Risk Stratification Strategies Highlight Pediatric Oncology Conference

The use of risk stratification strategies in pediatric oncology has led to improved regimens that focus on reduced-intensity approaches, according to Jacqueline M. Kraveka, DO, associate professor of pediatrics at the Medical University of South Carolina in Charleston and chair of the 2nd Annual International Congress on Pediatric Oncology™ to be hosted by Physicians’ Education Resource®, LLC (PER®) on October 27, 2023.¹

“We are able to mitigate the risk of toxicity by identifying patients who benefit from less aggressive therapy,” Kraveka said in an interview with Targeted Therapies in Oncology.

With ongoing clinical trials, pediatric and young adult cancer care has seen continuous improvement in survival for this population, with more than 82% of pediatric patients with cancer surviving 5 years after diagnosis.² Although conventional chemotherapy, surgery, and radiotherapy are the foundation of treatment, adverse events (AEs) such as risk of infection—bacterial and fungal—present clinical challenges.

“The emergence of different antifungal agents, when given prophylactically, has made a significant impact,” Kraveka said. Modalities to address infection-related mortality include bacterial and fungal prophylaxis, in addition to ancillary measures such as “ethanol locks, chlorhexidine gluconate baths, granulocyte colony-stimulating factor, intravenous immunoglobulin supplementation, and mandatory hospitalization in high-risk groups.”³

High-Risk Neuroblastoma

In the high-risk neuroblastoma setting, traditional therapy involves high-dose chemotherapy and hematopoietic stem cell transplant. All too often, though, the majority of patients relapse or have refractory disease, with few therapeutic options available. In addition, some patients are left with late AEs including hearing loss, short stature, reduced fertility, and secondary malignancy risk.⁴

In this setting, a 5-cycle standard regimen consists of topotecan/cyclophosphamide (cycles 1 and 2), cisplatin/etoposide (cycles 3 and 5), and vincristine/doxorubicin/cyclophosphamide (cycle 4). During the induction phase, surgical resection of the primary tumor is also a key component, with 2 large studies in North America and Europe demonstrating the benefit of superior event-free survival and lower rates of local failure.^5,6

Targeted Therapies in Relapsed/ Refractory Settings

The emergence of targeted therapies has garnered interest, particularly in the relapsed/refractory setting. Therapies undergoing evaluation include iodine-131 meta-iodobenzylguanidine (131I-MIBG), a targeted radiopharmaceutical, ALK inhibitors, and anti–GD2 monoclonal antibodies. In particular, the addition of 131I-MIBG or lorlatinib (Lorbrena) to high-intensive chemotherapy in patients with highrisk neuroblastoma in a phase 3 trial (NCT03126916) is undergoing investigation.

“It’s an exciting time in pediatric cancer because of targeted therapies that are in development,” Kraveka said. “In addition, the use of immunotherapy in pediatrics has led to advances in progression-free and overall survival [OS].”

Significant advances in targeted therapies have yielded notable results. FDA-approved targeted therapies in the pediatric setting include pazopanib (Votrient), crizotinib (Xalkori), rituximab (Rituxan), and brentuximab vedotin (Adcetris).

Pazopanib

In PALLETTE, a phase 3 global trial (NCT00753688), a total of 372 patients with metastatic nonadipocytic soft tissue sarcoma who relapsed on standard chemotherapy randomly received pazopanib (n = 246) or placebo (n = 123). The median PFS was 4.6 months (95% CI, 3.7-4.8) for the pazopanib arm compared with 1.6 months (95% CI, 0.9-1.8) for the placebo arm (HR, 0.31; 95% CI, 0.24-0.40; P < .0001). Investigators reported an OS of 12.5 months (95% CI, 10.6-14.8) with pazopanib compared with 10.7 months (95% CI, 8.7-12.8) with placebo (HR, 0.86; 95% CI, 0.67-1.11; P = .25).

Results of another study (NCT02180867) in which 81 eligible patients with soft tissue sarcoma were randomly assigned to receive pazopanib (n = 42) or control (n = 39) showed that pathological response in 42 evaluable patients at the second interim analysis was 58% (14 of 24 patients) in the pazopanib group and 22% (4 of 18 patients) in the control group. An analysis of survival outcomes is ongoing.

Crizotinib

A phase 1b trial of crizotinib (PROFILE 1013; NCT01121588) was evaluated in adolescent and adult patients 15 years and older who had ALK-positive advanced malignancies other than non–small cell lung cancer.⁸ In the trial, 44 patients were enrolled, consisting of 18 patients with lymphoma, 9 patients with inflammatory myofibroblastic tumors (IMTs), and 17 with other tumors. The objective response rate was 53% (95% CI, 28%-77%) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30%-93%) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2%-36%) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively.

Rituximab

In December 2021, the FDA approved rituximab in combination with chemotherapy for patients aged 6 months to 18 years with previously untreated, advanced-stage, CD20+ diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkittlike lymphoma (BLL), or mature B-cell acute leukemia (B-AL).⁹

The FDA approved the agent based on efficacy findings from the phase 3 Inter B-NHL Ritux 2010 trial (NCT01516580),¹⁰ a global multicenter, open-label, randomized trial of patients 6 months or older who were previously untreated and had advancedstage, CD20+ DLBCL, BL, BLL, or B-AL.

