Refractory High-risk Neuroblastoma Research Articles

High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy.

Immunotherapy has emerged as an attractive option for patients with relapsed or refractory high-risk neuroblastoma (HRNB). Neuroblastoma (NB), a sympathetic nervous system cancer arising from an embryonic neural crest cell, is heterogeneous clinically, with outcomes ranging from an isolated abdominal mass that spontaneously regresses to a widely metastatic disease with cure rates of about 50% despite intensive multimodal treatment. Risk group stratification and stage-adapted therapy to achieve cure with minimal toxicities have accomplished major milestones. Targeted immunotherapeutic approaches including monoclonal antibodies, vaccines, adoptive cellular therapies, their combinations, and their integration into standard of care are attractive therapeutic options, although curative challenges and toxicity concerns remain. In this review, we provide an overview of immune approaches to NB and the tumor microenvironment (TME) within the clinical translational framework. We propose a novel T cell-based therapeutic approach that leverages the unique properties of tumor surface antigens such as ganglioside GD2, incorporating specific monoclonal antibodies and recent advancements in adoptive cell therapy.

Survival outcomes in patients with high-risk neuroblastoma (HRNB) in remission after relapsed or refractory treatment receiving eflornithine (DFMO) maintenance.

10060 Background: Five-year overall survival in newly diagnosed HRNB patients is around 50%, with relapse as the primary cause of mortality. While survival for newly diagnosed HRNB has improved with new treatment advances, relapsed or refractory (R/R) patients continue to have poor outcomes, with a high risk of subsequent relapse even among those who achieve remission, underscoring the need for treatments to improve EFS in this group. DFMO has been evaluated as a chemopreventative therapy in a single arm phase 2 study designed to compare Event Free Survival (EFS) and Overall Survival (OS) outcomes with published data for HRNB. The results of patients treated after standard therapy have been previously published. We now present an analysis of EFS/OS for patients with R/R disease, who historically have had a two-year EFS of approximately 10%. Methods: A total of 140 HRNB patients were enrolled, prospectively divided into two strata. S1 included patients in initial remission after upfront therapy, whereas S2 included patients who had either relapsed or had disease refractory to standard induction chemotherapy but achieved remission with additional therapy. Patients received 2 years of continuous treatment with oral DFMO 750 ±250 mg/m2 BID and were followed for up to 7 years. Results: A total of 35 patients withR/R disease who had achieved remission after additional therapy were enrolled onto S2, including 28 patients in remission after one or more prior relapses and 7 refractory patients in remission after subsequent therapies. Of the relapsed patients, 23 had one prior relapse, while 5 patients had two or more relapses prior to enrollment; only one previously relapsed patient had received chemoimmunotherapy prior to enrollment in the study. For the entireS2 cohort, two-year EFS was 46% (95% CI 29%, 61%) with the lower confidence interval above the 10% historical control estimate. Four-year EFS was 46% (95% CI 29%, 61%) and OS 62% (95% CI 44%, 76%), with no relapses occurring after 18 months. For patients enrolled with refractory disease only (n=7) the four-year EFS was 85.7%. In the 28 relapsed patients, the four-year EFS was 35.7%, with single relapse patients (n=23) having an EFS rate of 39.1% and multiple relapsed patients (n=5) 20.0%. Conclusions: Patients in remission after chemotherapy for relapsed or refractory HRNB and treated with DFMO had improved EFS compared to the best historical estimate available at the time of the study. Although the number of patients is too small to support clear conclusions, the subgroup of refractory patients had outcomes that trended better than the relapsed subgroup with an EFS rate that was unexpectedly similar to prior reports of DFMO-treated S1 patients in remission after standard upfront therapy. Clinical trial information: NCT02395666 , NCT00026312 .

