ALKS 4230-Keytruda Combo Found to Reduce Tumor Size, Halt Disease Progression

ALKS 4230-Keytruda Combo Found to Reduce Tumor Size, Halt Disease Progression

The combination of Keytruda (pembrolizumab) and ALKS 4230 was able to halt disease progression and reduce tumor size in a small group of heavily pre-treated patients with advanced ovarian cancer, according to data from an ongoing Phase 1/2 trial.

Findings from the trial, called ARTISTRY-1 (NCT02799095), also showed the combination therapy had a manageable safety and tolerability profile.

Given these results, Alkermes, the developer of ALKS 4230, is now planning to launch a prospective study to evaluate the safety and effectiveness of this combination therapy in women with platinum-resistant ovarian cancer who also have been previously treated with bevacizumab.

“Based on the durable complete and partial responses observed in the ARTISTRY-1 intravenous dosing study in tumor types with high unmet need and limited treatment options for patients, we are considering potential regulatory strategies that may support expeditious development paths in both monotherapy and combination settings,” Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, said in a press release.

A poster detailing the study’s findings, titled “Clinical outcomes of ovarian cancer patients treated with ALKS 4230, a novel engineered cytokine, in combination with pembrolizumab: ARTISTRY-1 trial,” was presented at the Society for Immunotherapy of Cancer’s (SITC) 35th Anniversary Annual Meeting, recently held online.

ALKS 4230 is an investigational fusion protein made up of a modified version of interleukin-2 (IL-2), a molecule that’s important for T-cell function, and the high-affinity IL-2 alpha receptor chain.  It’s designed to promote the expansion and activation of cancer-killing immune cells, while preventing the activation of immunosuppressive cells.

The therapy’s safety, tolerability, and efficacy, alone or in combination with Keytruda, are being investigated in two Phase 1/2 trials — ARTISTRY-1 and ARTISTRY-2 (NCT03861793) — enrolling patients with different types of advanced solid tumors.

In ARTISTRY-1, the participants are receiving daily intravenous (into-the-vein) infusions of ALKS 4230 for five consecutive days, either alone or in combination with Keytruda. Keytruda, developed by Merck , also is given intravenously, on the first day of a 21-day cycle.

Conversely, in ARTISTRY-2, ALKS 4230 is being administered alone via a subcutaneous (under-the-skin) injection once weekly, or once every three weeks, for a period of six weeks. That treatment is followed by a combination with Keytruda.

During the meeting, the company presented data from a detailed analysis of a subset of women with advanced ovarian cancer who received ALKS 4230 in combination with Keytruda in ARTISTRY-1.

A total of 14 heavily pre-treated women were enrolled in the study, which is still recruiting participants across the U.S. and Europe. All of the women had previously been treated with platinum-based chemotherapy, and received a median of five prior lines of therapy.

All but one woman (13 patients in total) had completed at least one assessment and were included in the analyses. Data showed that, after a median treatment period of seven weeks, nine women saw their disease controlled and four had it worsen.

Three women were found to respond to the combination therapy to some extent: one achieved a complete response, another a partial response, and the third an unconfirmed partial response. All three women had platinum-resistant ovarian cancer and did not carry any mutations in the BRCA DNA repair genes. Of note, a complete response refers to complete cancer eradication, while a partial response refers to partial cancer elimination.

Two other women also saw their disease stabilize after treatment. Thus, a total of five of these patients experienced some type of clinical benefit from the ALKS 4230-Keytruda combo. At the time of the analyses, all five women had remained on treatment for five to 21 months.

Safety analyses also indicated that the combination therapy had a manageable safety profile, with most treatment side effects being only mild or moderate in severity. The most commonly observed side effects among these patients were chills, fever, and nausea. Importantly, the addition of ALKS 4230 did not seem to increase Keytruda’s previously established toxicity profile.

“The combination of ALKS 4230, an investigational agent, and pembrolizumab demonstrates an acceptable safety profile and provides some evidence of tumor shrinkage and disease stabilization in some patients with heavily pretreated [ovarian cancer]. This regimen could represent a new therapeutic option for these patients,” the researchers wrote.

Additional safety and efficacy analyses are still underway in other groups of patients participating in ARTISTRY-1.

Promising anti-tumor activity also has been observed in women with other cancers, including cervical and triple negative breast cancer, who received the ALKS 4230-Keytruda combo therapy.

A biopsy analysis was conducted in a patient with melanoma, the most serious type of skin cancer, who received ALKS 4230 alone in the dose-escalation portion of the study. It showed that the treatment increased markers of white blood cells’ infiltration, as well as the numbers of cancer killing immune T-cells, and PD-L1 tumor levels.

These observations supported ALKS 4230’s immunostimulatory effect, and backed up the rationale of combining this experimental therapy with Keytruda, an immune checkpoint inhibitor that tends to be more effective in patients whose tumors produce high levels of the PD-L1 protein.

During the meeting, Alkermes also presented data from seven dose-escalation groups of ARTISTRY-2, in a second poster titled, “Phase 1/2 study of subcutaneously administered ALKS 4230, a novel engineered cytokine, as monotherapy and in combination with pembrolizumab, in patients with advanced solid tumors: ARTISTRY-2”.

Data from this study showed that, in patients with different types of solid tumors that failed to respond to previous therapies, ALKS 4230 led to a dose-dependent increase in the numbers of cancer-killing immune cells.

Moreover, the safety and tolerability profile of subcutaneous or under-the-skin ALKS 4230 was found to be consistent with that of its intravenous or into-the-vein formulation. The maximum tolerated dose of the therapy’s subcutaneous formulation has not yet been determined.

“Accumulating evidence across the ARTISTRY clinical program provides insight into ALKS 4230’s potential as a novel treatment option, both as monotherapy in melanoma and in combination with pembrolizumab, for a number of tumor types that do not typically respond to current standards of care,” said Ira Winer, MD, PhD, associate professor at the division of gynecologic oncology at Wayne State University and the Karmanos Cancer Institute.

“The responses observed with the combination regimen in platinum-resistant ovarian cancer, triple negative breast cancer, and recently in cervical cancer, are encouraging signs of ALKS 4230’s potential utility in these cancers,” Winer said.

“In addition, the data presented at SITC from ARTISTRY-2 in patients with advanced solid tumors showed a safety profile and immune response comparable to ALKS 4230 administered intravenously, indicating that ALKS 4230 may offer an alternate subcutaneous dosing option for patients,” Winer added.

ARTISTRY-3 (NCT04592653), a third ARTISTRY trial, is now ongoing to assess the effects of ALKS 4230 in patients with different types of advanced, malignant solid cancers. That study, conducted in addition to ARTISTRY-1 and ARTISTRY-2, is a Phase 2 trial evaluating ALKS 4230 when given intravenously as a stand-alone therapy.