P<0.034). More patients also proceeded to stem-cell transplant with inotuzumab ozogamicin compared to standard chemotherapy (41% vs. 11%, P<0.001).
Overall, the study reported moderate side effects, the most common being cytopenia, including febrile neutropenia (16% vs. 22%), a disorder that reduces blood cell production, and liver toxicity. Common nonhematologic treatment-emergent side effects included nausea (32%), headache (28%) and pyrexia (27%). Patients in the chemotherapy arm experienced nausea (47%), pyrexia (43%) and diarrhea (40%).
Additionally, any-grade veno-occlusive liver disease (VOD) occurred more frequently in patients treated with inotuzumab ozogamicin compared to chemotherapy (11% vs. 1%). Five patients taking inotuzumab ozogamicin developed VOD during treatment and 10 patients developed VOD after subsequent stem cell transplant. Among those taking chemotherapy, one patient developed VOD after transplant. No cases of VOD occurred during treatment with chemotherapy.
Breakthrough Therapy Designation
In October 2015 the US Food and Drug Administration (FDA) granted a breakthrough therapy designation for inotuzumab ozogamicin, based on the Phase III INO-VATE ALL trial data.
The FDA’s breakthrough therapy designation is a regulatory process designed to expedite the development and review of novel, investigational, drugs that are intended to treat serious conditions in which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement compared to available therapy on a clinically significant endpoints.
Funding for this study was provided by Pfizer, Inc.