The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Abstract

Abstract: MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered "ready for routine use." Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies-56% of them within early clinical trials-mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA).

Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171.

Figure 1.

Study flow chart. Paired tumor and germline samples were analyzed in all patients with WES. CMTB, clinical molecular tumor board.

Figure 2.

Oncomap of potentially actionable alterations and canonical fusions in CNS tumors in 118 patients with 119 samples. Tumor types with five or fewer samples are grouped together in “Other.” Only alterations identified five or more times within the whole study are reported here. ATRT, atypical teratoid rhabdoid tumor; EPD, ependymoma; GCT, CNS germ cell tumor; HGG, high-grade glioma; LGG, low-grade glioma; matched, matched therapy received according to recommendations; MB, medulloblastoma; NA, not applicable; NCFUP, follow-up < 12 months; Other, other CNS tumors; subpathology, pathology subtype; supra, supratentorial.

Figure 3.

Oncomap of potentially actionable alterations and canonical fusions in sarcoma in 213 patients with 215 samples (A) and other solid tumors in 86 patients with 86 samples (B). Tumor types with five or fewer samples are grouped together in “Other.” Only alterations identified five or more times within the whole study are reported here. aRMS, alveolar rhabdomyosarcoma; CA, carcinoma; DSRCT, desmoplastic small round cell tumor; eRMS, embryonal rhabdomyosarcoma; EWS, Ewing sarcoma; matched, matched therapy received according to recommendations; MPNST, malignant peripheral nerve sheath tumor; NA, not applicable; NBL, neuroblastoma; NCFUP, follow-up < 12 months; NOS, not otherwise specified; NRSTS, non-rhabdomyosarcoma soft-tissue sarcoma; OS, osteosarcoma; Other, other solid tumor; RMS, rhabdomyosarcoma; RT, rhabdoid tumor; SS, synovial sarcoma; subpathology, pathology subtype; US, undifferentiated sarcoma; WT, Wilms tumor.

Figure 4.

Matched targeted treatment recommendations per genetic alterations (only one alteration by gene and those occurring in more than five cases are represented). GSi, gamma-secretase inhibitor; PD1/PD1Li, programmed cell death protein 1/ligand immune checkpoint inhibitors; TMB, tumor mutational burden.

Figure 5.

Tumor mutational load in main cancer types (only disease types with more than five cases are presented). Median mutational loads and quartiles 25 and 75 are shown as black solid lines for each tumor type. Samples with 2 to <10 mut/Mb are considered pediatric high, 10 to <100 hypermutators, and >100 ultrahypermutators. ALCL, anaplastic large cell lymphoma; ATRT, atypical teratoid rhabdoid tumor; CA, carcinoma; EPD, ependymoma; EWS, Ewing sarcoma; HB, hepatoblastoma; HGG, high-grade glioma; LGG, low-grade glioma; MB, medulloblastoma; NBL, neuroblastoma; NRSTS, non-RMS soft-tissue sarcoma; OS, osteosarcoma; Other ST, other solid tumors; RMS, rhabdomyosarcoma; WT, Wilms tumor.

Figure 6.

cfDNA and ctDNA ancillary study in 225 patients with extracranial solid tumors. A, cfDNA quantity per type of tumor (ng/mL of plasma, log₁₀ scale). **, indicates statistically significant difference (Wilcoxon test: 3e−04). B, ctDNA fraction calculated by the Facet tool after WES for each type of tumor. ***, indicates statistically significant difference (Wilcoxon test: 1.4e−08). C, Example of a sequencing result for a patient with an alveolar rhabdomyosarcoma. On the top, copy-number profiles generated by the Facet tool, showing the same chromosome alterations identified in the tumor/plasma. Middle, RB1 c.C1333T and TP53 c.A311G mutations were identified in tumor and plasma, whereas TP53 c.A355T was observed only in the plasma. Bottom, Venn diagram of SNVs detected in each type of samples with a good overlap (15 SNVs common between tumor and plasma). D, Oncoprint of SNVs in targeting potentially actionable genes detected in tumor (blue) and plasma (red) for 72 cases with both successful tumor and cfDNA analysis (only cases with at least one SNV in an actionable gene are reported here). Histograms on the top indicate the total number of SNVs in actionable genes in each case (blue, tumor; red, plasma); histograms on the right indicate the percentage of cases with alterations in the indicated actionable gene.