INO-VATE Updated Results Confirm PFS Benefit in Relapsed/Refractory ALL

Hagop Kantarjian, MD

Hagop 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 theNew England Journal of Medicine.^1,2

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;&nbsp;P<.001).

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= .04).

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.

&ldquo;Refractory/relapsed acute lymphoblastic leukemia has a very poor prognosis with a 5-year survival rate of less than 10%,&rdquo; said Kantarjian, professor, department of Leukemia, division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. &ldquo;There is an unmet medical need.&rdquo;

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&rsquo;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&rsquo;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 thePvalue 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;&nbsp;P= .03).

Significantly more patients proceeded to stem cell transplant with inotuzumab ozogamicin compared with standard chemotherapy (41% vs. 11%;P<.001).

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.

&ldquo;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,&rdquo; 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 (&plusmn;1.10) with inotuzumab ozogamicin compared with 9.9 months (&plusmn;0.85) with chemotherapy (P=.005).

&ldquo;This statistic analysis is an alternative that measures the average survival from the start of the study up to a specific part,&rdquo; he said. &ldquo;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.&rdquo;

Inotuzumab ozogamicin also resulted in superior outcomes across risk categories, including duration of first remission, across age groups, and by cytogenetic categories. However, patients with Ph-positive disease seemed to benefit less with inotuzumab ozogamicin versus chemotherapy.

&ldquo;This is because many of the patients with Ph-positive disease were entered from European sites where the patients received minimal prior chemotherapy and typically only one TKI,&rdquo; said Kantarjian. &ldquo;Therefore when they were randomized to the standard of care they were still sensitive to the intensive chemotherapy and were able to access subsequent TKIs. In fact, of the 28 patients randomized to the standard of care with Ph-positive disease, 16 had subsequent TKIs.&rdquo;

The median survival for patients with Ph-positive disease was 7.7 months with inotuzumab ozogamicin, which Kantarjian said is impressive compared with historical standards but still inferior to what was seen with chemotherapy in the trial.

The most common adverse events (AEs) observed for both inotuzumab ozogamicin and chemotherapy were cytopenias, including febrile neutropenia, which was seen in 16% of patients who received the experimental agent versus 22% in the control arm. Common non-hematologic treatment-emergent AEs with inotuzumab ozogamicin 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 with 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.

When looking at those who developed VOD on inotuzumab ozogamicin before the subsequent autologous stem cell transplant, VOD occurred at a rate of 3%, which was similar to the data seen in lymphoma, said Kantarjian.

In October 2015, the FDA granted inotuzumab ozogamicin a breakthrough therapy designation as a potential treatment for patients with relapsed or refractory, based on the primary analysis of the INO-VATE trial. Pfizer, the company developing inotuzumab ozogamicin, said that it was working closely with the FDA on the submission of data form the phase III trial for the medication in CD22-positive ALL. Additionally, Kantarjian said he would like to see the role for inotuzumab ozogamicin expand in the future.

&ldquo;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 monoclonal antibodies that targeted CD19 both in the salvage and in the frontline setting, and that this will hopefully improve the ultimate outcome of patients with ALL significantly compared to what we know today.&rdquo;

References

• Kantarjian H, DeAngelo D, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia (published online June 12, 2016). N Engl J Med. DOI: 10.1056/NEJMoa1509277.
• Kantarjian H, DeAngelo D, Advani A, 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. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract LB2233.