The neuroblastoma tumor microenvironment: From an in-depth characterization towards novel therapies

Neuroblastoma is a cancer of the sympathetic nervous system that develops in young children, either as low-risk or high-risk disease. The tumor microenvironment (TME) is now recognized as an important player of the tumor ecosystem that may promote drug resistance and immune escape. Targeting the TME in combination with therapies directly targeting tumor cells therefore represents an interesting strategy to prevent the emergence of resistance in cancer and improve patient’s outcome. The development of such strategies however requires an in-depth understanding of the TME landscape, due to its high complexity and intra and inter-tumoral heterogeneity. Various approaches have been used in the last years to characterize the immune and non-immune cell populations present in tumors of neuroblastoma patients, both quantitatively and qualitatively, in particular with the use of single-cell transcriptomics. It is anticipated that in the near future, both genomic and TME information in tumors will contribute to a precise approach to therapy in neuroblastoma. Deciphering the mechanisms of interaction between neuroblastoma cells and stromal or immune cells in the TME is key to identify novel therapeutic combinations. Over the last decade, numerous in vitro studies and in vivo pre-clinical experiments in immune-competent and immune-deficient models have identified therapeutic approaches to circumvent drug resistance and immune escape. Some of these studies have formed the basis for early phase I and II clinical trials in children with recurrent and refractory high-risk neuroblastoma. This review summarizes recently published data on the characterization of the TME landscape in neuroblastoma and novel strategies targeting various TME cellular components, molecules and pathways activated as a result of the tumor-host interactions.

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Early Salvage Chemo-Immunotherapy with Irinotecan, Temozolomide and Naxitamab Plus GM-CSF (HITS) for Patients with Primary Refractory High-Risk Neuroblastoma Provide the Best Chance for Long-Term Outcomes.

Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)-HITS-against primary resistant HR-NB. Eligibility criteria included having a measurable chemo-resistant disease at the end of induction (EOI) treatment. Patients were excluded if they had progressive disease (PD) during induction. Prior anti-GD2 mAb and/or I/T therapy was permitted. Each cycle, administered four weeks apart, comprised Irinotecan 50 mg/m2/day intravenously (IV) plus Temozolomide 150 mg/m2/day orally (days 1-5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously was used (days 6-10). Toxicity was measured using CTCAE v4.0 and responses through the modified International Neuroblastoma Response Criteria (INRC). Thirty-four patients (median age at treatment initiation, 4.9 years) received 164 (median 4; 1-12) HITS cycles. Toxicities included myelosuppression and diarrhea, which was expected with I/T, and pain and hypertension, expected with naxitamab. Grade ≥3-related toxicities occurred in 29 (85%) of the 34 patients; treatment was outpatient. The best responses were CR = 29% (n = 10); PR = 3% (n = 1); SD = 53% (n = 18); PD = 5% (n = 5). For cohort 1 (early treatment), the best responses were CR = 47% (n = 8) and SD = 53% (n = 9). In cohort 2 (late treatment), the best responses were CR = 12% (n = 2); PR = 6% (n = 1); SD = 53% (n = 9); and PD = 29% (n = 5). Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFS p = 0.0041 and OS p = 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment.

Reduction in curie score in neuroblastoma patients treated with naxitamab.

10042 Background: Patients with high-risk neuroblastoma (HR-NB) most frequently present with metastases in the bone marrow (BM; 70–89%) and bone (56–65%). Approximately 15% of HR-NB patients will be refractory to induction therapy and 50% will relapse. Naxitamab is a humanized GD2-binding monoclonal antibody approved in the US with granulocyte-macrophage colony-stimulating factor (GM-CSF) for treatment of patients ≥1-yr with refractory/relapsed (R/R) HR-NB in the bone or BM with partial response, minor response, or stable disease to prior therapy. Curie Score (CS) is an important tool for assessing extent of disease and treatment response. The reduction in CS by baseline disease status, i.e., refractory or relapsed, from Trial 201 pre-specified interim analysis (data cut-off 31-dec-2021) is reported. Methods: Ongoing Trial 201 (phase II, NCT03363373) evaluates naxitamab+GM-CSF in patients with R/R HR-NB with residual disease limited to bone/BM. Soft tissue and actively progressing disease were addressed prior to enrollment. Naxitamab was administered (intravenously) at 3mg/kg/day over 30-60 min on Days 1/3/5 with GM-CSF (subcutaneous) on Days -4 to 5 at 4-week cycles. 123I-MIBG scans were used to assess CS and treatment response according to INRC criteria per independent review. Results: Interim analysis included 52 (efficacy group) and 74 (safety) patients. The primary endpoint achieved an overall response rate (ORR) of 50% [95% CI: 35.8- 64.2] with complete response rate (CR) of 38%. A summary of changes in overall CS by disease status is reported in the table. Median change in CS from baseline to end of treatment (EOT) was −1 across refractory and relapsed subgroups and ranged from −18 to 18. Baseline CS (≤ 2 vs. ≥3) did not affect the safety profile. The most common adverse events were pain, hypotension, urticaria, and bronchospasm. The frequency of Grade 3 or higher and serious related adverse events was lower for patients with refractory vs. relapsed disease, i.e. lower rates of severe hypotension (51% vs. 68%), increased ALT (0% vs. 14%), and hypoxia (3% vs. 16%). Conclusions: Clinically meaningful reductions in CS were seen in patients regardless of baseline disease status (relapsed or refractory HR-NB). Baseline CS did not affect the safety profile. Refractory patients had a lower frequency of severe and serious related adverse events.. Clinical trial information: NCT03363373 . [Table: see text]

