Chemoimmunotherapy Combination Provokes Encouraging Responses in Recurrent High-Risk Neuroblastoma

Chemoimmunotherapy Combination Provokes Encouraging Responses in Recurrent High-Risk Neuroblastoma

The 4-drug combination of irinotecan, temozolomide, dinutuximab (Unituxin), and granulocyte-macrophage colony-stimulating factor (GM-CSF) elicited objective responses in nearly half of high-risk neuroblastoma patients, according to retrospective findings published in the Journal of Clinical Oncology.1

Overall, 48.6% (n=71) of patients achieved an objective response, including complete response (CR), partial response (PR), and minor response in 29%, 14%, and 5% % of patients, respectively. This includes 47% of the 133 patients with soft tissue and bone metastatic disease. In addition, the investigators detected a bone marrow response in 73% of the 58 patients with available post-treatment bone marrow data.

“Data on the timing and duration of response will help clinicians balance the risks and benefits of continuing treatment for [irinotecan/temozolomide/dinutuximab/GM-CSF] in relapsed patients [high-risk neuroblastoma]” the study’s lead author, Benjamin J. Lerman, MD, MS, of Children’s Hospital of Philadelphia and the University of Pennsylvania, and colleagues wrote in the journal article. “The survival results described in this study provide a new benchmark for evaluating new therapies in relapse. [high-risk neuroblastoma].”

This retrospective study sought to describe the response and progression-free survival (PFS) in patients with recurrent high-risk neuroblastoma who received the regimen of irinotecan, temozolomide, dinutuximab, and GM-CSF.

To be eligible, patients had to be under 30 years of age at diagnosis of high-risk neuroblastoma and receiving at least 1 cycle of irinotecan/temozolomide/dinutuximab/GM-CSF for progressive disease (PD) or recurrent disease. Patients also needed to have an objective response or stable disease after initial standard first-line therapy.

Patients were excluded if they had primary refractory disease and progressed through induction therapy. Those who received the combination due to suboptimal response to induction treatment were also excluded.

In total, 146 patients were analyzed in this study, which included those who received at least 1 cycle of irinotecan/temozolomide/dinutuximab/GM-CSF outside the context of a clinical trial from January 1, 2015 to June 1 2020. The study regimen consisted of intravenous (IV) irinotecan 50 mg/m2 once daily, temozolomide 100 mg/m2 once daily on days 1 through 5, dinutuximab 17.5 mg/m2 IV once daily once daily on days 2 to 5 and GM-CSF at 250 µg/m2 once daily on days 6 to 12 of a 21-day cycle.

For patients receiving the combination for multiple separate relapse events, the study only used data related to the first relapse event treated with the combination.

Patients received a median of 4.5 cycles of study treatment (interquartile range, 2-7; range, 1-31) for a median of 87 days. Of the 23% (n=34) of patients who received concurrent treatment at some point during their time on the combination, 5 received surgery, 23 received radiation, 2 received metaiodobenzylguanidine therapy, and 5 received other anticancer therapy.

The median age of patients at diagnosis was 51 months (interquartile range, 31-72), and 58.2% (n = 85) were male. A total of 67.8% (n = 99) of patients received study treatment after their first relapse or progression. Additionally, 63.0% (n=92) of patients had measurable disease at relapse or progression, and 55.5% (n=81) had received anti-GD2 therapy prior to study treatment.

Overall, 50 (37%) of the 134 patients had known tumor MYCN status, and 43 of those patients (32%) had tumors with MYCN amplification. In addition, 94 patients had known tumor ALK status, and 21 of those patients (22%) had tumors with ALK amplification or activating mutation.

A total of 58.2% (n=85) of patients discontinued study treatment due to stable disease (SD) or PE, 13.0% (n=19) discontinued due to unacceptable acute or chronic toxicity, 23, 3% (n=34) discontinued due to transition to another anticancer therapy, and 19.9% ​​(n=29) discontinued due to planned completion of treatment. Patients who discontinued combination therapy due to toxicity received a median of 3 cycles (range, 1-15) before discontinuation. At the time of data collection, 4 patients were still on study therapy.

