ALKS 4230 Under Exploration for Advanced Malignant Solid Tumors in ARTISTRY-3 Trial

Craig Hopkinson, MD

Investigators are evaluating the clinical and immunological impact of the experimental, engineered fusion protein ALKS 4230 on the tumor microenvironment of several advanced, malignant solid tumors in the recently initiated phase 2 ARTISTRY-3 trial.¹

“Data from the ARTISTRY-3 clinical trial will provide a deeper understanding of the effects of ALKS 4230 on immunologic activity in the tumor microenvironment across a variety of tumor types,” Craig Hopkinson, MD, chief medical officer and executive vice president of Research & Development at Alkermes plc, stated in a press release. “Findings from this trial may help us answer important mechanistic questions and identify the tumor types for which ALKS 4230 could offer the most clinical benefit, thereby helping to inform a potential registration strategy.”

ALKS 4230 is a novel, engineered fusion protein composed of altered interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, developed to selectively multiply tumor-killing immune cells while evading the activation of immunosuppressive cells. The agent does this by preferentially adhering to the intermediate-affinity IL-2 receptor complex. Because of the agent’s selectivity, it is capable of enhancing the antitumor effects of existing IL-2 therapy while mitigating certain limitations with those approaches.

In the single-center, open-label, phase 2 trial, investigators will examine the safety, tolerability, and pharmacokinetic profile of ALKS 4230 at an intravenous (IV) dose of 6µg/kg as lead-in monotherapy followed by ALKS 4230 in combination with pembrolizumab (Keytruda) in patients with advanced malignant solid tumors. They will also evaluate any treatment-emergent changes in the tumor microenvironment and peripheral blood immunophenotypes with the agent in this population.

Prior to treatment and following the monotherapy and combination phases of the trial, investigators will collect paired tumor biopsies to examine the impact of ALKS 4230 on the immune cells, including changes in the density and ratio of these cells, within the tumor microenvironment. Secondary end points of the trial will examine the antitumor activity of ALKS 4230, specifically with regard to overall response rate and duration of response.

This trial is the fourth to evaluate the investigational agent, according to Alkermes plc, the drug developer. In the phase 1/2 ARTISTRY-1 trial (NCT02799095), investigators are evaluating the effects of intravenous ALKS 4230 on patients with solid tumors to better understand its safety and tolerability, the recommended phase 2 dose of the agent, and its antitumor activity as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. In the phase 1/2 ARTISTRY-2 trial (NCT03861793), investigators are examining the subcutaneous administration of the agent in this patient population.

“Early clinical data from our ARTISTRY program showed that ALK 4230 selectively expanded cancer-fighting immune cells in the periphery, with negligible effects on regulatory T cells,” added Hopkinson.

Preliminary data from the monotherapy dose-escalation phase of the ARTISTRY-1 trial were presented during the 34th Annual Society for Immunotherapy of Cancer Annual Meeting.² These data were from 5 cohorts and doses ranged from 0.1 µg/kig daily to 6 µg/kg daily.

At the time of the presentation, 36 patients with refractory advanced solid tumors received treatment with the agent and it was found to selectively expand natural killer and CD8-positive T cells with no impact on regulatory T cells. The 6 µg/kg daily dose of the agent was determined to be the recommended phase 2 dose for intravenous administration.

At doses of 3 µg/kg and 6 µg/kg, 8 of 14 patients achieved stable disease. One patient who received the higher dose was heavily pretreated and had pancreatic adenocarcinoma. They received the monotherapy for the duration of 10 months, achieved stable disease, and maintained that stability for approximately 6 months. After disease progression, the patient was put onto combination therapy with pembrolizumab for the duration of 4.5 months.

With regard to safety, the most commonly experienced toxicities included fever and chills, which were anticipated. No grade 4 or 5 treatment-related adverse effects (TRAEs) were observed with the agent. The maximum-tolerated dose of ALKS 4230 has not been identified.

In the combination phase of the trial, patients received ALKS 4230 at a daily dose of 3 µg/kg in combination with pembrolizumab. A total of 26 patients received treatment with the combination and 12 of 18 who had evaluable scans were found to have achieved stable disease or better with the treatment.

Notably, 1 patient with ovarian cancer achieved a confirmed partial response at cycle 6 and showed complete normalization of CA-125 levels at cycle 4, which continued to be in the normal range. Another patient with triple-negative breast cancer experienced over a 50% reduction in target lesion size at cycle 8. Small new lesions developed at cycle 2, which is common with checkpoint inhibition. This patient experienced an immune-partial response per iRECIST criteria.

In this phase of the trial, the most frequently reported toxicities again included fever and chills, with no higher-grade, or grade 4 or 5, TRAEs experienced.

Initial data from ARTISTRY-2 were also reported at the meeting. The initial dose-escalation cohort for this trial was comprised of 7 patients and they received 0.3 mg of subcutaneous ALKS 4230. Early signs of tolerability were reported with no patients discontinuing treatment due to toxicities.

The agent is also under examination in the phase 2 ION-01 trial, which is evaluating the response rate of the agent in combination with pembrolizumab in patients with advanced or recurrent head and neck squamous cell cancer who were unable to achieve complete remission when treated with an anti–PD-(L)1 therapy.

References

1. Alkermes initiates phase 2 study designed to evaluate clinical and immunologic activity of ALKS 4230 on tumor microenvironment in patients with advanced solid tumors. News release. Alkermes plc. August 19, 2020. Accessed September 14, 2020. https://prn.to/2FsKwmQ.
2. Alkermes announces new data from ALKS 4230 Clinical Development Program at Society for Immunotherapy of Cancer’s (SITC) 34th Annual Meeting. News release. Alkermes plc.November 8, 2019. Accessed September 14, 2020. https://bit.ly/3kg7qN9.