Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited.
10056 Background: Larotrectinib is an FDA and EMA approved TRK inhibitor for TRK fusion solid tumors in patients with locally advanced or metastatic disease, or where surgical resection is likely to result in severe morbidity. Here we report the real-world activity and safety data on compassionate use and post-marketing authorization of larotrectinib collected in the SACHA-France study (NCT04477681), following the French Health Technology Assessment institution (HAS) request. Methods: All larotrectinib prescriptions made in France outside clinical trials since April 2019 for patients’ < 25 years-old were registered in the SACHA-France study. Safety and activity data were collected, with data cut-off of 23/01/2024. SACHA-France is open in all 31 French Society of Pediatric Oncology (SFCE) centers, it is approved as a real-world data source by the HAS and supported by the French National Agency for the Safety of Medicines and Health Products (ANSM). Results: 21 patients were included (4 compassionate use, 17 post-marketing authorization). Main cancer types were soft-tissue sarcomas (n=13, of them 7 infantile fibrosarcoma), followed by central nervous system (CNS) tumors (n= 7), and other solid extra-CNS tumors (n=1). All patients except one had a TRK fusion tumor: NTRK3 (n=10), NTRK2 (n=6, all CNS tumor) and NTRK1 (n=4). Median age at start of larotrectinib was 2.8 years (range: 0.2 -21.1). Ten patients had received no prior systemic therapy. Main reasons to start larotrectinib were to avoid mutilating surgery (n=9) and disease progression (n=9). Best objective response was reported as partial response in 13 out of 19 patients with evaluable disease (10/12 patients with soft tissue sarcomas, 2/6 patients with CNS tumors), with median time to response of 57 days. Of them, five patients with soft tissue sarcomas achieved a complete response after non mutilating surgery. Median treatment duration was 219 days (range: 10-1368, 5 patients still on therapy). Seven patients with soft tissue sarcomas stopped larotrectinib, after a median duration of 242 days (range: 122-1190), three of them after tumor surgery; none presented with tumor recurrence (follow-up: 350 days; range 40-636). At data cut-off, 8 patients had disease progression on-therapy (5/7 CNS tumors, 3/13 soft tissue sarcomas), with a NTRK resistance mutation identified in 2 out 3 patients with tumor biopsy. Adverse drug reaction (ADR) were reported in 2/21 patients (9%), including a grade 2 weight gain and a grade 3 neutrophil count decreased (1 patient each). Both ADRs were expected and required neither corrective treatment nor action on larotrectinib. Conclusions: Our real-world data confirm the favorable safety profile of larotrectinib with rapid and durable tumor-agnostic efficacy.
There is an alarming delay in Europe for anticancer medicines becoming accessible for children. Following a paediatric European Union marketing authorisation, national Health Technology Assessment (HTA) agencies evaluate effectiveness, and safety of medicines to support decision on their cost and reimbursement. This study (a SIOPE Access to Medicines project) aimed to evaluate how these HTA evaluations take place for anticancer medicines indicated for paediatric use in Europe and to explore where the delays for market access originate.We obtained HTA reports from the public domain for nine European countries for blinatumomab, dinutuximab beta and tisagenlecleucel. We evaluated the time elapsed between marketing authorisation for a paediatric indication and a national HTA decision and the nature of the decision.Out of 23 HTA decisions (four countries without blinatumomab report), 18 were positive, two with restrictions, three negative. For blinatumomab, tisagenlecleucel and dinutuximab beta, the median time to an HTA decision after regulatory approval for paediatric use was 353 days (range 193-751), 141 days (range 77-517) and 515 days (range 0-780), respectively, with variability between countries. Dinutuximab beta and tisagenlecleucel were first introduced in children, but did not result in shorter time to HTA decision. For blinatumomab, marketing authorisation followed 1008 days after the indication in adults, with HTA applications submitted a median of 167 days later, and a recommendation after 145 days.This study reveals ample variability in HTA decision making in nine European Union countries. Collaboration and alignment of required evidence is needed to facilitate robust scientific HTA assessments, also considering methodological challenges in paediatric oncology.
