Associate Principal Scientist Merck & Co., Inc., United States
Background: Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways that are suspected to activate HIF-2α are poorly understood, with limited understanding of prevalence and associations with clinical outcomes in real world settings.
Objectives: To estimate prevalence of HIF2α-related gene mutations across solid tumor types and to examine if the presence of these mutations is associated with patients’ overall survival (OS).
Methods: This is a retrospective observational study across 15 available tumor types, using data from the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB) collected up to Dec 31, 2020. Eligible patients were aged ≥ 18 years, diagnosed with advanced/metastatic solid tumors in 2018-2019. Mutations of SDHA, SDHB, SDHC, SDHD, FH, and VHL genes were assessed by FMI F1CDx. OS analysis from the first- and second-line therapy initiation (1L/2L) was performed with adjustment for delayed entry when the reported date of sequencing results was later than 1L/2L therapy. Patients were censored on the date of last visit recorded in the database. Cox proportional hazards models were used to examine relative risks of survival from 1L/2L by gene mutation status, adjusted for age, sex, race, practice type, and tumor type.
Results: A total of 9,467 patients with advanced/metastatic solid tumors were included in the analysis, with 52% women and median age of 66 years. The top five tumor types represented more than 75% of the patients, including non-small cell lung (27%), colorectal (19%), breast (13%), pancreatic (8%) and gastric (8%) cancers. Any mutation at SDHA, SDHB, SDHC, SDHD, FH, or VHL genes was observed in 1.8% of patients and varied across tumor types, with the highest prevalence in renal cell carcinoma (RCC) (44.8%). Excluding RCC, the prevalence was 0.9%. The prevalence of individual gene mutations varied by tumor type with the highest being VHL among RCC patients (43.7%). The median OS from 1L and 2L therapy among patients with any HIF-2α gene mutation was 15.3 and 14.0 months, respectively, compared to 13.7 and 9.9 months among patients without HIF-2α mutations. The adjusted hazard ratio (aHR) for OS from initiation of 1L therapy for patients with any HIF-2α mutations vs HIF-2α mutation negative patients was 1.01 (95%CI, 0.75-1.34). The aHR of OS from 2L therapy was 1.19 (0.82-1.74) for patients with any HIF-2α mutations vs HIF-2α mutation negative patients.
Conclusions: The prevalence of HIF-2α related gene mutations varied widely by gene type and tumor type. There was no association between HIF-2α mutation status and OS from 1L/2L treatment among patients evaluated in this study.
