177Lu girentuximab

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Also known as:

177Lu-labeled-girentuximab TLX250

Cancer types include:

kidney cancer

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Overview

177Lu-girentuximab (TLX250; 177Lu‑labeled girentuximab) is an investigational radioimmunotherapy that targets carbonic anhydrase IX (CAIX), which is highly expressed on clear cell renal cell carcinoma (ccRCC). Early monotherapy studies in metastatic ccRCC showed disease stabilization in a subset of patients, with myelosuppression as the principal dose‑limiting toxicity. Ongoing trials are evaluating combinations with immunotherapy and tyrosine kinase inhibitors. (onlinelibrary.wiley.com)

Mechanism of action

Target: CAIX, a hypoxia‑regulated transmembrane enzyme overexpressed in most ccRCCs; strong/diffuse CAIX expression is seen in ~90% of ccRCC across series. (onlinelibrary.wiley.com)
Antibody: Girentuximab (cG250) is a chimeric IgG1 that binds a conformational epitope in the CAIX catalytic domain without cross‑reacting with related CA isoforms CA I/II/XII in preclinical testing. (pubmed.ncbi.nlm.nih.gov)
Radionuclide: Lutetium‑177 is a medium‑energy beta emitter (Emax ≈ 0.5 MeV; range <2 mm) with gamma emissions (113 and 208 keV) that enable post‑therapy imaging; physical half‑life ≈ 6.7 days. These properties allow targeted radiation delivery and image‑based dosimetry. (pmc.ncbi.nlm.nih.gov)

Efficacy

Human data to date are primarily from single‑arm studies in progressive metastatic ccRCC:

Phase I (n=23): Maximum tolerated dose (MTD) 2405 MBq/m2. At 3 months after first cycle, 74% (17/23) had stable disease; 1 patient achieved a partial response lasting 9 months. Mean target‑lesion growth slowed significantly vs the 3 months pre‑treatment (≈40% to ≈6%; p<0.001). (pubmed.ncbi.nlm.nih.gov)
Phase II (n=14): After first infusion, 57% (8/14) had stable disease and 7% (1/14) achieved a partial response; overall disease stabilization in 9/14 patients. Retreatment was often precluded by hematologic toxicity. (pubmed.ncbi.nlm.nih.gov)

Combination therapy trials are ongoing (results pending):

STARLITE‑2 (NCT05239533): Phase 2 of 177Lu‑girentuximab plus nivolumab in previously treated ccRCC; ASCO meeting abstracts report trial-in-progress details and dose‑finding status. (ascopubs.org)
STARLITE‑1 (NCT05663710): Phase 1b/2 of 177Lu‑girentuximab plus cabozantinib and nivolumab in treatment‑naïve advanced ccRCC; design includes 177Lu‑girentuximab 1480 MBq/m2 q12 weeks up to 3 cycles; recruiting with no efficacy readout yet. (ascopubs.org)

Note: Girentuximab is also used as a PET imaging agent when labeled with 89Zr (TLX250‑CDx), which completed a Phase 3 study and is under FDA review for imaging ccRCC; this informs patient selection in some therapy trials. (telixpharma.com)

Safety

Hematologic toxicity is dose‑limiting.
Phase I: Dose‑limiting myelotoxicity above the MTD of 2405 MBq/m2; otherwise, no major non‑hematologic toxicities reported. (pubmed.ncbi.nlm.nih.gov)
Phase II: Grade 3–4 myelotoxicity occurred in most patients; prolonged thrombocytopenia frequently prevented retreatment. (pubmed.ncbi.nlm.nih.gov)

Safety in combination regimens with checkpoint inhibitors and cabozantinib is under active investigation; continuous safety monitoring is embedded in current trial designs, with dose‑finding adjustments reported in STARLITE‑2 abstracts. (ascopubs.org)

Development status and ongoing trials (selected)

Monotherapy trials completed: Phase I (NCT00142415) and Phase II (NCT02002312) in metastatic ccRCC. (pubmed.ncbi.nlm.nih.gov)
Combination trials in progress:
STARLITE‑2 (NCT05239533): 177Lu‑girentuximab + nivolumab; recruiting/active. (cdek.pharmacy.purdue.edu)
STARLITE‑1 (NCT05663710): 177Lu‑girentuximab + cabozantinib + nivolumab; recruiting/active. (cdek.pharmacy.purdue.edu)

Active trials using 177Lu girentuximab

Found 2 active trials using this drug:

Phase 1b/2 Study of Combination 177Lu Girentuximab Plus Cabozantinib and Nivolumab in Treatment naïve Patients With Advanced Clear Cell RCC

Sponsor: M.D. Anderson Cancer Center (other) Phase: 1/2 Start date: June 30, 2023

HealthScout AI summary: Treatment‑naïve adults with locally advanced or metastatic clear‑cell RCC (ECOG 0–1), including those with controlled, non–life‑threatening brain metastases, receive triplet therapy with 177Lu‑girentuximab (TLX250; CAIX‑targeted radiolabeled mAb delivering beta radiation), nivolumab (PD‑1 inhibitor), and cabozantinib (VEGFR/MET/AXL TKI). Key exclusions include prior systemic therapy for metastatic RCC, active autoimmune disease requiring therapy, recent major cardiovascular events, significant GI/fistula risk, uncontrolled hypertension, strong CYP3A4 modulators, and recent major surgery.

ClinicalTrials.gov ID: NCT05663710

A Phase 2 Open-label Study of Nivolumab Combined With Lutetium 177-Labeled Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients With Clear Cell Advanced Renal Cell Carcinoma

Sponsor: Memorial Sloan Kettering Cancer Center (other) Phase: 2 Start date: Feb. 16, 2022

HealthScout AI summary: Adults with unresectable or metastatic clear cell RCC that is CAIX-positive and previously treated with at least one PD‑1/PD‑L1–containing regimen receive nivolumab plus 177Lu‑girentuximab, a radiolabeled anti‑CAIX monoclonal antibody delivering beta radiation to CAIX‑expressing tumor cells. Eligibility requires evaluable disease on 89Zr‑girentuximab PET/CT, KPS ≥70, and adequate organ function; key exclusions include prior 177Lu‑girentuximab, uncontrolled CNS disease, significant autoimmune toxicity, and recent radionuclide therapy.

ClinicalTrials.gov ID: NCT05239533