TLR9 Pathway Activator Leads to Signs of Immune Activity With PD-1 Inhibitor in MSS mCRC

The novel combination of pixatimod (formerly PG545) and nivolumab (Opdivo) demonstrated tolerability and clinical benefit in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), according to results from a phase 1b trial (NCT05061017).¹ Signals of pharmacodynamic changes and biomarţers correlated with clinical benefit were also seen with the combination regimen.

"We are excited by the efficacy signal in [patients with] MSS mCRC. Although preliminary, a 12% objective response rate along with evidence of immune activation of DCs [dendritic cells], T cells, and related cytokines supports the underlying approach,ܺ" Keith Dredge, MD, CEO of Zucero Therapeutics, told Targeted Therapies in Oncologyި. ܹOnly 12% of [patients with] MSS mCRC receiving the combination had grade 3/4 adverse events, so [it] appears to be a safe combination. The discovery that panimmune inflammatory value [PIB] could be used as a screening biomarker to [identify] patients most likely to receive some clinical benefit is also an exciting development."

Investigators from Australia explored the combination of pixatimod, an activator of the TLR9 pathway that activates DCs, plus nivolumab in patients with advanced solid tumors in the open-label, multicenter, dose-escalation phase 1 study. They hypothesized that the addition of pixatimod to nivolumab would overcome the immunologically cold nature of certain tumors such as MSS mCRC and metastatic pancreatic ductal adenocarcinoma (mPDAC) where single-agent immune checkpoint inhibitors have typically produced modest to no responses and further treatment options are needed. Pixatimod creates an immunostimulatory effect in which natural killer cells are activated to eradicate cancer cells. It was expected to stimulate DCs and enhance the process by which tumor antigens present to T cells.

In preclinical studies, TLR9 agonists were found to increase the efficacy of anti-PD-1 therapies, supporting its study in humans.² The report of the phase 1b trial results published in the Journal for Immunotherapy of Cancer focused on 2 expansion cohorts of the trial: MSS mCRC and mPDAC. The primary goal was to determine the maximum tolerated dose, with secondary end points of safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics.

The study enrolled 58 patients across Australia. The participants had a life expectancy of at least 12 weeks, adequate organ function, and an ECOG performance status of 0 or 1. In the mPDAC cohort, patients were required to have received no more than 1 prior chemotherapy regimen in the metastatic setting. In the MSS mCRC cohort, patients had progressed after prior treatments, had no standard therapies available to them, or had chosen not to receive available treatments.

Patients were a median age of 60 (range, 35-80), and just over half were women (53.4%) and had an ECOG performance status of 0 (53.4%). Prior therapies consisted of chemotherapy in 98.3% of patients, radiotherapy in 25.9%, and targeted therapy in 12.1%. In the MSS mCRC group, 36.4% of patients had wild-type BRAF status, 42.4% had a KRAS mutation, 9.1% had a NRAS mutation, and 60.6% had the rectum as the primary tumor location.

Participants received 25 mg or 50 mg of intravenous weekly pixatimod, which was diluted in 250 mL of 0.9% saline solution prior to administration, plus 240 mg nivolumab every 2 weeks in 28-day cycles. Ultimately, 25 mg was chosen as the recommended phase 2 dose because 2 dose-limiting toxicities were reported with 50 mg of pixatimod. Prior to administration, patients also received paracetamol in an attempt to avoid infusion-related adverse events (AEs).

Of 47 evaluable patients, including 18 in the mPDAC cohort and 25 in the MSS mCRC cohort, no responses were seen in the mPDAC or other cancers groups. Only 2 patients with mPDAC achieved stable disease for 15 weeks. In the MSS mCRC group, 3 patients achieved a partial response and 8 had stable disease, for an objective response rate of 12% and a disease control rate of 44%. The longest duration of response was 48 weeks. Notably, 1 patient who achieved a partial response had a history of liver metastases.

Treatment-emergent AEs (TEAEs) were reported in all participants, with a total of 593 recorded events, including 67 severe TEAES, 3 life-threatening events, and 13 TEAEs that led to death. A total of 79.3% of AEs were considered potentially related to pixatimod in the 25-mg cohort, with the most common events being nausea (25.5%), fatigue (21.8%), diarrhea (18.2%), decreased appetite (14.5%), and pyrexia (12.7%). The most frequent AE of grade 3 or higher was hypertension. Seven patients discontinued because of treatment-related AEs.

PIV was calculated from blood samples collected at screening to determine an inflammatory score. Among patients with mCRC who had a partial response to or stable disease from the combination treatment, PIV scores were significantly lower than among those who did not benefit from treatment (P = .029).

In the patients with mCRC who achieved response, cytokine IP-10 levels increased. The ratio of IP-10 to IL-8 was higher in these patients, whereas those who did not benefit showed higher plasma IL-6 levels. Increases were also seen among the mCRC group in CD4-positive and CD8-positive effector memory T cells and proliferating CD4-positive and CD8-positive T cells. These changes were not reflected in patients with mPDAC.

“It was interesting to discover that unlike MSS mCRC, where increases in cytokines/ chemokines and T-cell markers indicated immune activation, [patients] with mPDAC did not exhibit an initial immune response to treatment, suggesting a fundamental difference in the status of the immune system between the 2 cancer types when considering how to initiate an antitumor immune response,ܺ" Dredge said. The investigators determined that activity in the MSS mCRC cohort warranted further investigation, but not for the mPDAC cohort.

Going forward, pixatimod will be investigated further as a monotherapy in patients with MSS mCRC without the use of paracetamol, as Dredge noted that it may have blunted the effect of the immune checţpoint inhibitor.³ Additionally, pixatimod with nivolumab is being explored in patients with PD-1 relapsed or refractory melanoma, non–small cell lung cancer, and MSS mCRC with added low-dose cyclophosphamide in a phase 2 trial (NCT05061017).

REFERENCES

1. Lemech C, Dredge K, Bampton D, et al. Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors. J Immunother Cancer. 2023;11(1):e006136. doi:10.1136/jitc2022-006136

2. Hammond E, Haynes NM, Cullinane C, et al. Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. J Immunother Cancer. 2018;6(1):54. doi:10.1186/ s40425-018-0363-5

3. Bessede A, Marabelle A, Guégan JP, et al. Impact of acetaminophen on the efficacy of immunotherapy in cancer patients. Ann Oncol. 2022;33(9):909-915. doi:10.1016/j. annonc.2022.05.010