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Journal of Clinical Oncology : Official... Jan 2024Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse...
PURPOSE
Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse after completion of immunotherapy was investigated previously in a single-arm, phase II study (NMTRC003B; ClinicalTrials.gov identifier: NCT02395666) that suggested improved event-free survival (EFS) and overall survival (OS) compared with historical rates in a phase III trial (Children Oncology Group ANBL0032; ClinicalTrials.gov identifier: NCT00026312). Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate DFMO as HRNB postimmunotherapy maintenance.
PATIENTS AND METHODS
NMTRC003B (2012-2016) enrolled patients with HRNB (N = 141) after standard up-front or refractory/relapse treatment who received up to 2 years of continuous treatment with oral DFMO (750 ± 250 mg/m twice a day). ANBL0032 (2001-2015) enrolled patients with HRNB postconsolidation, 1,328 of whom were assigned to dinutuximab (ch.14.18) treatment. Selection rules identified 92 NMTRC003B patients who participated in (n = 87) or received up-front treatment consistent with (n = 5) ANBL0032 (the DFMO/treated group) and 852 patients from ANBL0032 who could have been eligible for NMTRC003B after immunotherapy, but did not enroll (the NO-DFMO/control group). The median follow-up time for DFMO/treated patients was 6.1 years (IQR, 5.2-7.2) versus 5.0 years (IQR, 3.5-7.0) for NO-DFMO/control patients. Kaplan-Meier and Cox regression compared EFS and OS for overall groups, 3:1 (NO-DFMO:DFMO) propensity score-matched cohorts balanced on 11 baseline demographic and disease characteristics with exact matching on , and additional sensitivity analyses.
RESULTS
DFMO after completion of immunotherapy was associated with improved EFS (hazard ratio [HR], 0.50 [95% CI, 0.29 to 0.84]; = .008) and OS (HR, 0.38 [95% CI, 0.19 to 0.76]; = .007). The results were confirmed with propensity score-matched cohorts and sensitivity analyses.
CONCLUSION
The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.
Topics: Child; Humans; Eflornithine; Propensity Score; Neoplasm Recurrence, Local; Neuroblastoma; Recurrence; Disease-Free Survival
PubMed: 37883734
DOI: 10.1200/JCO.22.02875 -
Frontiers in Oncology 2023Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line...
Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line chemotherapy regimens. Chemotherapy combined with anti-GD2 antibodies has previously been shown to increase response and survival rates. We retrospectively analyzed a cohort of 25 patients with relapsed or refractory high-risk neuroblastoma who were treated with irinotecan/temozolomide chemotherapy in combination with the anti-GD2 antibody dinutuximab beta. The therapy resulted in an objective response rate of 64%, with 32% of patients achieving a complete response. Response to treatment was observed in patients with refractory disease (n=5) and those with first (n=12) or consecutive (n=8) relapses, including patients with progressing disease. In four patients, best response was achieved after more than 5 cycles, suggesting that some patients may benefit from prolonged chemotherapy and dinutuximab beta treatment. Fourteen of our 25 patients had previously received dinutuximab beta, four of whom achieved complete response and six partial response (objective response rate 71%). The therapy was well tolerated, even in heavily pre-treated patients and those who had previously received dinutuximab beta treatment. Toxicities were comparable to those previously reported for the individual therapies, and no discontinuations due to toxicities occurred. Combination of chemotherapy with dinutuximab beta is a promising treatment option for patients with relapsed or refractory high-risk neuroblastoma and should be further explored in clinical studies.
