[Ga]Ga-FAPI-46 PET accuracy for cancer imaging with histopathology validation: a single-centre, single-arm, interventional, phase 2 trial.

[BACKGROUND] The fibroblast activation protein α (FAP)-directed radiotracer [Ga]Ga-FAPI-46 for PET-CT has shown promising diagnostic accuracy in cancer staging in retrospective studies. We aim to investigate the positive predictive value (PPV) of [Ga]Ga-FAPI-46 PET for detecting FAP-expressing tumours and the potential association between PET radiotracer uptake intensity and immunohistochemical FAP expression.

[METHODS] This single-centre, single-arm, interventional, phase 2 trial was conducted at the University Hospital Essen, Essen, Germany. Adults aged 18 years or older undergoing initial staging or restaging were eligible if they had at least one measurable tumour lesion (>1 cm) and a confirmed or suspected diagnosis of breast cancer, colorectal cancer, endometrial cancer, oesophageal cancer, head and neck cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), prostate cancer, thyroid cancer, glioma, hepatocellular carcinoma, lymphoma, multiple myeloma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), sarcoma, seminoma, cancer of unknown primary origin, or other tumour types; had a planned or recent surgery or biopsy within 8 weeks before or after enrolment; and an ECOG performance status of 2 or less. Key exclusion criteria were previous external beam radiotherapy to the target lesion and receiving systemic cancer therapy within 1 month before enrolment. PET-CT images were acquired at a median of 11 min (IQR 10-14) after an intravenous injection of a median of 145 Megabecquerel (MBq; 124-154) of [Ga]Ga-FAPI-46 and analysed by three independent, masked readers. The study concluded on day 30 of follow-up if histopathological confirmation and archived tumour tissue were already available, or on the day of biopsy or surgery within 8 weeks of receiving [Ga]Ga-FAPI-46 PET-CT. Immunohistochemical FAP expression (score 0-3) was evaluated by an independent masked pathologist. The primary endpoint was the PPV of [Ga]Ga-FAPI-46 PET for detecting immunohistochemical FAP-positive tumours (histopathologically confirmed) on a per-patient and per-region basis, with a predefined threshold of PPV of at least 75%, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05160051, and is complete.

[FINDINGS] Between Dec 1, 2021, and Feb 6, 2024, 158 eligible participants were enrolled and three were excluded. 98 (63%) of 155 participants who received [Ga]Ga-FAPI-46 PET-CT were male and 57 (37%) were female. One (1%) participant was African, two (1%) were Asian, and 152 (98%) were White. The median age of participants was 62 years (IQR 55-70). The median follow-up was 29 days (29-30). The patient-based PPV of [Ga]Ga-FAPI-46 PET for detecting FAP-positive tumours based on immunohistochemical FAP staining was 90% (95% CI 84-95) and region-based PPV was 92% (85-96) in 127 (88%) of 144 participants with histopathological validation. Five (6%) of 90 adverse events were classified as possibly related to [Ga]Ga-FAPI-46. Seven (8%) adverse events were serious, none related to [Ga]Ga-FAPI-46. One participant died due to disease progression.

[INTERPRETATION] These results confirm the safety and potential of [Ga]Ga-FAPI-46 PET as an imaging biomarker for the detection of FAP-expressing tumours. Further studies are warranted to refine the specificity and define the role of [Ga]Ga-FAPI-46 PET in clinical practice.

[FUNDING] SOFIE Biosciences.