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma.

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.

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children’s Oncology Group

BackgroundIn the Children’s Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy...

62MO Naxitamab pivotal clinical trial planned interim analysis of PFS and OS in patients with relapsed or refractory high-risk neuroblastoma

Naxitamab (NAX) is a humanized GD2-binding monoclonal antibody approved in the US with granulocyte-macrophage colony-stimulating factor (GM-CSF) under accelerated approval based in part on ad hoc analysis of data from the registrational phase II 201 trial (NCT03363373). We report progression free (PFS) and overall survival (OS) results of prespecified interim analyses.

Hypofractionated Palliative Radiotherapy for Relapsed and Refractory High-Risk Neuroblastoma

<h3>Purpose/Objective(s)</h3> While palliative radiation therapy (RT) is frequently used in the management of relapsed/refractory high-risk neuroblastoma (HR-NBL) in pediatric patients, few studies have examined the role of palliative hypofractionated RT (hypo-RT) in HR-NBL. We sought to characterize outcomes after palliative-intent RT using conventionally fractionated (conv-RT) and hypo-RT regimens for patients with relapsed/refractory HR-NBL. <h3>Materials/Methods</h3> The Institutional Review Board approved a retrospective study of 37 patients who were diagnosed with HR-NBL between 1997-2021 and received palliative RT at two institutions. Patients receiving RT for central nervous system and liver metastases were excluded. Hypo-RT was defined as treatment courses using dose >2 Gy per fraction. Clinical and treatment characteristics and outcomes, including dates and locations of progression, were recorded. Fisher exact tests were used for categorical variables. Follow-up time was defined from start of RT. Cumulative incidence of in-field progression was analyzed using Gray's test with death as competing risk. Univariate analyses (UVA) were performed using Cox proportional-hazards regression. <h3>Results</h3> When analyzing by first course of palliative RT, there were 16 courses of conv-RT (43.2%) and 21 courses of hypo-RT (56.8%). The distribution of patients having further progression of disease before palliative RT, receiving palliative RT to bony and soft tissue sites, and undergoing chemotherapy before, during, and after palliative RT were not different between the two groups. With median follow-up of 10.3 months (range: 0.3-104.0), cumulative incidence of in-field progression at 10 months was not different between hypo-RT and conv-RT (30.0% vs 20.1%, p=0.80). After RT, patients had similar clinical benefit, defined as symptomatic relief or decrease in size of lesion (92.3% conv-RT vs. 90.0% hypo-RT, p=1.00). On UVA, further progression of disease before palliative RT, bony vs. soft tissue sites, receipt of chemotherapy before RT, receipt of concurrent chemotherapy with RT, and receipt of chemotherapy after RT were not associated with time to in-field progression. In addition, hypo-RT (Hazard ratio [HR]: 1.50, 95% confidence interval [CI]: 0.47-4.76, p=0.49) and biologically equivalent dose (BED) ≥29 Gy (HR: 1.44, 95% CI: 0.43-4.82, p=0.55) were not associated with time to in-field progression. <h3>Conclusion</h3> We found no difference in cumulative incidence of in-field progression and clinical outcomes between the conv-RT and hypo-RT groups. On UVA, hypo-RT and BED ≥29 Gy were not associated with longer time to in-field recurrence. Palliative hypo-RT can be considered for relapsed/refractory HR-NBL, especially when quality of life from shorter treatments may be of benefit.

