Novel Drug Combination Shows Early Activity in Microsatellite Stable CRC

The novel immunomodulatory agent pixatimod (PG545) in combination with the PD-1 inhibitor nivolumab (Opdivo) may benefit patients with advanced bowel cancers, including a small subset of those with colorectal cancer (CRC) considered to be microsatellite stable (MSS), according to early results from a phase Ib trial.

The data were presented by James Kuo, MBBS, a medical oncologist and the deputy medical director of Scientia Clinical Research, based in Sydney, Australia, during the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland.

“No patients with MSS stable CRC have been reported to respond to monotherapy with immune checkpoint inhibitor therapy,” said Kuo, in a statement. “However, in this study of a new drug combination, we observed clinical benefit in 4 out of 5 MSS CRC patients enrolled, including 2 demonstrating a reduction in tumor burden.”

Unlike patients who have microsatellite instability, MSS patients have tumors that possess less signals that alert the immune system to the cancer. Investigators in the space believed that this may be the reason that checkpoint inhibitors have not had much success as treatment for patients with MSS CRC.

A total of 16 patients were enrolled in the single-arm, phase Ib study (NCT02042781) between October 2017 and September 2018 with mixed tumor types: pancreatic cancer (n = 7), colorectal cancer (n = 5), uterine adenosarcoma (n = 1), squamous cell carcinoma (n = 1), endometrial carcinoma (n = 1), and adrenocortical carcinoma (n = 1). All patients had an ECOG performance status of 0 or 1 and had progressed on prior therapy.

Patients were given 240 mg of nivolumab every 2 weeks, while pixatimod was given weekly at a starting dose of 25 mg; both agents were administered intravenously.

The 25-mg dose of pixatimod was determined as the maximum-tolerated dose after 2 dose-limiting toxicities occurred at a 50-mg dose—1 patient died from organ failure, while another patient accumulated fluid in the lung, but has since recovered. Additionally, 1 patient was observed to have developed pneumonitis at the 25-mg dose, while another was believed to have encephalitis. The most frequent drug-related adverse events (AEs) included fatigue, nausea, and elevated liver enzymes; however, all of these AEs were considered to be manageable.

Responses were reported in 2 patients with metastatic CRC, one of which has had an 86% reduction in tumor burden for more than 1 year of treatment; the second patients remains on treatment for more than 6 months with an ongoing reduction of 38% in tumor burden despite a new growth in the bone, said Kuo. Another patient with CRC was observed to have stable disease at 16 weeks, he added. All 3 patients have MSS disease and have demonstrated an improvement in quality of life.

Evidence of dendritic cell stimulation, natural killer cell and/or T-cell activation was observed in the peripheral blood of some patients who were treated with the combination, and Kuo suggested that changes seen in immune cell type, number, and function could potentially be linked with the treatment of a PD-1 inhibitor and an immune-stimulating agent.

Four patients with CRC remain on the trial to date; the trial remains open for recruitment. Additionally, in October 2018, the trial expanded to evaluate the safety and effectiveness of a 25-mg dose of pixatimod plus a 240-mg dose of nivolumab in those with metastatic pancreatic ductal adenocarcinoma (mPDAC).

While these data are early, Kuo explained that the combination could have the potential to overcome intrinsic resistance to PD-1 inhibitors in MSS CRC.

Antoni Ribas, MD, PhD, a professor of medicine, surgery, and molecular and medical pharmacology of the University of California, Los Angeles, and co-chair of the EORTC-NCI-AACR Symposium, commented on the findings.

“Although these are results from just a small number of patients, the effect of this drug combination on a cancer subtype known to be inherently resistant to immune checkpoint inhibitors suggest that pixatimod may boost the effectiveness of nivolumab by providing another signal to the immune system, alerting it to these cancers,” Ribas said.

Kuo J, Bampton, D, Lemech, CR, et al. Preliminary results from a phase 1b study of pixatimod (PG545) in combination with nivolumab in patients with advanced solid tumors with an expansion cohort in patients with metastatic pancreatic cancer. In: Proceedings from the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 13-16, 2018; Dublin, Ireland. Abstract 9. https://bit.ly/2zZtFBp.