Adding bevacizumab to chemo enhances antitumour activity in children with R/R neuroblastoma

Adding bevacizumab (B) to temozolomide (T)-based chemotherapy increases overall response rate (ORR) in children with relapsed/refractory (R/R) neuroblastoma, according to results of the three-by-two factorial, randomized controlled phase II BEACON-Neuroblastoma trial.

In the trial, B plus T and irinotecan (I; BIT) demonstrated antitumour activity and acceptable tolerability. These findings will be validated in future studies. [J Clin Oncol 2024;doi:10.1200/JCO.23.00458]

To date, there has been a lack of randomized controlled trials comparing backbone chemotherapy regimens, including T monotherapy and T in combination with I (IT) or topotecan (To; TTo), used with or without new targeted therapies in R/R neuroblastoma. [J Clin Oncol 2006;24:5259-5264; J Clin Oncol 2011;29:208-213; Eur J Cancer 2014;50:170-177] “In BEACON-Neuroblastoma, we used a three-by-two factorial design to compare three T-based chemotherapy regimens [ie, T, IT, TTo] used with or without B in children and adolescents with R/R neuroblastoma,” wrote the researchers.

In the trial, 160 patients aged 1–21 years with R/R neuroblastoma (median age, 5 years; MYCN amplification, 23 percent; prior antidisialoganglioside [anti-GD2] immunotherapy, 40 percent) were randomized 1:1:1:1:1:1 to receive 6 cycles of 4-weekly T alone (200 mg/m²/day orally, days 1–5), 3-weekly IT (T: 100 mg/m²/day orally, days 1–5; I, 50 mg/m²/day intravenously [IV], days 1–5) or 4-weekly TTo (T: 150 mg/m²/day orally, days 1–5; To: 0.75 mg/m²/day IV, days 1–5), with or without B (B in BT and BTTo: 10 mg/kg IV, day 1 and day 15; B in BIT: 15 mg/kg IV, day 1). Patients with acceptable toxicities and response ≥stable disease after 6 cycles were allowed to continue the trial treatment for 12 cycles.

The primary endpoint of ORR during the first 6 cycles was 26 percent with B vs 18 percent without B (rate ratio [RR], 1.52; p=0.17), which met the predefined success criterion for ORR (p<0.2).

Adding B to T-based chemotherapy also showed a trend for improvement in progression-free survival (PFS) after a median follow-up of 1.5 years. PFS estimate at 1 year was 0.46 vs 0.38 in the B vs non-B arms, with a hazard ratio (HR) of 0.89 (95 percent confidence interval [CI], 0.63–1.27).

Notably, BIT demonstrated an ORR of 23 percent and a 1-year PFS estimate of 0.67. The unadjusted heterogeneity test for PFS further showed a potential interaction between B and I (p=0.11). “Future studies are warranted to compare BIT vs chemoimmunotherapy in R/R neuroblastoma,” the researchers added.

In the chemotherapy random assignments, ORRs were comparable between T-based regimens with or without I (n=121; 20 percent vs 21 percent; RR, 0.94) and regimens with or without To (n=61; 27 percent vs 23 percent; RR, 1.22). Trends for improvements in PFS were seen with IT (HR, 0.59; 95 percent CI, 0.39–0.90) and TTo regimens (HR, 0.59; 95 percent CI, 0.33–1.08).

The addition of B to chemotherapy was associated with increased myelotoxicity, including neutropenia (grade ≥3, 30.5 percent vs 23.5 percent without B) and anaemia (grade ≥3, 14 percent vs 3 percent). Proteinuria occurred among 10 patients receiving B-containing treatment, 4 of whom (5 percent) experienced grade ≥3 events. No proteinuria was reported in patients treated without B.

Adding I to T-based treatment was associated with increased grade ≥3 gastrointestinal adverse events (5 percent vs 1.5 percent), while the addition of To was associated with increased grade ≥3 myelotoxicity (30 percent vs 3 percent).