STING Agonist and Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy in Combination With Checkpoint Inhibition for Patients With Metastatic Kidney Cancer (SPARK)

To evaluate progression of metastatic renal cell carcinoma from the initiation of PULSAR radiotherapy in combination with IMSA101 injectable onward.

More details:

The study expects to accrue the 20 patients over a 3-4 year period. Patients with oligoprogressive disease (1-3 lesions) after treatment with Anti-PD1 / Anti-CTLA-4 will continue Anti-PD1 (nivolumab). All patients will have a mandatory PD-L1 PET (Pre-treatment and Week 12). All patients will undergo baseline biopsy (just before the administration of IMSA101 of the same lesion to be injected). SAbR will be delivered in 3 fractions at 12 Gy every 4 weeks (PULSAR regimen) to all progressing lesions. One lesion will also receive 5 intratumoral injections of IMSA101 (C1D1, C1D8, C1D15, C2D1, C3D1) immediately after radiation either on the same day or within 72 hours after the PULSE. Selected Phase 2 dosing of IMSA101 (1200mcg) will be utilized. At disease progression, patients have the option to undergo additional imaging and tissue/blood collections.

Overview

IMSA101 (also known as GB492) is an intratumoral small‑molecule stimulator of interferon genes (STING) agonist being developed for solid tumors. A first‑in‑human, open‑label phase 1 dose‑escalation study in advanced solid tumors has been published (IMSA101-101; NCT04020185). In that study, IMSA101 was tested as monotherapy and combined with a PD-(L)1 inhibitor. Provisional RP2D was 1,200 µg for monotherapy and 2,400 µg for combination therapy; antitumor activity was limited overall. (pmc.ncbi.nlm.nih.gov)

IMSA101 is also being explored in randomized phase 2 trials that add intratumoral IMSA101 to PD‑1 therapy and ultra‑fractionated stereotactic adaptive radiotherapy (PULSAR) in oligometastatic NSCLC/RCC and oligoprogressive solid tumors (NCT05846646; NCT05846659). (ascopubs.org)

IMSA101’s alternate name GB492 is used by Genor Biopharma in China. (genorbio.com)

Mechanism of action

• Target/pathway: Direct agonist of STING (TMEM173), a key adaptor in the cGAS‑STING innate immune pathway that induces type I interferons and pro‑inflammatory cytokines. IMSA101 is a synthetic analog of 2′3′‑cGAMP designed to resist degradation by the ectoenzyme ENPP1, thereby sustaining STING activation. (pmc.ncbi.nlm.nih.gov)
• Immune effects (preclinical): Intratumoral IMSA101 activates dendritic cells, increases antigen presentation, and can convert “cold” tumors to “hot.” It has also enhanced CAR‑T efficacy in murine models via induction of IL‑18 signaling. (pmc.ncbi.nlm.nih.gov)
• Route and PK: Given intratumorally; plasma half‑life ~1.5–2 hours with no detectable drug at 24 hours post‑dose and no accumulation. (pmc.ncbi.nlm.nih.gov)

Efficacy

First‑in‑human phase 1 (advanced solid tumors; intratumoral IMSA101 weekly ×3 then every 2 weeks; 22 monotherapy, 18 combination with PD‑(L)1): - Monotherapy: No objective responses; best responses were progressive disease in 77.3% and stable disease in 1/22 (4.5%). Median progression‑free survival 1.6 months. (pmc.ncbi.nlm.nih.gov) - Combination with PD‑(L)1: Overall response rate 5.6% (1 partial response in uveal melanoma); stable disease in 2/18 (11.1%); median progression‑free survival 1.7 months. (pmc.ncbi.nlm.nih.gov)

Ongoing development: - Two randomized phase 2A studies are evaluating the addition of IMSA101 to PD‑1 therapy plus PULSAR radiotherapy in oligometastatic NSCLC/RCC (IMSA101‑102; n≈40) and oligoprogressive solid tumors (IMSA101‑103; n≈45). Safety lead‑in uses 800 or 1,200 µg IMSA101; experimental arms receive five intratumoral injections over ~60 days alongside three monthly PULSAR fractions and PD‑1 therapy. Primary endpoints are progression‑free rates at 18 and 12 months, respectively. Results have not been reported. (ascopubs.org)

Safety

In the phase 1 study, IMSA101 was generally well tolerated up to 1,200 µg (monotherapy) and 2,400 µg (combination). Common IMSA101‑related adverse events: - Monotherapy: injection‑site pain (36.4%), fatigue (18.2%).
- Combination: chills (16.7%), injection‑site pain (11.1%), fever (11.1%).
Grade ≥3 IMSA101‑related AEs occurred in 9.1% (monotherapy) and 11.1% (combination). One dose‑limiting toxicity (grade 3 arthropathy) was observed in the combination arm; one grade 1 cytokine release syndrome resolved within a day. (pmc.ncbi.nlm.nih.gov)

Further reading

• Phase 1 first‑in‑human study (J Immunother Cancer, 2025; open access). (pmc.ncbi.nlm.nih.gov)
• ASCO 2024 trials‑in‑progress abstract for the randomized phase 2 studies (TPS2685). (ascopubs.org)
• Preclinical mechanistic study: IMSA101 enhances CAR‑T function via IL‑18 (Nat Commun, 2024). (pmc.ncbi.nlm.nih.gov)
• Genor Biopharma pipeline page noting GB492 (IMSA101). (genorbio.com)

Notes: As of the 2025 phase 1 publication, no randomized efficacy data or phase 2 clinical outcomes for IMSA101 have been reported publicly. (pmc.ncbi.nlm.nih.gov, ascopubs.org)

Last updated: Sep 2025

Inclusion Criteria:

* Patients must have metastatic ccRCC.

* Patients must have oligoprogression defined as progression in ≤3 lesions.

* All oligoprogression lesions must be suitable for radiation.

* Patients must have at least one site of disease that can be safely injected with IMSA101. Lung metastases are excluded.

* ECOG performance status 0-2.

* Age ≥ 18 years.

* Patients must have adequate organ and marrow function within 14 days prior to study entry.

* All IMDC risk categories are allowed.

Exclusion Criteria:

* Patients with progressive ultracentral/central chest lesions will be excluded