Summary Basis of Decision for Unituxin

 

Clinical Pharmacology

Dinutuximab, the medicinal ingredient of Unituxin, is a chimeric human/mouse monoclonal antibody against disialoganglioside (GD2), a glycolipid expressed on neuroblastoma cells and normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

Clinical Pharmacokinetic Comparability Study and Pharmacokinetics

Study DIV-NB-201 was a randomized, open-label, two-sequence crossover trial that evaluated the pharmacokinetic comparability, safety, and tolerability of dinutuximab manufactured by the United States National Cancer Institute (NCI) and dinutuximab manufactured by United Therapeutics Corporation. The study involved 28 pediatric patients with high-risk neuroblastoma.

The criteria for bioequivalence were met when examined with the statistical routines employed by Health Canada, in contrast to the outcome of the analysis provided by the sponsor. Based on the Health Canada-employed methods, the two products were considered pharmacokinetically comparable and no concerns were identified during the product quality review.

The sponsor also chose to include a population pharmacokinetic approach for characterization of the pharmacokinetic profile of dinutuximab in study DIV-NB-201 and in a cross-study population pharmacokinetic study, but both analyses were not considered in the final decision regarding this drug. The pharmacokinetic parameters of dinutuximab obtained by a non-compartmental analysis are included in the Unituxin Product Monograph.

While no specific studies have been conducted to evaluate the effect of sex, age, race, or organ impairment on dinutuximab pharmacokinetics, no apparent differences were observed on visual examination of the data in the studies conducted.

Immunogenicity

In clinical studies of pediatric patients treated with dinutuximab, anti-dinutuximab antibodies (also referred to as human anti-chimeric antibodies, HACA) were detected in 68 of 414 (16%) patients, and neutralizing antibodies were detected in 38 (56%) of those patients. The occurrence of neutralizing antibodies had no apparent impact on safety or efficacy based on a comparison of patients with and without detectable neutralizing antibodies. However, the small sample size precluded a determination of the clinical impact of the neutralizing antibodies. In addition, no marked differences in immunogenicity were observed in the comparative Study DIV-NB-201 (see Clinical Pharmacokinetic Comparability Study and Pharmacokinetics) between dinutuximab, manufactured by the United States National Cancer Institute (NCI) and dinutuximab, manufactured by United Therapeutics Corporation.

The clinical pharmacology data support the use of Unituxin for the recommended indication.

For further details, please refer to the Unituxin Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Unituxin, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), in the treatment of high-risk neuroblastoma was demonstrated in the pivotal study DIV-NB-301 (ANBL0032). Additional efficacy data were derived from the supportive study DIV-NB-302 (ANBL0032).

Pivotal Study - DIV-NB-301 (ANBL0032)

The pivotal study, DIV-NB-301 (ANBL0032), was a Phase III, multicentre, open-label, randomized clinical trial in pediatric patients with high-risk neuroblastoma who were randomized in a 1:1 ratio to receive Unituxin, GM-CSF, IL-2, and RA (hereafter referred to as immunotherapy plus RA) or RA alone.

Eligible patients must have completed intensive induction chemotherapy followed by autologous stem cell transplantation and radiation therapy. They must have achieved a partial response, very good partial response, or complete response according to the International Neuroblastoma Response Criteria at the pre-autologous stem cell transplantation evaluation prior to enrollment in the study. Patient enrollment and randomization took place between Day 50 and Day 77 post-autologous stem cell transplantation.

Patients randomized to the immunotherapy plus RA arm (number of patients [n] = 113) received up to five cycles of Unituxin in combination with GM-CSF or IL-2 plus RA, followed by one cycle of RA alone. Patients randomized to the RA arm (n = 113) received six cycles of RA.

Although eligible for enrollment in the study, patients with biopsy-confirmed residual disease following autologous stem cell transplantation were ineligible for randomization. These patients (n = 25) were non-randomly assigned to treatment in the immunotherapy and RA group and were excluded from the primary analysis, but included in the safety analysis (see Clinical Safety).