Abstract The US and European regulatory frameworks are changing for more patient-centric and scientifically -driven pediatric developments of anticancer medicinal products. Programs such ITCC P41 in the EU and NCI PIVOT2 in the US provide relevant comprehensive preclinical data to support decision making: should a drug/a combo be introduced in pediatric development? Continuous efforts should further improve relevance of pediatric cancer preclinical models, especially for immune oncology drugs. The development of pediatric precision oncology programs have installed individual patients’ tumor sequencing as a routine to best orientate therapeutic options and best learn from the early phase trials. There is a need to go beyond tumor sequencing. Early phase platform trials, such as AcSé ESMART3 and NCI COG Pediatric Match trial4 are aiming at accelerating drug development and facilitating patients’ access to innovation. The introduction of new adaptive designs and mixed criteria is essential to address the use of safety and efficacy to accelerate drug development. When starting an early phase trial, early interactions with regulatory authorities are essential to agree on a full development plan towards a potential market authorization filing. Randomized clinical trials (RCT) remain the gold standard for practice changing trials in newly diagnosed pediatric cancers. Efforts should be made to introduce alternative designs when RCT are not feasible or ethically unacceptable. The pediatric oncology community should make major investments in exploiting high quality real world data for indirect comparisons with single arm trials. The cooperative groups are essential stakeholders for the design and implementation of such programs. In conclusion, over the last 10 years, major efforts have been made by the pediatric oncology community in partnership with parents and advocates to increase capability and to create platforms and programs to accelerate the development of targeted and immune oncology drugs. ACCELERATE, the international multistakeholder (academia, advocacy, industry, regulatory networks) initiative, demonstrated the feasibility and high value of working together5. The regularly framework will better address pediatric patients’ needs when considering anticancer agents developed for adult. However, biology of pediatric malignancies is different from that of adult cancers and there is a need to invest in the development of specific pediatric anticancer assets that will target specific pediatric biological alterations. Childhood cancers will remain rare and ultra-rare with low, if any, return on investment. There is an urgent need to implement new business models to make the development of specific pediatric oncology drugs feasible and to support the appropriate evaluation of adult anticancer drugs in children6.1 https://itccp4.com; 2 https://ctep.cancer.gov/MajorInitiatives/Pediatric_PIVOT_Program.htm/; 3Geoerger B et al. Eur J Cancer 2024; 4Parsons DW et al. J Clin Oncol 2022; 5 https://www.accelerate-platform.org; 6Daems S et al. Nat Rev Drug Discov. 2023 Citation Format: Gilles Vassal. Are we ready to accelerate the development of new safe and effective anticancer medicines for children and adolescents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA026.
Abstract Tumor angiogenesis in neuroblastoma, the most frequent extracranial solid tumor in childhood, has been shown to be an important prognostic factor. High vascularity is reported in aggressive and disseminated neuroblastoma and we previously described all known mechanisms of angiogenesis present, including sprouting of new vessels by angiogenesis growth factors as well as integration of circulating endothelial cells from bone marrow origin. Despite multimodal therapy protocols including surgery, high dose chemotherapy with stem cell support, radiotherapy and differentiating agents, the prognosis of advanced disease remains poor suggesting the evaluation of new therapeutics with distinct mechanism of action like anti-angiogenic agents for neuroblastoma. We evaluated the new oral pan-VEGFR tyrosine kinase inhibitor AG-13736 in the IGR-N91 xenograft model derived from a primary neuroblastoma bone marrow metastasis. Oral treatment with 30 mg/kg BID during 2 weeks at advanced tumor stage yielded significant tumor growth delay in median time to reach 5 times initial tumor volume of 11.4 days compared to controls (p=0.0006; Mann-Whitney test). AG-13736 treatment down-regulated VEGFR-2 phosphorylation in IGR-N91 and resulted in significantly decreased vessel density and overall surface fraction of tumor vessels in all xenografts as measured by immunohistochemistry using CD34 antibody (mean OSFV at 14 days was 0.56% in treated tumors versus 1.29% in controls; p=0.0006; Mann-Whitney test). We further evaluated the effects of AG-13736 on circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) measured by flow cytometry. While only a transient reduction was observed in CECs, CEPs were significantly reduced during at least 28 days after treatment (0.40 +/−0.08 cells/ L before treatment compared to 0.02 +/−0.003, 0.00 +/−0.01 and 0.03 +/−0.02 at days 7, 14 and 28, respectively). The mTOR inhibitor rapamycin at 20 mg/kg once weekly resulted similarly to AG-13736 in significant tumor growth delays in IGR-N91 xenografts, however its combination to AG-13736 did not further increase their single agent activities. Thus, AG-13736 is a very potent anti-angiogenic new agent and demands further evaluation in neuroblastoma. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B1.
