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6563 Background: NTRK gene fusions have been identified as oncogenic drivers in patients (pts) with TRK fusion cancer across multiple solid tumors. Larotrectinib, a highly selective, CNS-active TRK inhibitor has shown high response rates, durable disease control, and a favorable safety profile in pts with TRK fusion cancer and is approved in over 40 countries. Larotrectinib has demonstrated rapid health-related quality of life (HRQOL) improvement in a group of 57 adult and pediatric pts (Kummar et al, Curr Prob Canc 2021). Here, we report updated HRQOL results for larger group of pts treated with larotrectinib. Methods: HRQOL data were collected in two ongoing trials (NCT02576431, NCT02637687) of larotrectinib in pts with TRK-fusion cancer using the EORTC QLQ-C30, EQ-5D-5L questionnaires and were analyzed descriptively and longitudinally. Scores from the EORTC QLQ-C30 Global Health Status (GHS), EQ-5D-5L VAS range from 0 to 100, with higher scores indicating better QOL. We also calculated the proportion of pts with either below normal or normal and above normal HRQOL scores against values in the literature for the US general population. Results: By July 2021, 113 adults with TRK-fusion cancer had received larotrectinib and completed the baseline (BL) and ≥ 1 post-BL questionnaire. The majority of pts had clinically meaningful HRQOL improvements during treatment (Table). For EORTC QLQ-C30 GHS, most adults maintained or improved scores from BL at or above the normal population level category. HRQOL improvements (change from BL > 0) occurred after ̃2 months of treatment in 75% of adults. Median duration of pts with sustained improvement in EORTC QLQ-C30 GHS, and EQ-5D-5L VASs was 12.5 months (range, 1.8-34.1), and 12.9 months (range, 1.8-34.0), respectively. HRQOL results were consistent across multiple data cuts. Conclusions: Patients with TRK-fusion cancer treated with larotrectinib continued to have rapid, clinically meaningful, and sustained improvements in HRQOL. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.

10001 Background: Approximately 15-20% of pediatric pts with ALL or LL will be refractory to/relapse after frontline treatment; relapsed disease is associated with poor outcomes. In a phase 2 study, 2 of 7 (28.6%) pts with T-cell ALL in first relapse achieved a complete response (CR) using the vincristine, prednisone, PEG-asparaginase, and doxorubicin (VPLD) reinduction backbone. DARA, a human IgGκ monoclonal antibody targeting CD38 approved for treating multiple myeloma, has shown preclinical efficacy in ALL models. We report the initial results of DARA plus VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL enrolled in the phase 2, open-label DELPHINUS study. Methods: Eligible pts were aged 1-30 y, had T-cell ALL or LL in first relapse or refractory to 1 prior induction/consolidation regimen, and had a performance status ≥70. DARA (16 mg/kg IV QW) was given with VPLD in Cycle 1 and with methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine in Cycle 2. Pts received age/risk-adjusted intrathecal therapy. Response was measured at the end of each cycle by local bone marrow morphology. The primary endpoint for ALL pts was CR rate in pediatric pts at the end of Cycle 1. Pts achieving CR after Cycles 1 or 2 could proceed to allogeneic HSCT off study. Overall response rate (ORR) was defined as CR or CR with incomplete hematological recovery (CRi) at any time before start of subsequent therapy or HSCT. Minimal residual disease (MRD) negativity (< 0.01%) at any time before disease progression, start of subsequent therapy, or HSCT was centrally reviewed by flow cytometry. Results: Twenty-four pediatric (age 1-17 y) and 5 young adult (age 18-30 y) ALL pts and 10 LL pts (age 1-30 y) received ≥1 DARA dose. Median (range) age was 10.0 (2-25) y (ALL) and 14.5 (5-22) y (LL); median (range) time from initial diagnosis to first study treatment was 2.0 (0.1-6.1) y (ALL) and 0.8 (0.5-6.0) y (LL). Pediatric ALL pts received a median (range) of 2 (1-3) treatment cycles; young adult ALL pts and LL pts each received 2 (1-2). Among pediatric ALL pts, 10 (41.7%) pts (90% CI, 24.6-60.3) achieved CR at the end of Cycle 1. ORR was 83.3% (CR, 13 [54.2%] pts; CRi, 7 [29.2%] pts) in pediatric and 60.0% (all CR) in young adult ALL pts and 40.0% (all CR) in LL pts. Ten (41.7%) pediatric ALL pts achieved MRD negativity. All pediatric ALL pts had a grade 3/4 TEAE. No pediatric ALL pt discontinued DARA primarily due to AEs and 1 (4.2%) died due to TEAEs (brain edema and hepatic failure) attributed to study treatment but unrelated to DARA. Conclusions: The addition of DARA to VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL showed initial activity, generating improved response rates compared to those achieved with backbone therapy alone, with a manageable safety profile. Clinical trial information: NCT03384654.