The primary efficacy endpoint of the study was investigator-assessed event-free survival, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death. The secondary efficacy endpoints included overall survival, tumour response, minimal residual disease, event-free survival and overall survival in the subgroup of high-risk International Neuroblastoma Staging System (INSS) Stage 4 neuroblastoma patients, and event-free survival and overall survival within other subgroups broken out by several baseline prognostic factors.

Planned interim analyses were carried out every six months starting after 20% of the planned events had occurred. To adjust for effects of repeated testing, statistical boundaries were set for the hazard ratio at each interim analysis.

At a pre-planned interim analysis for event-free survival, and subsequently, overall survival, the Data Safety Monitoring Committee recommended early cessation of randomization on the basis of shown superiority of immunotherapy plus RA over RA alone with regard to the event-free survival endpoint. This interim analysis was designated as the primary analysis. Subsequent analysis was conducted six months after the primary analysis (referred to as a confirmatory analysis) and three years after the confirmatory analysis (referred to as a follow-up analysis). Hazard ratios for immunotherapy plus RA arm versus RA alone arm were calculated for event-free survival and overall survival at each analysis point, using multivariate analysis to take into account prognostic variables that may have affected treatment outcomes. The hazard ratios (95% confidence interval [CI]) for event-free survival and overall survival in the primary analysis were 0.52 (0.33, 0.82) (p = 0.0046) and 0.59 (0.33, 1.05) (p = 0.0704), respectively. In the confirmatory analysis, the hazard ratio for event-free survival was 0.59 (0.39, 0.89) (p = 0.0124) and the hazard ratio for overall survival was 0.58 (0.34, 1.00) (p = 0.0501). The follow-up analysis resulted in a hazard ratio for event-free survival of 0.66 (0.44, 0.98) (p = 0.0378) and a hazard ratio for overall survival of 0.60 (0.37, 0.96) (p = 0.0351). The Kaplan-Meier curves of both endpoints at each point of analysis for the immunotherapy plus RA and the RA alone separated between three and six months post-randomization and remained separated to the data cut-off dates. Consistent separation of Kaplan-Meier curves implies real treatment differences.

A subgroup of intention-to-treat population with high-risk INSS Stage 4 neuroblastoma patients was also analyzed for event-free survival and overall survival. For event-free survival, Kaplan-Meier curves in the primary and confirmatory analyses showed statistically significant differences favouring immunotherapy plus RA over RA alone. For overall survival, the curves in each analysis remained separated but these differences were not statistically significant.

Supportive Study - DIV-NB-302 (ANBL0032)

Study DIV-NB-302 (ANBL0032) was an extension of the immunotherapy plus RA arm of study DIV-NB-301 (ANBL0032). The patient accrual continued solely into the immunotherapy plus RA arm once the randomization was terminated at the recommendation of the Data Safety and Monitoring Committee for reasons of improved efficacy over the RA alone arm. Eight hundred and thirty-eight patients were enrolled, 787 of whom received at least one dose of immunotherapy plus RA. The population accrued into this study was fundamentally similar to that accrued into the immunotherapy plus RA arm during randomization phase, with a few changes implemented through protocol amendments. The treatment regimen was the same except for some amended changes such as a narrowing of the acceptable range of infusion times. The primary endpoint remained event-free survival and the main secondary endpoint for the intention-to-treat population was overall survival. These endpoints were also determined for the subgroup of patients with INSS Stage 4 disease (n = 371). Since the study did not have a comparator group against which the treatment outcomes could be compared, only informal comparisons were made with the results in immunotherapy plus RA arm of the pivotal trial.

The two-year event-free survival (95% confidence interval) of 66% (62%, 70%) compared favourably with that of the immunotherapy plus RA arm in study DIV-NB-301 (ANBL0032) (two-year event-free survival, confirmatory analysis: 65.5% [56.1%, 75.2%]). The two-year overall survival was 83.3% (80%, 86.5%) in study DIV-NB-302 (ANBL0032), compared to 85.4% (78.2%, 92.6%) in that arm in the confirmatory analysis of study DIV-NB-301 (ANBL0032). In both studies, the Kaplan-Meier curves for both endpoints for immunotherapy plus RA-treated patients were very similar.