PubMed: 36816982
DOI: 10.3389/fonc.2023.1082771 -
Australian Prescriber Dec 2020
Review
PubMed: 33363307
DOI: 10.18773/austprescr.2020.068 -
Pediatric Blood & Cancer Sep 2022Dinutuximab, an immune-mediated therapy indicated for high-risk neuroblastoma, targets the protein disialoganglioside (GD2) on neuroblastoma cells, neurons, and... (Observational Study)
Observational Study
BACKGROUND
Dinutuximab, an immune-mediated therapy indicated for high-risk neuroblastoma, targets the protein disialoganglioside (GD2) on neuroblastoma cells, neurons, and peripheral nerve fibers. Off-target effects lead to severe nerve pain. Pain regimens including continuous infusion opioids are required during treatment courses. Our institution utilizes a combination of intravenous (i.v.) lidocaine infusions and morphine for the treatment of dinutuximab-associated neuropathic pain.
OBJECTIVE
The primary outcome of this study was to compare morphine equivalents for cycle 1 of dinutuximab at an institution that uses i.v. lidocaine (primary) versus those that do not (comparison). Secondary outcomes included both dinutuximab infusion time and safety of i.v. lidocaine.
METHODS
A retrospective, multicentered, electronic chart review was performed at three tertiary academic medical centers. Patients between 0 and 18 years of age during their first course of dinutuximab were included to evaluate the primary outcome of adjuvant morphine equivalents needed.
RESULTS
Twenty-one patients were identified for inclusion. Total morphine equivalents at the primary institution were 1.87 mg/kg versus 1.79 mg/kg at the comparison institutions (P = 0.413). Dinutuximab infusion time was statistically significantly less at the primary institution: 610.5 minutes versus 676.23 minutes (P = 0.046). Only one patient at the primary institution experienced nausea, vomiting, and paresthesias.
CONCLUSIONS
This study did not find a statistically significant difference in morphine equivalents between patients receiving i.v. lidocaine and those who did not. Lidocaine use resulted in a statistically significant lower dinutuximab infusion time. Our data suggest it is a safe adjuvant medication, for use outside of the pediatric intensive care unit, in the treatment of dinutuximab-associated neuropathic pain.
Topics: Antibodies, Monoclonal; Child; Humans; Lidocaine; Morphine Derivatives; Neuralgia; Neuroblastoma; Retrospective Studies
PubMed: 35441791
DOI: 10.1002/pbc.29653 -
Lung Cancer (Amsterdam, Netherlands) Apr 2022Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer.
INTRODUCTION
Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC.
MATERIALS AND METHODS
Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/m intravenous (IV)/irinotecan 350 mg/m IV (day 1), irinotecan 350 mg/m IV (day 1), or topotecan 1.5 mg/m IV (days 1-5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed.
RESULTS
A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia.
CONCLUSIONS
Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days.
CLINICALTRIALS
gov Identifier. NCT03098030.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Irinotecan; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma; Topotecan
PubMed: 35278766
DOI: 10.1016/j.lungcan.2022.03.003 -
European Journal of Cancer (Oxford,... Sep 2022Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease...
Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group.
PURPOSE
Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes.
METHODS
AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m/day over 20 h (2 days) and 17.5 mg/m/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10-34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics.
RESULTS
Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules.
CONCLUSIONS
The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.
Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neoplasm Recurrence, Local; Osteosarcoma; Young Adult
PubMed: 35809374
DOI: 10.1016/j.ejca.2022.05.035 -
Cancers Sep 2023Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment...
Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.
PubMed: 37760578
DOI: 10.3390/cancers15184609 -
Journal For Immunotherapy of Cancer Jul 2023Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic...
BACKGROUND
Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic pain by binding GD2-expressing sensory neurons. Previously, the IgG1 ch14.18 (dinutuximab) antibody was reformatted into the IgA1 isotype, which abolishes neuropathic pain and induces efficient neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) via activation of the Fc alpha receptor (FcαRI/CD89).
