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INO-VATE trial

INO-VATE Trial:

Study design

The first dual-arm, Phase III study to demonstrate efficacy of a single-agent antibody-based therapy (BESPONSA) vs standard chemotherapy in CD22+, Ph+ or Ph– relapsed/refractory B-cell ALL.2

To view the NEJM INO-VATE publication online please click here.

INO-VATE trial study design

Ara-C, cytarabine; CR, complete remission; CRi, complete remission with incomplete haematological recovery; FLAG, fludarabine/ara-C/granulocyte colony-stimulating factor; HiDAC, high-dose Ara-C; MXN, mitoxantrone; Ph+, Philadelphia chromosome-positive; Ph–, Philadelphia chromosome-negative

Figure adapted from Kantarjian HM et al. The Lancet Haematology 2017

Primary endpoints2

  • Complete remission or complete remission with incomplete haematological recovery (CR/CRi)
  • Overall survival (OS)

Secondary endpoints2

  • Progression-free survival (PFS)
  • Rate of subsequent haematopoietic stem cell transplantation (HSCT)
  • Minimal residual disease (MRD)
  • Duration of remission
  • Safety

Primary intention-to-treat analysis2

  • Of the 326 patients who underwent randomisation, the first 218 (109 in each group) were included in the analysis of CR
  • The survival analysis was designed to show significantly longer OS in the BESPONSA group (n=164) than in the standard chemotherapy group (n=162) at a prespecified two-sided boundary of P=0.0208

Patient characteristics

INO-VATE trial baseline characteristics (remission analysis population)2

The remission-analysis population includes the first 218 patients who underwent randomisation in the intention-to-treat population.

*Missing data for one patient in each group; †Unknown or missing data for 16 patients in each group; ‡Missing data for two patients in each group. Ph+, Philadelphia chromosome-positive; SCT, stem cell transplantation.

Table adapted from Kantarjian HM et al. New Engl J Med 2016

  • BESPONSA was used at first relapse in most patients (67%)2
  • Duration of first remission was <12 months in most treated patients2
  • 16% of BESPONSA patients had a prior HSCT2
  • Approximately 13% were Ph+2
  • 71% of BESPONSA patients had a bone marrow blast count ≥50%2

Treatment response

In the INO-VATE ALL study, four out of five patients achieved CR/CRi with single-agent BESPONSA.1

2.5 times as many patients achieved CR/CRi vs standard chemotherapy.2

Rates of CR/CRi(remission analysis population)

BESPONSA, n=109; standard chemotherapy, n=109.2

CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete haematological recovery

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

In the INO-VATE ALL study, almost nine out of 10 patients achieved CR/CRi with single-agent BESPONSA after first relapse.2

Rates of CR/CRi after first relapse2 (remission analysis population)

BESPONSA, n=73; standard chemotherapy, n=73.2

CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete haematological recovery

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

More than seven out of 10 responders achieved CR/CRi after a single cycle of BESPONSA therapy.1,2

Time to CR/CRi(remission analysis population)

CR, complete remission; CRi, complete remission with incomplete haematological recovery

Figure adapted from Scottish Medicines Consortium: inotuzumab ozogamicin 1mg powder for concentrate for solution for infusion (BESPONSA®). Available at: www.scottishmedicines.org.uk/media/3469/inotuzumab-ozogamicin-besponsafi... may-2018-for-website.pdf. Accessed 2 June 2020.

BESPONSA demonstrated consistently high CR/CRi rates across subgroups independently of duration of first remission, relapse number, age or disease burden.2

Rates of CR/CRi across subgroups2

CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete haematological recovery

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

Rapid and high remission rates were consistent with BESPONSA regardless of baseline disease burden.2

CR/CRi rate according to baseline disease burden (remission analysis population)2

BESPONSA, n=109; standard chemotherapy, n=109.2

Missing data on bone marrow blasts for two patients in each treatment group.2

CR, complete remission; CRi, complete remission with incomplete haematological recovery

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

Please view the following videos for more information on the treatment response.

Professor David Marks and Professor Elias Jabbour discuss treatment response in the INO-VATE trial.

MRD-negativity rate

In the 81% of BESPONSA-treated patients with CR/CRi, over three-quarters achieved MRD‑negativity.2

Among patients who achieved CR, 89.7% were MRD-negative in the BESPONSA arm vs 31.6% in the standard chemotherapy arm (P<0.001).2

MRD-negativity rate among patients who achieved CR/CRi2 (remission analysis population)

MRD rate in the remission-analysis population (BESPONSA, n=88; standard chemotherapy, n=32). Patients were considered MRD-negative when leukaemic cells comprised <0.01% of bone marrow blast, as measured by flow cytometry.2

CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete haematological recovery; MRD, minimal residual disease

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

Transplant rate

Four times more patients proceeded to transplant after treatment with BESPONSA without another intervening induction therapy than patients treated with standard chemotherapy.1

Direct HSCT rate without another intervening induction therapy (ITT population)1

BESPONSA, n=164; standard chemotherapy, n=162.1

HSCT, haematopoietic stem cell transplantation; ITT, intention-to-treat

Figure adapted from BESPONSA Hong Kong Prescribing Information November 2018

Please view the following video for more information on transplant rates.

