ME-344/Bevacizumab Combo Shows Early Efficacy in mCRC

ME-344 and bevacizumab can now have an additional 20 patients enrolled on the phase 1b trial for relapsed metastatic colorectal cancer.

The investigational agent ME-344 in combination with bevacizumab (Avastin) showed encouraging signs of antitumor activity in patients with relapsed metastatic colorectal cancer (mCRC), according to findings from an ongoing phase 1b trial (NCT05824559).¹

Results showed that 25% of 20 evaluable patients with mCRC in cohort 1 did not experience disease progression at week 16 of treatment with the combination, exceeding the 20% predetermined threshold in the study protocol. This now permits an additional 20 patients to the study, specifically in cohort 2.

Additional data showed that the median progression-free survival (PFS) was 1.9 months and the 4-month PFS rate was 31.2%. The median overall survival (OS) was 6.7 months, and 15 patients were censored at the time of the analysis. Forty-five percent of patients (n = 9) had stable disease. The combination was also found to be well tolerated.

MEI Pharma noted that although the threshold was met in cohort 1, the company will not initiate enrollment in a second cohort in order to continue advancing ME-344 through a new formulation.

"The data reported today, including progression-free survival, overall survival, and safety results of the combination, represent an important development supporting the potential of ME-344 in combination with [bevacizumab] to induce synthetic lethality in tumors using a completely novel therapeutic strategy," said Richard Ghalie, chief medical officer of MEI Pharma, the developer of ME-344. "The development of a new formulation with enhanced biologic activity is aimed at further improving patient outcomes and treatment convenience in a well-tolerated manner."

ME-344 is an investigational mitochondrial oxidative phosphorylation inhibitor. Combining it with bevacizumab is believed to lead to metabolic synthetic lethality and reduce glycolysis, which forces “tumors to switch to mitochondrial respiration via OXPHOS, [oxidative phosphorylation]” the company explained in a news release.

In the phase 1b trial, investigators are evaluating ME-344 in combination with bevacizumab in patients with relapsed mCRC that has failed standard therapies.² ME-344 is administered at 10 mg/kg once weekly for 3 weeks plus bevacizumab every 2 weeks in 28-day cycles, until disease progression or intolerability.

The primary end point is 16-week progression-free survival (PFS); secondary end points are overall PFS, duration of response, OS, and safety.

The trial has up to 2 cohorts with an estimated 20 patients each. In cohort 1, 23 patients with relapsed mCRC were enrolled. The median age was 58 years (range, 42-83), and the median number of prior lines of treatment was 4 (range, 1-8), and 78% of patients had received 3 or more prior lines of therapy. All patients previously were treated with bevacizumab and standard chemotherapy.

There were 23 patients enrolled in cohort 1, and 3 patients were not evaluable for the 16-week disease progression analysis because of early treatment discontinuation before the first disease assessment on treatment.

Two patients are currently enrolled in cohort 1.

Regarding safety, 2 patients (9%) discontinued treatment because of adverse effects (AEs), which were fatigue and sepsis, the latter of which was not deemed related to treatment. The most common all-grade and grade 3 or higher treatment-related AEs were fatigue (35%; 13%) and abdominal pain (13%; 9%).

The trial is being conducted at member centers of the Academic GI Cancer Consortium.

"At MEI we are committed to our mission of developing novel drug candidates to address known resistance mechanisms to standard-of-care cancer therapies, and ME-344 holds significant potential as a novel therapeutic strategy to advance this mission," said David Urso, president and chief executive officer of MEI Pharma. "We believe that the best approach to optimize the potential of ME-344 for patients, prioritize resource utilization, and build value for shareholders, is to continue advancing the program via the development of a new formulation of ME-344. In the short term, this plan will reduce expenditures on the ME-344 program and ultimately, if successful, create an improved formulation for continued clinical development."

References

1. MEI Pharma reports initial data from clinical study evaluating ME-344 in combination with bevacizumab (Avastin®) in relapsed metastatic colorectal cancer patients. News release. MEI Pharma. April 11, 2024. Accessed April 18, 2024. https://shorturl.at/hpwyJ
2. ME-344 and bevacizumab in previously treated metastatic colorectal cancer. ClinicalTrials.gov. Updated April 15, 2024. Accessed April 18, 2024. https://shorturl.at/dlCK9