Inhibiting the oxidative phosphorylation (OXPHOS) pathway with novel agents such as lixumistat (IM156) could suppress the growth of cancer cells and decrease resistance to available therapies, positioning it as an attractive treatment approach in pancreatic cancer, according to Shubham Pant, MD, MBBS, and Ryan W. Huey, MD, MS.
“OXPHOS is a pathway [that] basically provides nutrition to the cancer cells,” Pant, director of clinical research and professor in the Department of Investigational Cancer Therapeutics and Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive®. “In pancreatic cancer, it’s a source of adenosine triphosphate [ATP], and it’s very sensitive.”
“The OXPHOS pathway plays an important role in the survival of pancreatic cancer cells and may offer a mechanism in which it can grow and ultimately become resistant to therapeutics such as chemotherapy,” Huey, associate professor in the Department of GI Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, added in a separate interview with OncLive. “We have some drugs that work in pancreatic cancer, but unfortunately, they don’t work as well or for as long as we would like. If we can inhibit OXPHOS [and] suppress the growth of tumor cells, [we can] conceivably help the drugs that we are giving work for a longer period.”
Lixumistat is a novel biguanide mitochondrial PC1 inhibitor of OXPHOS.1 PC1 is a key component in the electron transport chain of the OXPHOS pathway that binds and oxidizes nicotinamide adenine dinucleotide hydride prior to the electron transfer that forms ATP.
Targeting the OXPHOS Pathway in Cancer Care: Key Takeaways
- The OXPHOS pathway provides ATP and metabolic precursors to cancer cells, making it a potentially attractive target for anticancer therapies.
- Lixumistat is a novel biguanide PC1 inhibitor; PC1 is a key component of the OXPHOS pathway.
- Data from the phase 1b COMBAT-PC trial showed that patients with PDAC who received lixumistat at the RP2D of 400 mg daily (n = 10) plus gemcitabine and nab-paclitaxel experienced a DCR of 80%, an ORR of 50%, a median PFS of 7.4 months, and a median OS of 18 months.
What data have been reported with lixumistat?
Lixumistat was initially examined for the treatment of patients with advanced solid tumors in a phase 1 first-in-human study (NCT03272256). The dose-escalation study enrolled adult patients with advanced solid tumors refractory to standard therapies with an ECOG performance status of 2 or less, including those with gastric, colorectal, and breast cancers, as well as glioblastoma multiforme.
Among efficacy-evaluable patients (n = 16), no objective responses were observed with lixumistat monotherapy. However, 7 patients achieved stable disease for a disease control rate (DCR) of 32%. The median progression-free survival (PFS) was 54 days (95% CI, 47-71).
In terms of safety, no dose-limiting toxicities (DLTs) were reported at any dose level. Patients treated across all dose levels (n = 22) experienced any-grade treatment-related adverse effects (TRAEs) at a rate of 86%. The most common any-grade TRAEs included nausea (68%), diarrhea (46%), and emesis (41%). The maximum tolerated dose was not reached, but the study authors noted that lixumistat was not well tolerated at the 1200-mg, once-daily dose; 800 mg once daily was selected as the recommended phase 2 dose (RP2D).
The study authors concluded that, unlike other PC1 inhibitors, lixumistat was tolerable at the RP2D. Although single-agent activity was modest and the monotherapy expansion cohorts did not proceed, they noted that further development would be focused on combining lixumistat with targeted therapies or chemotherapy.
Now lixumistat is being evaluated in combination with gemcitabine and nab-paclitaxel (Abraxane) for the treatment of patients with advanced pancreatic cancer in the ongoing phase 1b COMBAT-PC trial (NCT05497778).2 The single-center study enrolled patients with treatment-naive metastatic pancreatic ductal adenocarcinoma with measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.
During the dose-escalation phase, patients received intravenous gemcitabine and nab-paclitaxel at respective doses of 1000 mg/m2 and 125 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Oral lixumistat was given at a starting dose of 400 mg daily beginning on day 3.
The primary objective of the study was to assess the safety and tolerability of the combination. Efficacy was also assessed via DCR, overall response rate (ORR), PFS, and overall survival (OS).