891P Naxitamab treatment for relapsed or refractory high-risk neuroblastoma: Outcomes from the first prespecified analyses of the Pivotal 201 Trial

Naxitamab is a humanized GD2-binding monoclonal antibody approved in the US with GM-CSF for the treatment of relapsed/refractory high-risk neuroblastoma (HR-NB) in the bone/bone marrow (BM). This accelerated approval was based in part on an ad hoc analysis of data from the registrational phase II 201 trial (NCT03363373). Here we report the first results of a prespecified analysis from this same trial. Trial 201 is an ongoing phase II trial evaluating naxitamab+GM-CSF in patients with relapsed/refractory HR-NB with residual disease limited to bone/BM. Patients with progressive or residual soft tissue disease were not eligible. Naxitamab was administered over 30-60 min in the outpatient setting on Days 1/3/5 with GM-CSF on Days –4 to 5; cycles were 28 days. Efficacy was evaluated by independent pathology and radiology review per revised International Neuroblastoma Response Criteria. Assuming an actual overall response rate (ORR; complete response [CR] + partial response [PR]) of 45%, a sample size of 37 patients was considered sufficient to ensure ≥90% power to exclude an overall response rate of ≤20% at an α-level of 0.05. At data cutoff (Dec 31, 2021) there were 52 patients in the efficacy population and 74 in safety. The ORR was 50.0% (26/52; 95% CI 36-64%) with a CR rate of 38.5% (95% CI 25-53%). The trial met the primary endpoint for the prespecified analysis as the lower 95% CI for ORR was >20%. Disease control rate (CR+PR+minor response+stable disease) was 78.8% (41/52; 95% CI 65-89%) The adverse event (AE) profile was like previous reports with most being infusion-related reactions including hypotension and pain. 44.6% (33/74) of patients experienced ≥1 treatment-emergent serious AE; 6.8% (5/74) patients discontinued naxitamab due to treatment-emergent AEs. There were no deaths related to naxitamab. Based on this prespecified analysis, naxitamab provides a significant and clinically relevant response in patients with relapsed/refractory HR-NB limited to bone/BM – frequent sites of residual disease. These efficacy results combined with a manageable safety profile demonstrate that naxitamab addresses a significant unmet medical need.

Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma.

Simple SummaryBeta glucans, complex polysaccharides, can prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of monoclonal antibodies. In a phase I study (clinicaltrials.gov NCT00492167), we treated patients with intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles of therapy with 3F8 + BG. One patient developed DLT: transient self-limiting hepatic transaminase elevation at a BG dose of 120 mg/kg/day. Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. BG lacked major toxicity and, in combination with 3F8, demonstrated anti-neuroblastoma activity against resistant disease. The recommended phase II dose was established at 40 mg/kg/day.Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

Dinutuximab (Unituxin)

&#x0D; CADTH recommends that Unituxin (in combination with irinotecan, temozolomide, and granulocyte macrophage colony-stimulating factor [GM-CSF]) should be reimbursed by public drug plans for the treatment of patients with relapsed or refractory high-risk neuroblastoma if certain conditions are met.&#x0D; Unituxin should only be reimbursed if delivered in a specialized pediatric cancer centre by health care professionals with experience and knowledge of managing neuroblastoma and the toxicities of anti-GD2 therapy and if the cost of Unituxin is reduced.&#x0D; Unituxin should only be covered for patients who have not had previous treatment for relapsed or refractory high-risk neuroblastoma or have not had a severe reaction or progressive disease with upfront anti-GD2 immunotherapy.&#x0D;

Naxitamab combined with granulocyte-macrophage colony-stimulating factor as consolidation for high-risk neuroblastoma patients in complete remission.

