Alnodesertib Receives FDA Fast Track Designation For ATM– Metastatic CRC

A confirmed ORR of 50% was observed among 20 patients with ATM-negative cancers, with a median DOR of 5.7 months and several responses ongoing.

The FDA has granted fast track designation to alnodesertib (ART0380) in combination with low-dose irinotecan for the third-line treatment of adult patients with Ataxia-Telangiectasia Mutated (ATM)–negative metastatic colorectal cancer (CRC), according to a news release from the drug’s developer, Artios Pharma Limited.1

The regulatory decision is supported by findings from the phase 1/2a STELLA trial (NCT04657068), which evaluated the combination in patients with advanced or metastatic solid tumors.2 Specifically, clinical responses were observed in 8 ATM-deficient solid tumor types, including metastatic CRC. Furthermore, across disease states, the alnodesertib/irinotecan combination displayed a manageable safety profile and favorable tolerability, showing feasibility for long-term dosing.

“Patients with third-line [CRC have] a dismal prognosis, with current standards of care for third-line metastatic CRC delivering response rates in the single digits. In our studies to date, alnodesertib has demonstrated compelling clinical activity in [patients with] ATM-negative metastatic CRC as well as in other heavily pretreated cancer types with high endogenous replication stress,” Ian Smith, chief medical officer of Artios, said in the news release on the FDA decision.1 “These results, together with activity across other solid tumors, highlight alnodesertib’s potential to deliver meaningful benefit where treatment options are limited.”

According to data the developers presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting, 58 patients with ATM-negative solid tumors received the study treatment at the recommended phase 2 dose (RP2D). The RP2D was composed of 200 mg of alnodesertib on days 1 to 3 and 8 to 10 and 60 mg/m2 of irinotecan on days 1 and 8 of each 21-day cycle.

Furthermore, a confirmed ORR of 50% was observed among patients with ATM-negative cancers (n = 10/20), with a median duration of response (DOR) of 5.7 months and several responses ongoing. With a confirmed ORR of 22% (n = 4/18) among those with ATM-low cancers, the median DOR was not reached.

“Artios is exploiting a new area of DNA damage response called replication stress with [alnodesertib], and the data from our phase 1/2a study shows robust clinical activity and good tolerability in a large, identifiable patient population,” Smith stated in a news release on the study’s findings.2 “These are unprecedented data for the ataxia-telangiectasia and Rad3-related protein [ATR] inhibitor class, and they validate our unique approach of combining [alnodesertib] with a low dose of irinotecan to amplify replication stress. We are encouraged by the incidence and durability of the responses in ATM-deficient cancers, including those of particularly high unmet need, such as pancreatic [cancer] and [CRC].”

Patients in the open-label phase 1/2a study received oral alnodesertib intermittently, either on days 2 to 4 and 9 to 11, 1 to 3 and 8 to 10, or continuously in each 21-day cycle.3 Patients received alnodesertib as monotherapy or in combination with irinotecan or gemcitabine. Gemcitabine was given on days 1 and 8 of 21-day cycles.

The primary end points of the trial were maximum tolerated dose, adverse effects (AEs) with alnodesertib monotherapy or with irinotecan, and progression-free survival per RECIST v1.1 criteria. Secondary end points included AEs with alnodesertib/gemcitabine, pharmacokinetics, and immunohistochemistry.

Alnodesertib was developed as an oral selective small molecule ATR inhibitor. The developers combined alnodesertib with low-dose chemotherapy to target cancers with high endogenous replication stress, including ATM protein-deficient tumors. Following clinical responses observed in the phase 1/2a STELLA trial, the developers are conducting expansion trials in earlier-line settings, particularly among those with CRC or pancreatic cancers.

References

1. Artios receives US FDA Fast Track designation for alnodesertib in ATM-negative metastatic colorectal cancer (mCRC). News release. Artios Pharma Limited. September 24, 2025. Accessed September 24, 2025. https://tinyurl.com/yzr7zfd4
2. Artios Pharma reports differentiated clinical activity in STELLA phase 1/2a study for lead program ART0380 at the American Association for Cancer Research (AACR) Annual Meeting 2025. News release. Artios Pharma Limited. April 29, 2025. Accessed September 24, 2025. https://tinyurl.com/ym23mvxz
3. A study of ART0380 for the treatment of advanced or metastatic solid tumors. ClinicalTrials.gov. Updated June 8, 2025. Accessed September 24, 2025. https://tinyurl.com/y62btkke