177Lu-FAP-2286 Displays Preliminary Antitumor Activity in Advanced or Metastatic Solid Tumors

The targeted radiotherapy candidate lutetium-177-FAP-2286 (¹⁷⁷Lu-FAP-2286) produced preliminary evidence of antitumor activity with a manageable safety profile in patients with advanced or metastatic solid tumors, according to data from the phase 1/2 LuMIERE trial (NCT04939610) presented at the 35th Annual EANM Congress.^1,2

Among 11 patients treated with doses of ¹⁷⁷Lu-FAP-2286 up to 7.4 GBq, 1 (9.1%) patient achieved a confirmed partial response and completed 6 doses of ¹⁷⁷Lu-FAP-2286 at 3.7 GBq. This patient has continued without disease progression or subsequent anticancer therapy more than 12 months after the first dose of ¹⁷⁷Lu-FAP-2286. Additionally, 1 heavily pretreated patient in the 5.55 GBq cohort experienced stable disease.

“The LuMIERE trial is the first prospective trial of a FAP peptide targeted radionuclide therapy and is currently in the dose-escalation phase. To date we have not seen evidence of significant associated toxicities that would limit therapy, and have seen some evidence of early efficacy,” Thomas A. Hope, MD, director of Molecular Therapy in the Department of Radiology and Biomedical Imaging at the University of California, San Francisco, and principal investigator of the LuMIERE trial, stated in a press release.

“We are excited about these results and the fact that FAP is expressed across a number of tumor types, and we look forward to seeing the future results.”

The 2 functional elements of ¹⁷⁷Lu-FAP-2286 include a targeting peptide that binds to FAP and a site that can be used to attach radioactive isotopes for imaging and therapeutic use. Malignancies such as pancreatic ductal adenocarcinoma, unknown primary cancer, salivary gland cancer, mesothelioma, colon cancer, bladder cancer, sarcoma, squamous non–small cell lung cancer, and head and neck squamous cell carcinoma (HNSCC) have been associated with high FAP expression.

LuMIERE enrolled patients who were at least 18 years old with refractory or progressive advanced/metastatic solid tumors following prior treatment who had no satisfactory alternative treatment options. Patients were required to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of at least 6 months. No prior systemic radionuclide therapy was permitted.

Prior to treatment, investigators conducted PET/CT scans with ⁶⁸Ga-FAP-2286 to select patients for treatment with ¹⁷⁷Lu-FAP-2286. The dose-escalation portion of the trial was designed to enroll up to 30 patients to receive ¹⁷⁷Lu-FAP-2286 at doses of 3.7 GBq (100 mCi), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi), or 9.25 GBq (250 mCi). Enrollment is ongoing at dose level 3 of 7.4 GBq. ¹⁷⁷Lu-FAP-2286 was administered on day 1 of each 6-week cycle for up to 6 cycles.

The primary end points of the trial were to evaluate the safety and tolerability of ¹⁷⁷Lu-FAP-2286 and to determine the recommended phase 2 dose and treatment schedule. Secondary end points were to measure the radiation dosimetry of ¹⁷⁷Lu-FAP-2286, evaluate the preliminary efficacy of ¹⁷⁷Lu-FAP-2286, determine the tumor uptake using ⁶⁸Ga-FAP-2286, and compare ⁶⁸Ga-FAP-2286 to ¹⁸F-FDG on PET/CT.

The median age of enrolled patients was 64 years (range, 27-71), 36.4% were female, 45.5% were White, 36.4% were Black or African American, and 45.5% had an ECOG performance status of 0. Tumor and histology type included colorectal adenocarcinoma (n = 3), pancreatic ductal adenocarcinoma (n = 2), and 1 each for adenoid cystic carcinoma, gallbladder adenocarcinoma, HNSCC, neuroblastoma, pseudomyxoma peritonei of appendiceal origin, and soft-tissue sarcoma desmoplastic small round cell tumor. All patients received at least 3 prior anticancer therapies.

Regarding safety, 90.9% of patients experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade, and 45.5% experienced a grade 3 or higher TEAE. The most common any-grade TEAEs included fatigue (45.5%), anemia (27.3%), arthralgia (27.3%), abdominal distension (18.2%), back pain (18.2%), constipation (18.2%), and diarrhea (18.2%). Investigators observed 1 event each of grade 3 or higher abdominal distension, cholangitis, hyponatremia, increased blood bilirubin, lymphopenia, and spinal compression fracture.

One instance of grade 4 lymphopenia related to the study drug was reported in 1 patient in the 5.55 GBq cohort and was considered a dose-limiting toxicity. There were no serious AEs observed, and treatment did not lead to any discontinuations.

“This presentation of updated data from the phase 1/2 LuMIERE study continues to support the hypothesis that ¹⁷⁷Lu-FAP-2286 gets to the tumor, stays in the tumor, and avoids off-target tissue. These initial phase 1 data further support the potential clinical utility of ¹⁷⁷Lu-FAP-2286 as a targeted radionuclide therapy to treat a variety of advanced solid tumors,” Patrick J. Mahay, president and chief executive officer of Clovis Oncology, stated in a press release. “We anticipate additional clinical data from the LuMIERE study to be presented at a medical conference in the first quarter of 2023.”

References

1. Clovis Oncology highlights updated LuMIERE phase 1 data of targeted radiotherapy candidate FAP-2286 at the 35th Annual EANM Congress. News release. Clovis Oncology. October 17, 2022. Accessed October 18, 2022. https://bit.ly/3S97qPG
2. Hope TA, Aggarwal R, Goenka AH, et al. ¹⁷⁷Lu-FAP-2286 in patients with advanced or metastatic solid tumors: updated data from a phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity (LuMIERE). Presented at: 35th Annual EANM Congress; October 15-19, 2022; Barcelona, Spain. Abstract OP-355. https://bit.ly/3CFwiJa