Naxitamab-based chemoimmunotherapy for resistant high-risk neuroblastoma: Preliminary results of HITS pilot/phase II study.

Abstract

10025 Background: Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare. We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a pilot HITS protocol against resistant HR-NB now expanded to a phase II study (NCT03189706). Methods: Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria. Results: Forty-six (23 enrolled on protocol and 23 on compassionate-use basis) heavily prior-treated patients (median age at enrollment: 6.6 years; median number of prior relapses: 2) have received 175 (median 2; range 1-12) cycles to date. At enrollment, 7 patients had HR-NB refractory to induction chemotherapy while 39 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other > grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and were complete (n = 9), partial (n = 8), and mixed (n = 1); 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and PD (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12; 75%). Conclusions: High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB. This ongoing phase II study may define a broader role for naxitamab which was recently granted breakthrough designation by the FDA. Clinical trial information: NCT03189706.

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

“…Previously, we reported our initial experience using naxitamab in combination with Irinotecan and Temozolomide (I/T) according to the HITS pilot study in relapsed and refractory HR-NB subjects [24]. Like other studies, [17,18,20,21] we reported responses in both refractory and relapse cases.…”

“…Initial studies showed how the combination of I/T plus anti-GD2 mAbs demonstrated objective responses in patient's refractory response to chemotherapy and even to single-agent anti-GD2 mAb [17,18,24]. The subsequent question is when to best use this salvage strategy in an already complex multimodality schema of HR-NB management.…”

Prognostic value of xenograft engraftment in patients with metastatic high‐risk neuroblastoma

“…First‐line treatments included radiotherapy in 57.6% (38 of 66) of cases, and immunotherapy in 56.3% (36 of 66) 28 . Immunotherapy was included as second‐line treatment for relapse or progression in 29 (58.0%) patients 29,30 …”

Monoclonal Antibodies (mAbs) Approved for Cancer Treatment in the 2020s

“…Naxitamab is a humanized GD2-specific monoclonal antibody (also known as naxitamab-gqgk or hu3F8), which in November 2020, was approved for the treatment of patients (≥ 1-year-old) with R/R neuroblastoma (either in the bone or bone marrow), in conjunction with GM-CSF, who have previously undergone prior treatments and have responded to it in the form of partial responses, stable diseases, or even minor responses (43)(44)(45)(46)(47)(48). Naxitamab, under the tradename Danyelza TM , was approved for medical use based on the findings of a phase 1/2 and a phase 2 clinical trial (clinical trial identifier: NCT01757626 and NCT03363373, respectively) in the both of which the safety and clinical efficacy of Naxitamab were investigated in R/R patients with high-risk neuroblastoma (43,46).…”