ONCOS-102, Keytruda Combo May Reduce Tumor Size in Treatment-resistant Melanoma, Early Trial Data Show

Melanoma patients who become resistant to immune checkpoint inhibitors may regain susceptibility to such treatments after receiving Targovax‘s immune activator ONCOS-102, early clinical trial findings suggest.

The trial is testing a combination of ONCOS-102 and the immune checkpoint inhibitor Keytruda (pembrolizumab) in advanced or surgery-ineligible melanoma patients whose tumor continued to progress despite treatment with an anti PD-1 antibody, such as Keytruda or Opdivo (nivolumab).

Early results showed that the combination reduced tumor size in three of the nine patients enrolled, including one patient whose disease completely disappeared.

“We are very pleased to confirm our hypothesis that ONCOS-102 has the potential to immune activate checkpoint-inhibitor-resistant patients to respond to PD-1 blockade with Keytruda,” Magnus Jäderberg, chief medical officer of Targovax, said in a press release.

“It is promising to see this level of clinical responses after only three ONCOS-102 injections, including a complete response, which is rare in this heavily pre-treated patient population,” he said.

ONCOS-102 is an experimental cancer therapy that consists of a harmless virus armed with an immune activator molecule. It is engineered to kill tumor cells by triggering an anti-tumor response in the body.

The therapy strengthens immune response against tumors that are already responding to immunotherapies, but also bolsters responses against tumors the immune system is less likely to recognize, such as the case in advanced melanoma patients whose disease progressed after a first treatment.

In animal studies, a combination of ONCOS-102 and Keytruda also induced an abscopal effect, meaning that tumors not injected with ONCOS-102 also shrank by an average of 70%.

Keytruda is an antibody that targets and blocks the activity of the PD-1 receptor (a protein found on the surface of immune cells), preventing cancer cells from avoiding being targeted and killed by immune cells.

The Phase 1 trial (NCT03003676) — ongoing at the Memorial Sloan Kettering Cancer Center in New York, Fox Chase Cancer Center in Philadelphia, and University of Maryland in Baltimore — is evaluating a sequential treatment with ONCOS-102 and Keytruda in patients with advanced melanoma whose disease progressed despite prior PD-1 treatment.

In part 1, patients received three injections of ONCOS-102 directly into the tumor, all given during the first week. Then, starting on day 22, Keytruda was given every three weeks. Patients were followed until week 24.

The main goal of this phase is to determine the safety of the sequential treatment. Additional (secondary) aims include progression-free survival, objective response rate, and change in the size of individual lesions. Researchers will also evaluate changes in blood and tumor immune parameters.

The newly reported results have shown that the sequential treatment was well-tolerated and led to encouraging signs of efficacy, with an overall response rate of 33%. One patient achieved a complete response, and two patients had partial responses.

Moreover, ONCOS-102 triggered pro-inflammatory cytokines, or signalling molecules, against tumors in all nine patients, and led to an increase in tumor-infiltrating T-cells in eight patients. As was the case in mice, immune infiltration was also detected in tumors that had not been injected with ONCOS-102.

Immune cells armed against tumor proteins were also detected in circulation in four patients, which supports ONCOS-102’s ability to activate a systemic immune response against tumors.

Part 2 is now recruiting participants to assess the safety and efficacy of a more intensive treatment. Patients will receive four injections of ONCOS-102, followed by a combination of ONCOS-102 and Keytruda.

“Based on our experience so far, we speculate that patients will benefit from receiving more ONCOS-102 injections over a longer period of time and we will follow with interest the effect of the intensified dosing regimen in the second patient cohort of the trial,” said Jäderberg.

Added Alexander Shoushtari, principal investigator of the trial running in New York: “It is encouraging to see clinical responses in this hard-to-treat population of advanced melanoma. Earlier this year, we decided to expand the trial to test a more intensified schedule of ONCOS-102, and it will be interesting to see whether this regimen can generate more and deeper clinical responses.”