Professor Matthias Stelljes discusses transplant rates from the INO-VATE trial and the importance of allogeneic haematopoietic stem cell transplant (HSCT) in the treatment of adult ALL.

Overall survival

Median OS favoured BESPONSA (HR 0.77; 97.5% CI 0.58–1.03; two-sided P-value=0.04).2 BESPONSA more than doubled the 2-year OS rate vs standard chemotherapy (23% vs 10%).2

Median OS and probability of survival at 2 years (ITT population)1,2

CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; SC, standard chemotherapy

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

Please view the following video for more information on overall survival.

Professor David Marks explains the OS curve with BESPONSA.

Progression-free survival

PFS was more than doubled with BESPONSA vs standard chemotherapy (median 5.0 vs 1.8 months; HR 0.45; 97.5% CI 0.34–0.61; P<0.001).2

Progression-free survival (ITT population)2

PFS was defined as time from date of randomisation to earliest date of the following events: death; progressive disease, including objective progression, relapse from CR/CRi and treatment discontinuation due to global deterioration of health status; starting new induction therapy; or post-therapy HSCT without achieving CR/CRi.

CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete haematological recovery; ITT, intention-to-treat; PFS, progression-free survival; SC, standard chemotherapy; HR, Hazard ratio

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

Safety

BESPONSA is well tolerated, with a manageable safety profile.1,2

All-cause adverse events (AEs)2*

*Data represent the safety population (data cut-off date of 2 October 2014). AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0; All-cause AEs with ≥20% incidence occurring in either arm in the safety population (any treatment cycle) in descending order of total frequency across arms.

AE, adverse event; SC, standard chemotherapy

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

BESPONSA is associated with less thrombocytopenia and febrile neutropenia than standard chemotherapy.2

Incidence of ≥Grade 3 thrombocytopenia and febrile neutropenia2

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

Liver-related AEs are more common with BESPONSA than with standard chemotherapy.2

Incidence of ≥Grade 3 liver function tests2*

Figure adapted from Kantarjian HM et al. New Engl J Med 2016

ALT, alanine aminotransferase; AST, aspartate aminotransferase

Haematological safety profile of BESPONSA

Please view the following video for more information on the haematological safety profile.

Professor Matthias Stelljes discusses the haematological safety profile of BESPONSA.

Incidence of VOD/SOS

In the INO-VATE ALL study, VOD/SOS was reported in 23 patients (14%) treated with BESPONSA1

  • In five (3%) during or after BESPONSA treatment without subsequent HSCT (occurring up to 56 days after last dose)3
  • In 17 (22%) who proceeded to subsequent HSCT (occurring 3–57 days after transplantation) – five cases were fatal3

Quality of life

BESPONSA enables improved efficacy outcomes without compromising patient quality of life.4

Patients receiving BESPONSA had significantly better appetite, were significantly more ambulatory, and experienced less impact on family and social life.4

*P<0.05; †95% CI error bar (–0.01 to 0.07) within the symbol. Estimated means were least squares means of each domain’s post-baseline scores, estimated from repeated measures mixed-effects models with treatment, time, treatment-by-time interaction and baseline scores as covariates.

EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire; EQ-5D, EuroQoL 5 Dimensions questionnaire; EQ-VAS, EQ visual analogue scale

Figures adapted from Kantarjian HM et al. ASH 2016

CI, confidence interval; EORTC, European Organisation for Research and Treatment of Cancer; SC, standard chemotherapy

  1. BESPONSA®​ Prescribing Information. Pfizer Corporation Hong Kong Limited. Version Nov 2018.
  2. Kantarjian H, DeAngelo D, Stelljes M et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. New England Journal of Medicine. 2016;375(8):740-753. doi:10.1056/nejmoa1509277
  3. Kantarjian H, DeAngelo D, Advani A et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. The Lancet Haematology. 2017;4(8):e387-e398. doi:10.1016/s2352-3026(17)30103-5
  4. Kantarjian H, Su Y, Jabbour E et al. Patient-Reported Outcomes from a Global Phase 3 Randomised Controlled Trials of Inotuzumab Ozogamicin vs Standard of Care Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia. Presentation presented at the: 2016; ASH.
  5. Scottish Medicines Consortium: inotuzumab ozogamicin 1mg powder for concentrate for solution for infusion (BESPONSA®). Available at: http://www.scottishmedicines.org.uk/media/3469/inotuzumab-ozogamicin-bes.... Accessed 2 June 2020.