METHODS
To generate an antibody suitable for clinical application, we engineered an IgA molecule (named IgA3.0 ch14.18) with increased stability, mutated glycosylation sites and substituted free (reactive) cysteines. The following mutations were introduced: N45.2G and P124R (CH1 domain), C92S, N120T, I121L and T122S (CH2 domain) and a deletion of the tail piece P131-Y148 (CH3 domain). IgA3.0 ch14.18 was evaluated in binding assays and in ADCC and antibody-dependent cellular phagocytosis (ADCP) assays with human, neuroblastoma patient and non-human primate effector cells. We performed mass spectrometry analysis of -glycans and evaluated the impact of altered glycosylation in IgA3.0 ch14.18 on antibody half-life by performing pharmacokinetic (PK) studies in mice injected intravenously with 5 mg/kg antibody solution. A dose escalation study was performed to determine in vivo efficacy of IgA3.0 ch14.18 in an intraperitoneal mouse model using 9464D-GD2 neuroblastoma cells as well as in a subcutaneous human xenograft model using IMR32 neuroblastoma cells. Binding assays and PK studies were compared with one-way analysis of variance (ANOVA), ADCC and ADCP assays and in vivo tumor outgrowth with two-way ANOVA followed by Tukey's post-hoc test.
RESULTS
ADCC and ADCP assays showed that particularly neutrophils and macrophages from healthy donors, non-human primates and patients with neuroblastoma are able to kill neuroblastoma tumor cells efficiently with IgA3.0 ch14.18. IgA3.0 ch14.18 contains a more favorable glycosylation pattern, corresponding to an increased antibody half-life in mice compared with IgA1 and IgA2. Furthermore, IgA3.0 ch14.18 penetrates neuroblastoma tumors in vivo and halts tumor outgrowth in both 9464D-GD2 and IMR32 long-term tumor models.
CONCLUSIONS
IgA3.0 ch14.18 is a promising new therapy for neuroblastoma, showing (1) increased half-life compared to natural IgA antibodies, (2) increased protein stability enabling effortless production and purification, (3) potent CD89-mediated tumor killing in vitro by healthy subjects and patients with neuroblastoma and (4) antitumor efficacy in long-term mouse neuroblastoma models.
Topics: Humans; Animals; Mice; Immunoglobulin A; Neuroblastoma; Immunotherapy; Immunoglobulin G; Antibody-Dependent Cell Cytotoxicity; Disease Models, Animal
PubMed: 37479484
DOI: 10.1136/jitc-2023-006948 -
The Journal of Pharmacology and... Sep 2019Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical... (Review)
Review
Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior are especially visible in relapsed or refractory cases and hamper therapeutic success. Although the introduction of novel antitumor agents, such as dinutuximab, isotretinoin, irinotecan, or I-131- metaiodobenzylguanidine, has increased survival rates, the situation in high-risk NB remains dismal. Moreover, treatment is particularly aggressive in these patients, leading to short- and long-term toxicities. The extensive research performed using nanotechnology in recent decades has prompted its application as a therapeutic alternative to overcome some of the common limitations of conventional chemotherapy. Nevertheless, the therapeutic role of nanomedicine in pediatric tumors like NB is not fully elucidated, and to date, only albumin-bound paclitaxel nanoparticles have reached clinic stages. In this review, we summarize the current therapeutic strategies for NB with special attention to the use of nanomedicine. We also highlight the preclinical studies on passive and active targeting nanodelivery of therapeutics in experimental NB models.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Delivery Systems; Humans; Nanotechnology; Neuroblastoma
PubMed: 30635473
DOI: 10.1124/jpet.118.255067 -
Targeted Oncology Jan 2023The anti-GD2 antibody dinutuximab beta (Qarziba) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive... (Review)
Review
The anti-GD2 antibody dinutuximab beta (Qarziba) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. Topics such as the mode of preparation and administration, the concomitant use of interleukin-2, the recommended pediatric age and dose for its use, or the adequate management of possible toxicities are important aspects to review. The objective of this article was to update the clinical guide to management with dinutuximab beta of children with neuroblastoma based on the most recent published evidence and our own experience in clinical practice.
Topics: Child; Humans; Neuroblastoma; Antibodies, Monoclonal; Europe
PubMed: 36504394
DOI: 10.1007/s11523-022-00930-w