Indication

The New Drug Submission for Unituxin was filed by the sponsor with the following indication:

• Unituxin (dinutuximab) is indicated for the treatment of high-risk neuroblastoma in pediatric patients, when used in combination with cytokines, as part of a multimodality therapy.

To ensure safe and effective use of the product, Health Canada revised the proposed indication to reflect the treatment regimen used and the target patient population studied in the pivotal clinical trial. Accordingly, Health Canada approved the following indication:

• Unituxin (dinutuximab) is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of high-risk neuroblastoma in pediatric patients who achieve at least a partial response to prior first-line multi-agent, multimodality therapy.

For more information, refer to the Unituxin Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Unituxin, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), in the treatment of high-risk neuroblastoma was evaluated in the pivotal study DIV-NB-301 (ANBL0032) (described in the Clinical Efficacy section) and two supportive studies, DIV-NB-302 (ANBL0032) and DIV-NB-303 (ANBL0931).

The safety population of the pivotal study DIV-NB-301 (ANBL0032) included 249 treated patients. Of these, 138 patients received immunotherapy plus RA (113 randomized patients and 25 non-randomized patients with biopsy-confirmed residual disease following autologous stem cell transplantation) and 111 patients received RA alone. All patients in the safety population were analyzed according to the treatment received. As per the protocol of the Children's Oncology Group (COG), sites were required to report only grade 3 or higher-grade adverse events, although as least one grade 1 or 2 adverse event was reported in 169 and 181 patients, respectively.

The main analysis for safety was part of the confirmatory analysis (herein referred to as confirmatory safety analysis), conducted 6 months after the close of randomization. In this analysis, the most commonly reported adverse events in the immunotherapy plus RA group included: pyrexia (70%), platelet disorder (65%), lymphopenia (62%), drug hypersensitivity (59%), hypotension (58%), hyponatremia (56%), increased alanine aminotransferase (54%), abdominal pain (54%), low hemoglobin (49%), vomiting (44%), diarrhea (42%), and hypokalemia (42%). The proportions of patients experiencing grade 3, 4, and 5 toxicity in the immunotherapy plus RA group were 93%, 49%, and 1%, respectively (compared to 55%, 22%, and 1%, respectively, in the RA alone group). The incidence of grade 3 or higher-grade toxicities attributable to study therapy overall was 92.8% in the immunotherapy plus RA group and 36.9% in the RA alone group. Specific types of such adverse events in the immunotherapy plus RA arm that exceeded 19% included lymphopenia (48.6%), thrombocytopenia (34.1%), fever (37%), anemia (28.3%), granulocytopenia (28.3%), hypokalemia (31.2%), abdominal pain (28.3%), drug hypersensitivity (25.4%), elevated alanine aminotransferase (21%), hyponatremia (21.7%), capillary leak syndrome (21.7%), and pain (19.6%).

Initially, adverse events of special interest, also called targeted toxicities, included drug hypersensitivity, capillary leak syndrome, and peripheral neuropathy. This list was expanded in the follow-up safety analysis to include hypotension, urticaria, anaphylactic reactions, dyspnea, cytokine release syndrome, and acute respiratory distress syndrome. These adverse events were reported regardless of grade. In the follow-up safety analysis of the immunotherapy plus RA arm, adverse events that were attributable to study therapy included hypotension reported in 50% of patients, hypersensitivity (53.4%), urticaria (39.2%), capillary leak syndrome (38.5%), and anaphylactic reactions (25%). Only 4.1% of these patients experienced cytokine release syndrome and/or dyspnea and no patients experienced acute respiratory distress syndrome. The higher incidences of targeted toxicities occurred during course 2 and 4 when IL-2 was given. The proportion of patients reporting capillary leak syndrome and/or anaphylactic reactions was nearly twofold greater in courses 2 and 4 compared to other courses. According to the confirmatory safety analysis, only six deaths occurred in the first 30 days after the last study therapy: four in the immunotherapy plus RA arm and two in the RA alone arm. All except two deaths were due to progressive disease. One patient in the immunotherapy plus RA arm died from therapy-related causes. This death was due to capillary leak syndrome secondary to an overdose of IL-2 evoked by a medication error. The second death, which occurred in the RA alone arm, was attributed to hypoxia of unknown origin.

