Novel IL-2 Molecule Shows Early Promise in Phase 1/2 Studies for Solid Tumors

Ira Winer, MD, PhD

The ARTISTRY clinical trial program is currently exploring the potential use of ALKS 4230 to treat patients with gynecologic cancers and other solid tumors. The agent is a convenient potential new agent as the interleukin (IL)-2 molecule is being tested both as an intravenous and subcutaneous injection.

In the phase 1/2 ARTISTRY-1 clinical trial (NCT02799095), investigators aimed to gain a better understanding of the safety and tolerability of intravenous ALKS 4230 either as monotherapy or in combination with the immune checkpoint inhibitor pembrolizumab (Keytruda).

The ongoing study aimed to assess the characterization of adverse events (AEs) and maximum tolerated IV dose in part A which is the monotherapy dose escalation phase of the study, safety and efficacy of ALKS 4230 monotherapy in part B which is the monotherapy dose expansion phase and the safety and efficacy of ALKS 4230 in combination with pembrolizumab in part C of the study. Secondary end points include disease control rate, duration of response, serum concentrations, and immunophenotyping of peripheral blood mononuclear cells. In part A, patients had to have a solid tumor to be enrolled, while they were required to have a diagnosis of either melanoma or renal cell carcinoma for part B.

In addition, the ongoing phase 1/2 ARTISTRY-2 study (NCT03861793) is exploring the safety and tolerability of subcutaneous ALKS 4230. The dose escalation phase of this study was designed to determine the recommended phase 2 dose of the subcutaneous regimen. The primary end points in this study include the incidence of AEs and the clinical activity of SC ALKS 4230 as a monotherapy and in combination with pembrolizumab. This study will also evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of SC ALKS 4230.

In an interview with Targeted Oncology, Ira Winer, MD, PhD, physician, Karmanos Cancer Institute, discussed the findings from the ARTISTRY-1 and ARTISTRY-2 studies which were presented at SITC in November 2020, focusing on the safety and efficacy of ALKS 4230 as treatment of patients with gynecologic cancers as well as other solid tumors.

TARGETED ONCOLOGY: How does ALKS 4230 differentiate itself from other novel agents on the market?

Winer: ALKS 4230 is basically a molecule that is a combination of both IL-2 as well as a portion of the receptor, and what it does is it is able to circumvent some of the side effects of high dose interleukins and cytokines and at the same time also activate the immune environment, both the cells as well as a lot of the microenvironment around them. For example, it does not typically, at least for most of the lower doses, activate regulatory T cells, which we know is an important aspect of immune response in terms of therapies, especially with checkpoint inhibitors. It also does activate CD8-positive T cells at a high level in addition to NK cells, which is a mixed bag, but the NK/CD8 ratio to T regulatory (Treg) cells is very important in terms of IL-2, generally, which is very active historically.

It has side effects, and again, some of the similar important side effects for high dose IL-2 are the more immediate side effects with things like cytokine release syndrome, which this drug does not have. It's very important, and by model therapy, it is active in something such as melanoma, but [with] the combination therapy, it especially [is active] in the gynecologic setting and also in other settings. We've seen activity that improves both the number of responses in terms of objective responses but also the clinical benefit for patients and the durability of responses, which is impressive.

TARGETED ONCOLOGY: How do the updated data from ARTISTRY-1 contribute to our understanding of the agent in ovarian cancer both as monotherapy and in combination with pembrolizumab?

Winer: It's not an approved agent for monotherapy because, in ovarian cancer, at least to date, while there are some data emerging over time, and there probably is a subset of patients with ovarian cancer that will respond to single-agent [therapeutics], most of these patients will not respond to single agents for immunotherapies, except maybe in the setting where you have a dual antibody. Although this isn't a single agent; it's a double agent in 1, so mostly for these [responding] patients, these were all in the dual arm. They all had ALKS 4230 plus the pembrolizumab.

If you look at monotherapy, with checkpoint inhibitors with ovarian cancer, you're looking at about 10% to 14% response rates. In some subsets of patients, you might have a higher response rate but very rarely, and the durability of the responses is just not there. When we see 5, 6, or 7 patients that are responding, objective responses are seen in 5 patients, and then when you see stability of disease in multiple other patients in a very small subset of patients because we're only looking at 15 to 16 patients, that's pretty impressive. When we see a durability of response—for example, 1 of my patients has a complete response, now almost 2 years out from when we initiated the trial with a heavily pretreated patient talking about 5 to 7 prior [agents]—so not saying it's a homerun, but it's something that is very impressive.

TARGETED ONCOLOGY: Could you elaborate more on the safety profile of this regimen?

Winer: When we're looking at any treatment, whether it's a clinical trial or conventional agents, especially for ovarian, but even for any patient that has resistant disease, we always want to balance the quantity and quality. Especially in ovarian cancer with platinum-resistant and platinum-refractory disease, we definitively want to balance even more so the quality. It's an intensive regimen, especially in our industry, but even with that intensive regimen, they're out there doing things that they weren't able to do previously, and so that quality is definitely there. And we're also seeing the durability and the quantity. That's something that we're looking for, for our patients.

TARGETED ONCOLOGY: Looking at ARTISTRY-2, how would you quantify the activity that we're seeing across solid tumors?

Winer: The activity is less of an issue because it's very early in that program, so they were looking more at PK and PD type things. It seems that the PKs are similar, though they're still escalating, and it also seems that the side effects are also similar to the ARTISTRY-1 program. In terms of the option that it might give our patients, which again we don't have the data yet, if you can do a subcutaneous injection once a week versus having to do an infusion 5 days a week and have similar efficacy, then obviously that's a win for the patients.

TARGETED ONCOLOGY: Could you elaborate any more on the data that have been done to compare the intravenous and subcutaneous administration treatments?

Winer: It seems that the PK and the PD are very similar in that they don't have a lot yet in terms of on-treatment biopsies, which for example, in the phase 2 trial with ovarian, the plan is to do that and have more on-treatment biopsies to confirm what they're seeing in a small number of patients. However, it does appear that with all these agents, we're seeing an increase of PD-L1 at the tumor level with ALKS 4230 even in monotherapy, an increase of CD8-positive cells and NK cells, and a similar decrease level of T regs, which is again that good combination that you really want to see. That's kind of where we are right now, but more data have to be obtained. They're still in the setting of dose-escalation with the subcutaneous version of it.

The one thing that is good now is I think they will start getting more data because previously, with the subcutaneous regimen, a lot of the patients had to have a month, 28 days, of the subcutaneous prior to adding the pembrolizumab, which is obviously, for some of our patients, a difficult thing to do; they need that information before to make sure that it was safe and that it was efficacious in terms of the PK and PD.

TARGETED ONCOLOGY: What are your final thoughts on these studies?

Winer: The interesting thing about this program in general is that it does seem to be not just 1 single tumor type. We've now seen success in cervix; there's at least 1 patient with triple-negative breast cancer, pancreatic cancer, melanoma—and melanoma is actually with a single agent, not even requiring a doublet—and so I think that there is a potential for significant improvement. In the gynecologic space again, we have patients that respond to immunotherapy, but we want to see that 15% get to the 30%, 50%, or 60% and have durable responses. That's why it was very exciting.

Interviewed conducted on November 13, 2020.