Lee, Alice A.

10007 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1-21 years with relapsed or refractory solid tumors, CNS tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations in their tumor. Arm B (APEC1621B) evaluated the orally bioavailable FGFR inhibitor erdafitinib in patients whose tumors harbored activating alterations in FGFR 1/2/3/4. Methods: Patients received oral erdafitinib 4.7 mg/m 2 /dose (Max dose: 8 mg) daily for 28-day cycles until disease progression or drug related dose limiting toxicity (Max 26 cycles). Disease assessments were performed every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included progression free survival (PFS). Results: A total of 20 evaluable patients (median age: 15 yrs) were enrolled from June 2018 to July 2022 in this first study of erdafitinib in pediatric patients. The most common diagnosis (n = 17) was glioma or glioneuronal tumor (11 low grade and 6 high grade). Three patients had non-CNS solid tumors (1 each with neuroblastoma, osteosarcoma, and rhabdomyosarcoma). FGFR alterations detected consisted of activating hotspot mutations in FGFR1 (n = 16), FGFR2 (n = 1), FGFR4 (n = 1), and FGFR1 fusions (n = 2; FGFR1: TACC1, FGFR1: TACC3). Partial responses were confirmed by central review in 2/20 patients (10%, 90%CI: 3.4%, 26.2%), both with low grade gliomas or glioneuronal tumors (LGG, LGGNT) and FGFR1 hotspot mutations (K687E and N577K). A best response of stable disease (SD) was observed in 6 additional patients with gliomas with a median duration of SD of 6.5 cycles. Six-month PFS was 45% (95% CI: 23.1%, 64.7%) and six-month OS was 89.7% (95%CI: 64.8%, 97.3%). Treatment related adverse events included those previously reported with FGFR inhibitors including hyperphosphatemia and nail changes or infections. Grade 1 vision changes were also reported. There was one Grade 3 spinal cord compression and one Grade 4 intracranial hemorrhage. Conclusions: Erdafitinib was generally well tolerated in this heavily pre-treated cohort of children with relapsed tumors harboring FGFR alterations. Partial responses or stable disease were observed in the majority (6/11, 54%) of patients with FGFR1-mutant low grade gliomas or glioneuronal tumors, suggesting the possible benefit of FGFR inhibitor therapy for these patients. Further studies would be necessary to more thoroughly evaluate the activity of erdafitinib for patients with other histologies and FGFR alteration types or combination approaches that include other targeted and/or cytotoxic agents. Clinical trial information: NCT03210714 .

Abstract Importance: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. Objective: To investigate age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. Design, Setting, and Participants: We included 167,483 participants from 2 prospective U.S. cohort studies with 1190 incident cases of pancreatic cancer identified during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248,893 pancreatic cancer cases documented in the U.S. Surveillance, Epidemiology, and End Results (SEER) Program. Exposures: Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and Black race in the SEER program. Main outcomes and measures: Risk of developing pancreatic cancer by age evaluated by Cox, logistic, or Poisson regression, as determined by the study design. Results: In the prospective cohorts, all 5 risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations greatly attenuated among those over 70 years. The HRs comparing participants with 3-5 risk factors to those with no risk factors were 9.24 (95% CI, 4.11-20.77) among those aged ≤60 years, 3.00 (95% CI, 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI, 1.10-1.94) among those over 70 years (Pheterogeneity = 3×10-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS, the polygenic risk score was most strongly associated with pancreatic cancer risk among those aged ≤60 years, with lesser associations identified in older participants (Pheterogeneity = .01). In the SEER Program, male sex and Black race were also more strongly associated with pancreatic cancer risk among younger individuals (Pheterogeneity < 1×10-8). Conclusions and relevance: Inherited and lifestyle factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy. Citation Format: Chen Yuan, Jihye Kim, Qiao-Li Wang, Alice A. Lee, Ana Babic, PanScan/PanC4 I-III Consortium, Laufey T. Amundadottir, Alison P. Klein, Donghui Li, Marjorie L. McCullough, Gloria M. Petersen, Harvey A. Risch, Rachael Z. Stolzenberg-Solomon, Kimberly Perez, Kimmie Ng, Edward L. Giovannucci, Meir J. Stampfer, Peter Kraft, Brian M. Wolpin. The age-dependent association of risk factors with pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5891.