Investigators reported 10 event-free survival events in the treatment arm (rituximab + chemotherapy) vs 28 deaths in the che motherapyalone group (HR, 0.32; 90% CI, 0.17, 0.58; P = .0012). At the interim analysis, 20 deaths had occurred in the LMB chemotherapy arm compared with 8 deaths in the rituximab plus chemotherapy arm, with an estimated OS HR of 0.36 (95% CI, 0.16-0.81).

Brentuximab Vedotin

In November 2022, the FDA approved brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients 2 years and older with previously untreated high-risk classical Hodgkin lymphoma.¹¹ Efficacy was based on event-free survival (EFS) rates from the randomized, open-label, actively controlled AHOD1331 (NCT02166463) trial.¹² There were 23 events (8%) in the treatment arm consisting of brentuximab vedotin plus vincristine, etoposide, prednisone, and cyclophosphamide and 52 events (17%) in the control arm (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) with a corresponding HR of 0.41 (95% CI, 0.250.67; P = .0002).¹²

Looking Ahead

Kraveka is encouraged by the therapeutic advances in pediatric oncology and is especially buoyed by the role of next-generation sequencing in helping to identify which patients will benefit from emerging therapies. A greater understanding of tumor biology will lead to identifying new targets, Kraveka said. “For example, we don’t know how to target Ewing sarcoma yet, so we’re working to identify those agents that can target certain mutations. There is still work to be done,” she noted.”

Pediatric Oncology Conference

The 1-day virtual conference will also address emerging biomarkers in gliomas, managing pediatric neuroblastomas, strategies to manage myeloid leukemias, future directions for soft tissue sarcomas, and other clinical challenges. Community oncologists, medical students, fellows, residents, nurses, and nurse practitioners will benefit from the multidisciplinary program.

“We hope the program excites the attendees so that they gain better knowledge about state-of-the-art approaches and provides a look to what the future might bring,” Kraveka concluded.

REFERENCES:

1. Haeusler GM, Thursky KA, Slavin MA, et al. Risk stratification in children with cancer and febrile neutropenia: a national, prospective, multicentre validation of nine clinical decision rules. EClinicalMedicine. 2020;18:100220. doi:10.1016/j.eclinm.2019.11.013

2. Sung, L, Miller TP, Phillips R. Improving symptom control and reducing toxicities for pediatric patients with hematological malignancies. Hematology Am Soc Hematol Educ Program. 2020;2020(1):280-286. doi:10.1182/hematology.2020000114

3. Villeneuve S, Aftandilian C. Neutropenia and infection prophylaxis in childhood cancer. Curr Oncol Rep. 2022;24(6):671-686. doi:10.1007/s11912-022-01192-5

4. DuBois SG, Macy ME, Henderson TO. High-risk and relapsed neuroblastoma: toward more cures and better outcomes. Am Soc Clin Oncol Edu Book. 2022;42:1-13. doi:10.1200/EDBK_349783

5. Holmes K, Pötschger U, Pearson ADJ, et al. Influence of surgical excision on the survival of patients with stage 4 high-risk neuroblastoma: a report from the HR-NBL1/ SIOPEN study. J Clin Oncol. 2020;38(25):2902-2915. doi:10.1200/JCO.19.03117

6. von Allmen D, Davidoff AM, London WB, et al. Impact of extent of resection on local control and survival in patients from the cog a3973 study with high-risk neuroblastoma. J Clin Oncol. 2017;35(2):208-216. doi:10.1200/JCO.2016.67.2642

7. Weiss AR, Chen YL, Scharschmidt TJ, et al. Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(8):1110-1122. doi:10.1016/S14702045(20)30325-9

8. Gambacorti-Passerini C, Orlov S, Zhang L, et al. Longterm effects of crizotinib in ALK-positive tumors (excluding NSCLC): a phase 1b open-label study. Am J Hematol. 2018;93(5):607-614. doi:10.1002/ajh.25043

9. FDA approves rituximab plus chemotherapy for pediatric cancer indications. FDA. December 2, 2021. Accessed September 15, 2023. https://bit.ly/48gy2au

10. Minard-Colin V, Auperin A, Pillon M, et al. Results of the randomized Intergroup trial Inter-B-NHL Ritux 2010 for children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and mature acute leukemia (B-AL): evaluation of rituximab (R) efficacy in addition to standard LMB chemotherapy (CT) regimen. J Clin Oncol. 2016;34(suppl 15):10507. doi:10.1200/JCO.2016.34.15_suppl.10507

11. FDA approves brentuximab vedotin in combination with chemotherapy for pediatric patients with classical Hodgkin lymphoma. FDA. November 10, 2022. Accessed September 16, 2023. https://bit.ly/3EKRVsV

12. Seagen announces US FDA approval of new indication for Adcetris (brentuximab vedotin) for children with previously untreated high risk Hodgkin lymphoma. News release. Seagen Inc. November 10, 2022. Accessed September 16, 2023. http://bit.ly/3AfJWCo