Naxitamab is a humanized anti-disialoganglioside (GD2) monoclonal antibody approved for treatment of bone/bone marrow refractory high-risk neuroblastoma (HR-NB). Compassionate use (CU) expanded access program at Hospital Sant Joan de Deu permitted treatment of patients in complete remission (CR). We here report the survival, toxicity, and relapse pattern of patients in first or second CR treated with naxitamab and sargramostim (GM-CSF). Seventy-three consecutive patients with HR-NB (stage M at age >18months or MYCN-amplified stages L1/L2 at any age) were treated in first or second CR. Treatment comprised five cycles of subcutaneous (SC) GM-CSF for 5days at 250μg/m2 /day (days -4 to 0), followed by naxitamab + SC GM-CSF for 5days at 500μg/m2 /day (days 1-5). Naxitamab was infused over 30minutes at 3mg/kg/day, days 1, 3, and 5, outpatient. Fifty-five patients were in first CR and 18 in second CR. Seventeen patients had MYCN-amplified NB and 11 detectable minimal residual disease in the bone marrow. Fifty-eight (79.5%) patients completed therapy. Four (5%) experienced grade 4 toxicities and 10 (14%) early relapse. Three-year event-free survival (EFS) 58.4%, 95% CI=(43.5%, 78.4%) and overall survival (OS) 82.4%, 95% CI=(66.8%, 100%). First CR patients 3-year EFS 74.3%, 95% CI=(62.7%, 88.1%), and OS 91.6%, 95% CI=(82.4%, 100%). EFS is significantly different between first and second CR (p=.0029). The pattern of relapse is predominantly (75%) of an isolated organ, mainly bone (54%). Univariate Cox models show prior history of relapse as the only statistically significant predictor of EFS but not OS. Consolidation with naxitamab and GM-CSF resulted in excellent survival rates for HR-NB patients in CR.

Naxitamab: First Approval.

Naxitamab (DANYELZA®, naxitamab-gqgk) is a humanised (IgG1) anti-GD2 (hu3F8) monoclonal antibody was developed by the Memorial Sloan Kettering Cancer Center (with commercial rights licenced to Y-mAbs therapeutics Inc.) for the treatment of neuroblastoma, osteosarcoma and other GD2-positive cancers. Naxitamab was recently granted accelerated approval by the US FDA for marketing as treatment (in combination with granulocyte-macrophage colony-stimulating factor) for paediatric patients at least one year of age and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy. This article summarizes the milestones in the development of naxitamab leading to this first approval.

Impact of Initial Prognostic Factors and Intensity of Salvage Therapy on the Outcome of Progressive / Refractory High-Risk Neuroblastoma

Background: High-risk Neuroblastoma (N. B) patients have a poor outcome with 5-year survival rates of 50%. Patients with stage 4 disease or MYC-N amplification showed post-progression 5y O. S. of 7% to 8%. Other studies proved the same dismal outcome in high-risk relapsed patients. This study aimed to detect the O. S. and EFS of N. B patients post-progression. Secondary to explore, if initial prognostic factors, high-intensity salvage therapy and other treatment modalities could improve the outcome of progressive /refractory disease. Methods: Seventy patients of high-risk Neuroblastoma needed salvage therapy, either due to refractory/progressive disease or irresectability of the primary tumor. Initial prognostic factors and different treatment strategies were collected and correlated with the outcome. Results: Fifty-seven (57 /70) patients died from progressive disease with a median survival of 20.6 months with three y EFS and O. S. of 9.5% and 35.7%, respectively. Objective response (CR/VGPR/PR) post-induction, consolidation by HSCT, radiotherapy, and maintenance therapy; affected survival significantly post salvage therapy. Multivariate analysis revealed that the only independent factor that significantly affected O. S was maintenance therapy. The independent factors that affected the EFS negatively were the presence of liver metastases, poor response post-induction, and not administering radiotherapy. Conclusion: Response to induction had a significant impact on the outcome post salvage. Salvage therapy did not improve the outcome for those with inadequate induction response. Initial front-line targeted therapy like antiGD2 is needed to improve the outcome, especially for chemo-resistant ones.

Randomized comparisons of bevacizumab (B) and irinotecan (I), added to temozolomide (T), in children with relapsed or refractory high-risk neuroblastoma (RR-HRNB): First survival results of the ITCC-SIOPEN BEACON-Neuroblastoma phase II trial.