The primary endpoint was the proportion of patients with an objective response after receiving the combination, which was defined as CR, PR, or minor response on a disease assessment after initiation of study treatment; PFS; and duration of response (DOR) after objective response. The investigators sought to assess the timing and duration of response and to identify the molecular and clinical factors associated with PFS in these patients.

Patients who achieved an objective response received a median of 2 cycles (range, 1-9) from the start of study treatment to their first disease evaluation showing an objective response. One patient required more than 6 cycles to achieve a first objective response; this patient received 9 cycles of treatment.

The median time between diagnosis and first relapse was 26 months (range, 17-38) in patients who achieved an objective response versus 18 months (range, 12-35) in non-responders (P = .04). Additionally, white patients were more likely to respond, with 71.2% (n = 40) of white patients responding and 53.3% (n = 51) non-responding (P = .03). Responders were also more likely to have received prior anti-GD2 therapy, at 64.8% (n=46) vs. 46.7% (n=35; P = .03) in non-responders and tumor ALK aberrations were less frequent in responders, at 11.3% (n = 8) vs. 17.3% (n = 13; P = .02) in those who did not respond.

In addition, the median age of responders (54 months; range, 33.0-80.5) was greater than that of non-responders (44 months; range, 30.5-64.5; P = 0.15), and more responders had stage M disease, with 97.2% (n = 69) vs. 89.3% (n = 67; P = .13). Responders were also less likely to have measurable disease at the time they received study therapy, at 56.3% (n=40) vs. 69.3% (n=52; P = .12).

Although all of the above distinctions met the criteria for inclusion in the multivariate model, after multivariate adjustment, only the comparison between white and non-black and non-white patients retained statistical significance. No covariate was independently associated with PFS.

Of the total population, 21% (n=31) had DS and 30% (n=44) progressed on study treatment. Of the 79 patients who initially had SD, minor response, or PR, 72% (n = 57) achieved their best response at first disease assessment. Of the 22% of patients with DS or better at the first post-study treatment disease assessment who experienced an improvement in response designation at a later assessment, 5 had initial DS, 3 had a minor initial response, and 14 they had initial PR.

In the overall study population, the median PFS was 13.1 months (95% CI, 9.8-16.5), the 6-month PFS rate was 62% (95% CI, 55%-71%), the 1-year PFS rate was 51% (95% CI, 43%-60%), and the 2-year PFS rate was 28% (95% CI, 20%- 40%).

For all patients who had an objective response, the median DOR was 15.9 months (95% CI, 14; not available). [NA]), the 6-month PFS rate was 86% (95% CI, 78%-95%), the 1-year PFS rate was 68% (95% CI, 57%-81%) and the 2-year PFS rate was 44% (95% CI, 32%-61%).

Additionally, 21 patients who achieved an objective response discontinued study treatment and received no further anticancer therapy, with a median additional PFS of 10.4 months (95% CI, 7.4-NA). Of those patients, 14 had CR and 7 had PR. Of these patients, the 6-month PFS rate was 73% (95% CI, 54% to 99%) and the 1-year PFS rate was 26% (95% CI, 10% to 67 %).

In total, 108 patients relapsed or progressed 0 to 30 months after starting study treatment. Of these, 56% (n=60) relapsed while actively receiving study treatment, 31% (n=33) relapsed after transition from study treatment to another anticancer therapy, and 14% ( n = 15) relapsed after discontinuation of study treatment. without additional therapy.

Bone was the most common site of relapse (76.9%; n=83), followed by metastatic soft tissue in 54.6% (n=59) and lymph nodes in 54.6% (n=59), bone marrow in 30.6% (n = 33), lung in 16.7% (n = 18), and brain in 5.6% (n = 6).

“These data establish a new response and survival baseline for comparison during future trials in patients with relapsed/progressive neuroblastoma in the chemoimmunotherapy era,” the study authors concluded.

Reference

  1. Lerman BJ, Li Y, Carlowicz C, et al. Progression-free survival and response patterns in patients with recurrent high-risk neuroblastoma treated with irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor. J Clin Oncol. Published online October 7, 2022. doi:10.1200/JCO.22.01273

Leave a Comment