FDA Grants Fast Track Designation to Alnodesertib Plus Irinotecan in ATM-Negative mCRC

The FDA has granted fast track designation to alnodesertib (formerly ART0380) for use in combination with a low dose of irinotecan for the third-line treatment of patients with ATM-negative metastatic colorectal cancer (mCRC).1

The designation is supported by data from the ongoing phase 1/2a STELLA trial (NCT04657068), which is evaluating the combination of alnodesertib and irinotecan in patients with advanced or metastatic, ATM-deficient cancers with no satisfactory alternative treatment options.2

“The fast track designation for alnodesertib underscores its first-in-class potential for [patients with] third-line mCRC with ATM-negative tumors,” Mike Andriole, chief executive officer of Artios, stated in a news release.1 “Approximately 3000 patients with ATM-negative third-line mCRC succumb to this disease annually in the United States, with no treatment options that specifically address this protein deficiency. Alnodesertib has the potential to be the first treatment specifically for this invariably lethal disease. Additionally, we are encouraged by the durable responses this program has demonstrated across other tumor types, highlighting its ability to target replication stress across a range of solid tumors.”

Alnodesertib is a potential first-in-class, orally administered, selective small inhibitor of ATR that is designed to be used in combination with DNA-damaging agents.1,2 In cancers with high replication stress, the combination of DNA-damaging therapy and ATR inhibition can target endogenous and exogenous replication stress and inhibit subsequent cellular rescue.

What Data Have Been Presented on the Combination of Alnodesertib and Irinotecan?

Preliminary data from the dose-escalation and dose-expansion portions of the phase 1/2a trial were presented at the 2025 AACR Annual Meeting.2

In dose escalation, patients received escalating doses of alnodesertib ranging from 25 mg to 400 mg on days 1, 2, 3, 8, 9, and 10, in combination with 60 mg/m2 of irinotecan on days 1 and 8 of every 21-day cycle. The recommended phase 2 dose (RP2D) of alnodesertib selected for dose expansion was 200 mg.

Baseline characteristics in the RP2D cohort (n = 58) indicated that the median age was 60 years (range, 22-83). Most patients had an ECOG performance status of 1 (62%) and had liver involvement (60%). The median number of prior lines of therapy was 3 (range, 1-7) in the overall population and the CRC population (n = 19). Prior irinotecan had been administered to 59% of patients; 34% of patients had ATM-negative cancers.

Minimum follow-up was 7 months at the time of the data cutoff, at which point 97% of patients who received the RP2D experienced any-grade treatment-related adverse effects (TRAEs; grade ≥ 3, 60%).

Any-grade and grade 3 or greater TRAEs, respectively, included neutropenia (53%; 45%), anemia (41%; 19%), fatigue (34%; 2%), diarrhea (31%; 2%), nausea (28%; 2%), vomiting (21%; 0%), abdominal pain (10%; 2%), constipation (9%; 0%), pyrexia (3%; 0%), decreased appetite (14%; 0%), hypomagnesemia (10%; 2%), asthenia (14%; 2%), hypokalemia (5%; 2%), alopecia (12%; not available), peripheral edema (3%; 0%), fall (2%; 0%), and dehydration (2%; 0%).

No deaths occurred because of TRAEs.

With respect to antitumor activity in the intention-to-treat population of patients with ATM-negative cancers (n = 20), the confirmed objective response rate was 50%, and the median duration of response was 5.7 months. Of the 6 patients with CRC, 1 experienced stable disease, and the remaining 5 achieved confirmed partial response.

Median overall survival and progression-free survival were 14.1 months and 12.1 months, respectively, in patients with ATM-negative disease treated at the RP2D.

“Patients with third-line CRC face a dismal prognosis, with current standards of care for third-line mCRC delivering response rates in the single digits. In our studies to date, alnodesertib has demonstrated compelling clinical activity in ATM-negative patients with mCRC as well as in other heavily pretreated cancer types with high endogenous replication stress,” Ian Smith, chief medical officer of Artios, added in the news release. “These results, together with activity across other solid tumors, highlight alnodesertib’s potential to deliver meaningful benefit where treatment options are limited. The FDA’s fast track designation recognizes both the strength of our early clinical data and the urgent need for new therapies, while also providing the opportunity for enhanced interactions with the agency.”

References

1. Artios receives U.S. 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://www.artios.com/press-release/artios-receives-u-s-fda-fast-track-designation-for-alnodesertib-in-atm-negative-metastatic-colorectal-cancer-mcrc/
2. Ulahannan S, Henry JT, Moore KN, et al. First results of ART0390 (an ATR kinase inhibitor) with low dose irinotecan in advanced or metastatic solid tumors. Cancer Res. 2025;85(suppl 2):CT267. doi:10.1158/1538-7445.AM2025-CT267