The follow-up safety analysis was performed three and a half years after patient randomization was terminated and three years after the confirmatory safety analysis. Results of this analysis were very similar to those in the confirmatory safety analysis. The proportion of grade 3, 4, and 5 toxicities were 93%, 49%, and 1% in the immunotherapy plus RA group versus 59%, 23%, and 1%, respectively, in the RA alone group.

Overall, the addition of Unituxin, GM-CSF, and IL-2 to RA therapy was associated with a substantial increase in the number and severity of reported adverse events as compared to therapy with RA alone. Adverse events tended to be more prevalent and more severe during IL-2 courses as compared to GM-CSF courses. Given the fact that only six subjects discontinued study therapy due to an adverse event during this study and given that only one death could be directly attributable to study therapy with immunotherapy plus RA, this regimen appears tolerable for most subjects when administered in specialized clinical setting by highly trained and experienced healthcare providers.

Supportive Studies - DIV-NB-302 (ANBL0032) and DIV-NB-303 (ANBL0931)

Study DIV-NB-302 (ANBL0032) was a non-randomized extension of the immunotherapy plus RA arm of the pivotal study DIV-NB-301 (ANBL0032). It involved continuation of patient accrual solely into the immunotherapy plus RA arm once randomization was terminated at the recommendation of the Data Safety and Monitoring Committee for reasons of improved efficacy over the RA alone arm (see Clinical Efficacy).

The safety profile in this single-cohort study reflected that of the immunotherapy plus RA group in the pivotal study. Similar high rates of attributable toxicities were reported in studies DIV-NB-301 (ANBL0032) and DIV-NB-302 (ANBL0032) in the immunotherapy plus RA groups, both for non-targeted and targeted toxicities. Ninety percent of patients reported at least one targeted toxicity: hypotension (67%), hypersensitivity (59%), urticaria (54%), capillary leak syndrome (47%), anaphylactic reaction (17%), dyspnea (13%), cytokine release syndrome (12%), and acute respiratory distress syndrome (2%). No new safety signals were noted. As in study DIV-NB-301 (ANBL0032), higher incidences of toxicity, particularly grade 4 hypotensive events, anaphylactic reactions, and capillary leak syndrome, were reported during courses 2 and 4 following IL-2 administration.

Study DIV-NB-303 (ANBL0931) was the second major supportive study, designed as a multicentre, single-arm study with a primary objective to better define the safety profile of the immunotherapy plus RA regimen. One hundred and four patients received at least one dose of study therapy and 77% of them completed study therapy. Among 24 patients who discontinued study therapy prematurely, 14 patients discontinued study drug due to toxicity (8 patients) or withdrawal of consent (6 patients). As in studies DIV-NB-301 (ANBL0032) and DIV-NB-302 (ANBL0032), the most common (≥25%) grade 3 or higher-grade adverse events attributable to Unituxin were pyrexia (64%), pain (39%), decreased platelet count (39%), hypokalemia (39%), decreased lymphocyte count (35%), hyponatremia (28%), hypotension (27%), and decreased neutrophil count (25%). Just over half of reported adverse events were considered related to the immunotherapy plus RA regimen. Overall, the safety profile of the Unituxin-containing regimen was similar to that observed in studies DIV-NB-301 (ANBL0032) and DIV-NB-302 (ANBL0032), except for the occurrences of nasal congestion (20%) and wheezing (15%), which were not reported in study DIV-NB-301 (ANBL0032).

A Serious Warnings and Precautions box was included in the Unituxin Product Monograph to highlight the risk of serious and potentially life-threatening infusion reactions and the risk of neurotoxicity (i.e., severe neuropathic pain, severe peripheral sensory neuropathy, and severe peripheral motor neuropathy). Required premedication and hydration prior to each Unituxin infusion, guidelines for pain management and infusion reactions, and dose modifications and/or discontinuation strategies for severe adverse reactions are also included in the Unituxin Product Monograph.

For more information, refer to the Unituxin Product Monograph, approved by Health Canada and available through the Drug Product Database.