At a median follow-up of 12.9 months, findings from COMBAT-PC presented during the 2025 European Society for Medical Oncology Gastrointestinal Cancers Congress revealed that among efficacy-evaluable patients who received lixumistat at the RP2D of 400 mg daily (n = 10), the DCR was 80%, and 50% of patients achieved a partial response. The median PFS was 7.4 months, and the median OS was 18 months.
Regarding safety, no grade 4 or 5 toxicities were reported, and no DLTs were reported at the RP2D. Common AEs that were deemed to be related to lixumistat included grade 1 or 2 nausea/vomiting, rash, fatigue, and diarrhea.
“We were encouraged that we did not see any grade 4 or 5 toxicities. We saw occasional DLTs at 800 mg, but not at 400 mg, and the majority of AEs were grades 1 and 2,” Huey said. “[We want] to ensure that this is safe for patients, and some of the [efficacy] signals that we saw were encouraging, but this was a single-arm study [that was] not randomized. The big question is: [Will] this hold up in a randomized phase 3 study?”
Lixumistat received orphan drug designations from the FDA for the treatment of patients with pancreatic cancer in November 2022 and for the treatment of those with glioblastoma multiforme in December 2023.3,4
“[Additional treatments] for patients with metastatic pancreatic cancer are an unmet need,” Pant said. “[Lixumistat] is unique because it targets the metabolism of the pancreatic cancer cells, and it could potentially improve outcomes for patients with pancreatic cancer.”
Are there any other agents targeting the OXPHOS pathway in development?
Beyond lixumistat, another novel agent that was developed to target the OXPHOS pathway is ME-344, a synthetic small molecule mitochondrial inhibitor that was designed based on the isoflavone ring structure.5
ME-344 has been most extensively investigated for the treatment of patients with pretreated metastatic colorectal cancer (CRC). In a phase 1b study (NCT05824559), the agent was evaluated in combination with bevacizumab (Avastin) in adult patients with metastatic CRC who experienced disease progression following treatment with standard therapies. The primary efficacy end point was 16-week PFS rate; other efficacy end points included PFS, ORR per RECIST 1.1 criteria, and OS.
Findings from the trial published in Investigational New Drugs demonstrated that the estimated 16-week PFS rate among patients who received the combination (n = 23) was 30.6% (95% CI, 12.2%-51.3%), and the median PFS was 1.9 months (95% CI, 1.6-4.7). The median OS was 6.7 months (95% CI, 3.4-not reached). No objective responses were reported among the 20 patients who were evaluable for response.
In terms of safety, the most common any-grade AEs included fatigue (48%), abdominal pain (35%), diarrhea (30%), and constipation (30%). At the time of the final analysis, all patients had discontinued treatment. The study authors concluded that although ME-344 plus bevacizumab was well tolerated, and although the study was closed due to sponsor decision to pursue a new formulation with longer plasma exposure, further investigation of ME-344 could be considered.
References
- Janku F, Beom SH, Moon YW, et al. First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2022;40(5):1001-1010. doi:10.1007/s10637-022-01277-9
- Pant S, Saj F, Huey R, et al. A phase Ib dose-escalation trial of gemcitabine and nab-paclitaxel in combination with lixumistat in patients with advanced pancreatic cancer (COMBAT-PC). Ann Oncol. 2025;36(suppl 1):S104. doi:10.1016/j.annonc.2025.05.278
- ImmunoMet Therapeutics announces first patient dosed in a phase 1b trial of IM156 in pancreatic cancer. News release. ImmunoMet Therapeutics. November 17, 2022. Accessed November 19, 2025. https://immunomet.com/immunomet-therapeutics-announces-first-patient-dosed-in-a-phase-1b-trial-of-im156-in-pancreatic-cancer/
- Search orphan drug designations and approvals. FDA. December 27, 2023. Accessed November 19, 2025. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=979623
- Boland PM, Lenz HJ, Ciombor KK, et al. A phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer. Invest New Drugs. 2025;43(1):60-68. doi:10.1007/s10637-024-01489-1
