RRx-001 Plus Irinotecan Improves Efficacy vs Regorafenib in Colorectal Cancer

In the phase 2 ROCKET trial (NCT02096354), treatment with the small molecule NLRP3 inhibitor, RRx-001, plus irinotecan elicited a statistically significant and clinically meaningful progression-free survival (PFS) benefit compared with regorafenib (Stivarga) in patients with advanced colorectal cancer, according to a release from EpicentRx Inc.¹

Findings published in the journal Clinical Colorectal Cancer, showed that the median overall survival (OS) was 8.6 months for RRx-001 plus irinotecan vs 4.7 months for regorafenib, and the median PFS was 6.1 months vs 1.7 months, leading to a statistically significant result (P = 0.0030). The overall response rate (ORR) was 20.8% with RRx-001 and irinotecan compared with no response for regorafenib alone.

The toxicity profile of RRx-001 plus irinotecan was also improved vs regorafenib in the study. Overall, these findings show the potential chemoprotective effects of RRx-001.

"Granted, ROCKET was a small trial; however, as a [gastrointestinal] oncologist, treatment with regorafenib is commonly associated with significant skin irritation and fatigue, among other symptoms. I think oncologists would welcome a better-tolerated, more active alternative for patients with colorectal cancer who have progressed on front-line therapy. Hence, these results from ROCKET, if confirmed in a phase 3 trial, would likely lead to additional options for third line colorectal cancer and beyond treatment," stated Tony Reid, MD, gastrointestinal oncologist and chief executive officer of EpicentRx, Inc, in a press release.

The phase 2, randomized, open-label ROCKET trial randomized 34 patients in a 2:1 ratio. Patients were given either a priming dose of intravenous RRx-001 at 4 mg weekly for 2 months, followed by irinotecan, a chemotherapy agent, or oral regorafenib at 160 mg for 3 weeks on, 1 week off until progression.²

Enrollment in the study was open to patients aged 18 years and older with third- or fourth-line colorectal cancer who had previously received the irinotecan-containing chemotherapy regimen, irinotecan, fluorouracil (5-FU), and folinic acid (leucovorin; FOLFIRI). Patients were required to have measurable disease by CT or MRI, a life expectancy of 12 weeks or greater, an ECOG performance status of 0 or 1, and adequate organ function.

Investigators assessed the primary end point of OS and secondary end points of number of patients with adverse events, ORR, clinical benefit rate, PFS, duration of response, time to progression, response to subsequent therapies, and quality-of-life.

Three patients out of 24 (12.5%) had received prior single agent irinotecan in the RRx-001 randomized arm and 2 of 10 (20%) in the regorafenib randomized arm.³ Many patients had also received irinotecan combination therapies before randomized treatment. Additionally, 15 patients in the RRx-001 received irinotecan post-RRx-001 in the randomized trial.

In the RRx-001 plus irinotecan arm, there were 5 partial responses which led to an ORR of 20.8%. In the treatment arm, 9 of the 24 patients (37.5%) had a tumor that harbored a KRAS mutant type compared with the control arm in which 6 of 10 (60%) patients had a tumor that harbored a KRAS mutant type.

Regarding safety, RRx-001 plus irinotecan had a substantially improved toxicity profile compared with regorafenib. With irinotecan treatment, there were no observed cases of severe diarrhea, likely due to protection of the gastrointestinal tract from RRx-001. Moreover, with a reduction of side effects from chemotherapy, including severe diarrhea, fewer dose delays or dose reductions were seen, as well as an improvement in antitumor outcomes.

RRx-001 is a highly selective NLRP3 inhibitor. The agent has vascular normalization and tumor associated macrophage polarization properties which allows it to resensitize tumors to previously administered therapies.

Currently, RRx-001 is also under investigation in a phase 3 trial of patients with small cell lung cancer, and in a phase 2 trial for protection against oral mucositis in first-line head and neck cancer. Investigators are additionally working on its development as a medical countermeasure for nuclear and radiological emergencies and as a treatment for neurodegenerative diseases, such as Parkinson’s and ALS/MND.

REFERENCES:

RRx-001 + irinotecan significantly improved progression free survival (PFS) versus regorafenib in the randomized phase 2 ROCKET trial in advanced colorectal cancer. News release. News release.EpicentRx Inc. December 14, 2022. Accessed January 13, 2023. https://prn.to/3X8d33E

A phase 2 randomized, open-label study of RRx-001 vs regorafenib in subjects with metastatic colorectal cancer (ROCKET). ClinicalTrials.gov. Updated May 16, 2022. Accessed January 13, 2023. https://clinicaltrials.gov/ct2/show/NCT02096354

Reid TR, Abrouk N, Caroen S, et al. ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer [published online ahead of print, 2022 Dec 2]. Clin Colorectal Cancer. 2022;S1533-0028(22)00126-8. doi:10.1016/j.clcc.2022.11.003