10030 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types across all ages. Larotrectinib is a first-in-class, central nervous system (CNS)-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for pediatric and adult patients (pts) with TRK fusion-positive cancer, demonstrating an objective response rate (ORR) of 88% across 78 pediatric pts with non-CNS cancers (van Tilburg et al, SIOP 2021). We report an analysis of the efficacy and safety of larotrectinib in an expanded dataset of pediatric pts with TRK fusion-positive cancer. Methods: Pediatric pts (< 18 years) with non-CNS TRK fusion-positive cancer in larotrectinib clinical trials (NCT02637687, NCT02576431) were included and ORR (RECIST v1.1) was investigator (INV)-assessed. Data cut-off was July 20, 2021. Results: A total of 94 pts were included in this analysis. Tumor types included infantile fibrosarcoma (52%), other soft tissue sarcoma (40%), congenital mesoblastic nephroma (2%), thyroid cancer (2%), bone sarcoma (1%), breast cancer (1%), and melanoma (1%). Pts had gene fusions involving NTRK1 (43%), NTRK2 (3%), or NTRK3 (54%). Median age was 2.2 years (range 0–18 years). Of the 62 (66%) pts who received prior systemic therapy, 32 (52%) received ≥2 lines. The INV-assessed best ORR for the 93 evaluable pts was 84% (95% confidence interval [CI] 75–91): 35 (38%) complete response (CR; including two pending confirmation and 10 pathological CR), 43 (46%) partial response (two pending confirmation), 11 (12%) stable disease, two (2%) progressive disease, and two (2%) not determined. The median time to response was 1.8 months. Overall, median duration of response was 43.3 months (95% CI 23.4–NE); median follow-up was 26.0 months. Median progression-free survival and overall survival (OS) were 37.4 months (95% CI 22–NE) and not reached, respectively; median follow-up was 21.2 and 30.3 months, respectively. The 36-month OS rate was 93% (95% CI 86–99). Treatment duration ranged from 1+ to 63+ months. At data cut-off, 31 pts had progressed; 18 continued treatment post-progression for ≥4 weeks. There were no treatment-related deaths. Treatment-related adverse events (TRAEs) occurred in 81% of pts (23% were Grade [G] 1, 28% G2, 25% G3, and 5% G4). The most common TRAE was increased aspartate aminotransferase (31 pts [33%]). Four pts (4%) discontinued treatment due to TRAEs. Neurological TRAEs occurred in 12% of pts (5% were G1, 4% G2, and 2% G3). The most common neurological TRAE was headache (5 pts [5%]). Conclusions: In this expanded dataset, larotrectinib continues to demonstrate rapid and durable tumor-agnostic efficacy, extended survival, and a favorable safety profile in pediatric pts with TRK fusion-positive cancer. These results highlight the importance of identifying NTRK gene fusions in pediatric solid tumors. Clinical trial information: NCT02576431, NCT02637687.

10505 Background: Activation of anaplastic lymphoma kinase has been detected in several pediatric malignancies, including anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), neuroblastoma and others. Preliminary findings from this phase 1, multicenter, dose-escalation study (NCT01742286) indicated a Maximum Tolerated Dose (MTD)/Recommended Dose for Expansion (RDE) of the potent oral ALK inhibitor ceritinib to be 510 mg/m2 (fasted) and 500 mg/m2 (fed) in pediatric patients (pts). Here, we report final safety, pharmacokinetics (PK) and efficacy results. Methods: Children aged ≥1 to 2 [fasted], n = 13; 500 mg/m2 [fed], n = 42). Systemic exposure of ceritinib between the two doses was comparable, so data were pooled for efficacy assessment. The ORRs (95% CI) were 75% (34.9-96.8) for pts with ALCL, 70% (34.8-93.3) for IMT and 20% (7.7-38.6) for neuroblastoma. The median DOR was 15 months (95% CI: 5.8, 22.2) for the 6/30 pts with neuroblastoma who had confirmed CR or PR treated at fasted/fed MTD/RDE. Median DOR was not reached for those with ALCL and IMT. Most common adverse events (AEs) (N = 83; all-grades, all-causality, ≥50% of pts): vomiting (86.7%), diarrhea (78.3%), increased ALT (65.1%), increased AST (59.0%), nausea (56.6%), and abdominal pain (50.6%). Grade 3/4 AEs were observed in 80.7% of pts (mostly transaminase elevations) and were manageable. Six pts (7.2%) were discontinued from ceritinib due to a grade 3/4 AE (mostly transaminase elevation). Conclusions: Substantial activity was observed with ceritinib at the RDE in pts with IMT, ALCL and heavily pretreated neuroblastoma. The toxicity profile of ceritinib in children was manageable and similar to that previously reported in adults. Clinical trial information: NCT01742286.