Novel Targeted Cytotoxic Shows Preliminary Safety and Efficacy in Advanced Solid Tumors

Jacob S. Thomas, MD

The novel targeted cytotoxic agent INT230-6 alone or in combination with pembrolizumab (Keytruda) demonstrated prolonged tumor burden reductions and safety that compares favorably with traditional cytotoxic chemotherapy in patients with pretreated advanced solid tumors, according to findings from the phase 1/2 KEYNOTE A10 study, explained lead study author Jacob S. Thomas, MD.

Patients with solid tumors that progressed on standard treatment were eligible for enrollment on the trial. The dose of INT230-6 was determined by tumor volume and injected every 2 weeks for 5 cycles. Upon demonstrated safety, treatment was intensified by increasing the number of tumors that were injected, loading per tumor, and total dose. In another arm, patients received 200 mg of pembrolizumab intravenously every 3 weeks plus INT230-6.

INT230-6 consists of cisplatin, vinblastine, and an amphiphilic penetration enhancer that facilitates improved intratumoral permeability.

A total of 52 patients spanning several cancer types were enrolled in the monotherapy arm, and 7 patients were enrolled in the combination arm. Patients had received a median of 3 prior treatments.

The results, which were presented during the 2020 ASCO Virtual Scientific Program, demonstrated that several injected and non-injected tumors had more than a 30% decrease in diameter. Further assessments revealed significant reductions in tumor volume of greater than 50%. Moreover, patients with stable disease experienced a median increase of 50% in circulating CD4 and CD8 T cells.

Dose-dependent responses demonstrated that patients who received INT230-6 monotherapy in more than 50% of their tumors at a dose/tumor volume ratio of more than 1:4 were more likely to achieve stable disease. A total of 13 patients experienced stable disease that lasted for more than 6 months, correlating with reduced tumor viability on immunohistochemistry and an increase in tumor-infiltrating lymphocytes.

Regarding safety, no dose-limiting toxicity was reported across doses ranging from 0.3 mL up to 160 mL. However, 2 patients experienced drug-related tumor pain that was classified as a serious adverse effect (AE). The most frequently reported treatment-related AEs included pain at the injection site (50%), fatigue (35.2%), and nausea (33.3%). Most AEs were grade 1/ 2, 14.9% were grade 3, and none were grade 4 or higher.

“We’ve demonstrated that the injection of INT230-6 leads to increased immune cell infiltration into tumors. This is very important in order to potentially turn the ‘cold tumors’ into ‘hot tumors,’ which can then improve the efficacy of checkpoint inhibitors and other immuno-oncology agents,” said Thomas. “If we’re able to further demonstrate this in other solid tumors, this could have potential implications for many different tumor types.”

In an interview with OncLive, Thomas, hematologist/oncologist at the University of Southern California Medical Group, discussed the pharmacodynamic profile of INT230-6 as well as preliminary safety and efficacy data with the agent in advanced solid tumors.

OncLive: Could you provide some background on the KEYNOTE A10 study?

Thomas: INT230-6 is a novel agent that is composed of cisplatin and vinblastine, which are well-known cytotoxic chemotherapies. These agents are included in a novel formulation made specifically for tumor delivery. The formulation improves the permeability of the drugs, specifically for image-guided intratumoral injections. This study is reporting the preliminary efficacy of INT230-6 alone and in combination with the checkpoint inhibitor pembrolizumab.

What is the mechanism of action of INT230-6?

The mechanism of action of the agent is direct cell cytotoxicity. Preclinically, as well as in the clinical studies that have been done to date, [the agent has] demonstrated an ability to recruit the immune system cells into the tumor, which can then lead to abscopal responses or improvements in the immune system response against the cancer. That’s the rationale for combining this agent with a checkpoint inhibitor like pembrolizumab.

What is the design of the trial?

This is a typical phase 1/2 trial that allows for patients with all types of solid tumors to participate. Initially, we injected only superficial lesions for safety. Once we demonstrated that it was safe to inject into superficial lesions, we started injecting patients with deeper tumors using CT or ultrasound guidance. The study proceeded and demonstrated safety during dose escalation.

With higher and higher doses, we haven’t seen any grade 4/5 AEs. The grade 3 AEs we have seen thus far have typically been temporary and well managed. The most common grade 3 AE is injection site pain, but that has been transient and manageable with pain medication. Another common AE is low-grade nausea, which again, is very transient. Overall, the drug is very safe and well tolerated.

Could you discuss the preliminary efficacy of the agent?

[We have demonstrated] evidence of preliminary efficacy with INT230-6 as a single agent and in combination with pembrolizumab. We have seen prolonged responses in several different tumor types, well over 1 year in a few cases. These are patients who received 5 injections while on the study and then achieved prolonged stable disease after that, so we’ve seen some definite evidence of activity.

What are the next steps for this research?

In this analysis, we showed [data on] the first few patients treated with the combination. We’re going to continue to accrue to this cohort [to further explore] the combination. We also have plans to open up a cohort [that will examine] a CTLA-4 antibody in combination with INT230-6. Our future plans are primarily to continue to accrue to these expansion cohorts.

Reference

Thomas JS, El-Khoueiry AB, Walters IB, et al. Pharmacodynamic, safety, and efficacy results of a phase I/II trial of intratumoral INT230-6 alone (IT-01) or in combination with pembrolizumab (PEM) (Keynote A10) in patients with advanced solid tumors. J Clin Oncol. 2020;38(suppl 15):3016. doi:10.1200/JCO.2020.38.15_suppl.3016