10501 Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR) &lt;1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat. Results: From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with: median age 5.8 years; 113 and 47 measurable and evaluable disease; 67 and 93 refractory and relapsed disease; 35 had MYCN amplification. Median follow-up was 15.4 months. PFS and OS are shown in the table. In the main comparisons (I v. no I, B v. no B), I improved PFS and OS (98% probability that true HR&lt;1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19). However, there was some, but not conclusive, evidence of a positive interaction between B and I for both PFS (HT: p=0.06) and OS (HT: p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both (BIT) does. Twice as many patients had serious adverse events with BIT (57%) than with T (26%) or IT (27%), with BT at 40%. Conclusions: The BEACON results show that single agent T is suboptimal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are better than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evaluation is needed. Clinical trial information: ISRCTN40708286. [Table: see text]

Outcome in patients with refractory high-risk neuroblastoma.

10537 Background: Outcome for high-risk neuroblastoma (HRNBL) patients (pts) with refractory disease at end of induction (EOI) is poor. The impact of therapies such as I-131-MIBG or irinotecan/temozolomide/dinutuximab (I/T/DIN) prior to autologous stem cell transplant (ASCT) on outcome is unknown. Methods: A multi-center, retrospective study of HRNBL pts diagnosed between 2008-2018 with refractory disease at EOI was conducted. Demographics, tumor biology, treatment response, and outcomes were abstracted. 3-year (yr) EFS and OS from time of diagnosis were estimated by the Kaplan-Meier method. Results: 3-yr EFS and OS were 54% and 79% for the 136 pts analyzed. 91 pts received no additional therapy prior to ASCT (Cohort 1); 32 pts received post-induction therapy prior to ASCT (Cohort 2); and 13 pts did not undergo ASCT (Cohort 3). The prevalence of metastatic disease in Cohort 1, 2, and 3 was 65%, 97%, and 85%. 3-yr EFS and OS were not statistically different between Cohort 1 (3-yr EFS and OS; 62% and 81%) and Cohort 2 [3-yr EFS and OS; 49% (p = 0.48) and 82% (p = 0.19)]. Outcome for Cohort 3 pts was significantly worse than Cohort 1 [3-yr EFS: 15% vs. 62% (p &lt; .001); and 3-yr OS: 48% vs. 81% (p = 0.003)] and Cohort 2 [3-yr EFS: 15% vs. 49% (p &lt; .001); and 3-yr OS 48% vs. 82% (p = 0.035)]. For Cohort 2 pts with metastatic disease, post-induction therapy included I/T/DIN (n = 12), MIBG (n = 16), MIBG plus I/T/DIN (n = 1), and other (n = 2). Metastatic disease response was observed in 10/12 (83%) pts who received I/T/DIN and 9/16 (56%) who received MIBG. MIBG plus I/T/DIN (n = 1) or MIBG with chemotherapy (n = 1) also induced response. Among the 21 pts with metastatic disease response, 3-yr EFS and OS were 69% and 94%; significantly better than Cohort 2 patients who did not respond to post-induction therapy [3-yr EFS and OS: 11% (p = 0.016) and 66% (p = 0.2)]. 6 Cohort 2 pts achieved a complete response (CR) in metastatic sites following I/T/DIN (n = 5) or MIBG (n = 1), and all are alive without relapse with median follow-up of 3.4 years (range 2.7-8.1). The single Cohort 3 patient who achieved a metastatic CR with I/T/DIN and did not undergo ASCT remains disease-free 2.4 years from diagnosis. Conclusions: Patient characteristics differed in the 3 Cohorts, reflecting the influence of refractory disease on treatment decisions. For Cohort 2 pts, outcome was better for those with metastatic disease at EOI who responded to post-induction therapy compared to those who did not. Pts who achieved a metastatic CR of refractory disease had excellent survival. Prospective studies testing the efficacy of I/T/DIN in pts with refractory metastatic disease at EOI are warranted.

LBA64 - Bevacizumab for children with relapsed & refractory high-risk neuroblastoma (RR-HRNB): Results of the BEACON-neuroblastoma randomized phase II trial - A European ITCC-SIOPEN trial

BackgroundBEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. MethodsPatients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT) or topotecan-temozolomide (TTo), with or without bevacizumab (Bev). The Bev randomization (Bev versus no-Bev) had two parts: Part 1 had a 2-stage Minimax Jung design with overall response (OR) as primary endpoint. Part 1 success criterion was ≥4 more responses in Bev arm compared to no-Bev. Protocol was amended to incorporate Part 2 (40 additional patients), including progression-free survival (PFS) as co-primary endpoint. OR was defined as complete or partial response (CR, PR) by RECIST (INRC for patients without measurable disease). OR and toxicity data for the Bev randomization is reported. ResultsFor Part 1 (n=106), 17 of 52 pts on Bev had responses [33%] and 8 of 54 pts on no-Bev had responses [15%]. The trial success criterion for the primary endpoint of ORR was met. Including Part 2 (total n=154), 21 of 77 patients on Bev (7CR, 14PR) and 13 of 77 patients on no-Bev (1CR, 12PR) had responses. Response data was not available for 6 patients; 13 patients not assessable for response (discontinued before first assessment) were considered to be non-responders. OR rate [with 90% CI] was 27% [18-35%] for patients on Bev and 17% [10-24%] for patients on no-Bev. In subgroup analysis, there was no interaction between T, IT and TTo and treatment with/without Bev (heterogeneity test, p=0.8). 86% Bev and 58% no-Bev patients had grade ≥3 toxicities as per CTCAE v4.0; the most common grade ≥3 toxicities associated with Bev were platelet count decrease and anemia. ConclusionsBev reached the Phase II success criterion for OR within Part 1 of the trial when added to temozolomide-based chemotherapy in RR-HRNB. The toxicity profile for Bev is acceptable. Longer follow-up is needed before assessing whether it impacts PFS or overall survival. Clinical trial identificationNCT02308527; EudraCT: 2012-000072-42. Legal entity responsible for the studyUniversity of Birmingham. FundingRoche. DisclosureL. Moreno: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma; Licensing / Royalties, I am member of Siopen Executive Committee, Siopen receives royalties for the sales of dinutuximab beta: Eusa Pharma. D. Valteau-Couanet: Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties, Member of Siopen Executive Committee, SIOPEN receives royalties for the sales of dinutuximab beta: Eusa Pharma; Research grant / Funding (institution): Ophelia; Travel / Accommodation / Expenses: Jazz Pharma. K. Nysom: Advisory / Consultancy: Bayer. N. Gerber: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Novartis. R. Ladenstein: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Apeiron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Eusa Pharma; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A.D. Pearson: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Genentech. All other authors have declared no conflicts of interest.

Temozolomide versus irinotecan-temozolomide for children with relapsed and refractory high risk neuroblastoma (RR-HRNB): Results of the BEACON-Neuroblastoma randomized phase 2 trial—A European Innovative Therapies for Children with Cancer (ITCC) - International Society of Pediatric Oncology Europe Neuroblastoma Group (SIOPEN) trial.

10001 Background: BEACON-Neuroblastoma is a randomized Phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a 2x2 factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT), with or without bevacizumab. Here we report the results of the irinotecan randomization (T vs. IT), which had a probability-based Bayesian design. Primary endpoint was best overall response (complete or partial) during the first 6 courses, by RECIST for measurable disease patients and International Neuroblastoma Response Criteria for evaluable disease patients for which overall response rate (ORR) was calculated. Results: From 2013 to 2018, 61 patients were randomized to treatment with T and 60 to IT. Median age was 5.8 years. 85 and 36 had measurable and evaluable disease respectively; 55 and 66 had refractory and relapsed disease; 22 had MYCN amplification. Baseline characteristics were balanced between the arms. Response data was not yet available for 2 patients on T. Response was not assessable for 17 patients (did not have treatment or stopped early) who were considered non-responders. The ORR was 24% for T and 17% for IT (risk ratio (RR) = 0.70, 95% credible interval 0.32 to 1.44). The probability that the RR for ORR was &gt;1.0 was 17%, meaning that IT did not show greater activity than T. There was no interaction between treatment with/without bevacizumab (heterogeneity test, p=0.7). 27 (44%) T and 35 (58%) IT patients had grade ≥3 toxicities as per CTCAE v4.0. Diarrhea occurred in no patients on T and 7 (12%) on IT; hematological toxicities included anemia (6 T, 4 IT), neutropenia (14 T, 22 IT) and thrombocytopenia (14 T, 11 IT). Conclusions: Irinotecan does not improve the response rate when added to temozolomide in RR-HRNB, but does increase diarrhea. Longer follow-up is needed before assessing whether it impacts progression-free or overall survival. Number of responses by treatment arm. Clinical trial information: NCT02308527. [Table: see text]