NK T-Cell Agonist Under Investigation in Combination With Pembrolizumab in Melanoma and NSCLC

The natural killer (NK) T-cell agonist IMM60 may overcome resistance to PD-1 inhibitors when combined with immunotherapy in patients with melanoma and non–small cell lung cancer (NSCLC), according to Nicholas Coupe, MBBS, PhD, who emphasized the tolerable safety profile seen so far with this combination.

The phase 1/2 IMPORT-201 trial (NCT05709821) is investigating IMM60 as monotherapy in patients with melanoma who have progressed on immunotherapy and patients with NSCLC who have progressed on immunotherapy and platinum-based chemotherapy. The study is also evaluating IMM60 plus pembrolizumab (Keytruda) in patients with melanoma and patients with previously untreated, PD-L1–high NSCLC. So far, 12 patients have received a total of 52 infusions of IMM60 at doses up to 9 mg/m². The investigators have observed no dose-limiting toxicities or IMM60-related serious adverse effects (AEs). Additionally, 1 patient who received IMM60 plus pembrolizumab experienced only low-grade AEs consistent with those expected with pembrolizumab.¹

“Preclinical work [with IMM60] indicates that we may be able to enhance the effect of immunotherapy and, more importantly, potentially overcome some areas of immunotherapy resistance,” Coupe said in an interview with OncLive^®.

In the interview, Coupe, a consultant medical oncologist at Oxford University Hospitals NHS Foundation Trust in England, discussed the potential for IMM60 to overcome resistance to immunotherapy in patients with melanoma and NSCLC; the safety profile of this agent in combination with pembrolizumab; and the importance of enrolling patients in the IMPORT-201 trial.

OncLive: What is the mechanism of action of IMM60?

Coupe: IMM60 is an invariant NK T-cell agonist. It’s a unique therapy. Invariant NK T cells are cells that have a broad range of activity across the immune system, affecting both the adaptive and the innate arms of the immune system. Once activated, invariant NK T cells can have direct effects upon tumors.

Preclinical work shows that PD-L1 expression in tumor cells can be directly upregulated by these cells. They can also engage favorably with antigen-presenting cells, such as dendritic cells, which can potentially enhance their immunogenic effect against tumor cells. These cells can also increase the ability of cytotoxic T cells to be recruited to attack tumor cells. They can also engage with B cells, potentially affecting the way antibodies engage with tumors. There is also some evidence that invariant NK T cells play a key role in optimizing the tumor microenvironment, making it a favorable environment for the destruction of tumor cells. There has been some research in this area in the past, and a preceding compound has [had] some activity in this setting, but the pharmacokinetic and pharmacodynamic profiles of IMM60 supersede that, and hopefully, we’ll show some promising clinical activity in time.

What has been seen with IMM60 in preclinical studies?

The main findings we’ve seen preclinically are that IMM60 can have a direct effect upon tumor cells. Preclinical work shows activity directly against melanoma xenografts in mouse models. Evidence also shows that, when given in combination with existing immunotherapies, such as PD-1 inhibitors, there is synergy. There is an additive effect, [as well as] an enhanced effect, when we give the 2 drugs together. Particularly exciting and relevant to our work is that there is some evidence showing that we could [use IMM60 to] reverse PD-1 resistance and theoretically resensitize tumors that have become resistant to conventional immunotherapies.

What was the rationale for the IMPORT-201 trial?

We hope [IMM60] will complement existing immunotherapies that have had such a positive effect upon multiple tumor types. Although [some patients have experienced] considerable gains from immunotherapy, many patients unfortunately do not benefit from these [agents], particularly [those with] lung cancer. Hopefully, we can bridge this gap.

What patient populations did this trial observe?

[Two patient populations are being] targeted in this study. We’re targeting patients with metastatic melanoma and [patients with] metastatic NSCLC. These 2 populations are being targeted because we already know [these patients] are potentially sensitive to immunotherapy.

In the safety arm of this study, we’ve tested IMM60 as a single agent in pretreated patients. These patients have already had immunotherapy and, in some cases, chemotherapy. We will treat a separate population of untreated patients with IMM60 in combination with immunotherapy. This is the initial phase where [we are collecting] more information about the safety of IMM60 alone and in combination with pembrolizumab. Once we’ve completed that, we have plans to roll over to a phase 2 study, where we’ll compare the combination of IMM60 and pembrolizumab vs pembrolizumab alone.

What findings from this study were presented at the 2023 ASCO Annual Meeting?

We’ve only treated a small number of patients so far, which is expected given that this is a first-in-human, early-phase study. From a safety point of view, IMM60 at varying dose levels has been shown to be safe. Only a small number of grade 1/2 toxicities have been [observed] in the patients so far. We’re not seeing a significant increase in toxicity as we increase our dose levels. For this reason, we are [considering] expanding into additional dose levels. The first point is, [IMM60 is] relatively safe.

The pharmacokinetics we presented demonstrate that the drug is reaching appropriate concentrations in the blood. That’s something we can work on with future dose levels.

From an efficacy point of view, we need to be a bit careful when we comment on efficacy from a phase 1 study. However, we have seen evidence of tumor reduction. Notably, in the [patients who received] IMM60 alone, we have seen tumor reduction in several sites. What’s particularly important is the patients who’ve had a tumor reduction have been heavily pretreated and would not have any standard options normally available to them. That’s potentially exciting.

We also presented the response data for a patient treated with the combination of IMM60 and pembrolizumab. This patient had a response after 3 months’ worth of treatment. It’s difficult to say whether that response was because of the pembrolizumab or the IMM60. Those answers may become clearer with time.

What are the next steps for this research?

The immediate priority is to complete the phase 1 study. We need to work out the optimal dose that we should take through to phase 2. Currently, the protocol was set up to only look at 3 dose levels but given that we’ve seen such a favorable safety profile, we are having discussions about trying some higher doses. We’ll need to see how that pans out. Once we’ve established that, we will complete a safety cohort seeing whether we can test that dose safely in combination with pembrolizumab.

Once the phase 1 study has finished, we will move into phase 2, where we will test IMM60 and pembrolizumab vs pembrolizumab alone in patients with lung cancer and melanoma. For both these tumor types, there will be a [treatment] option in patients who are treatment naïve, those who have never had pembrolizumab. We’re also testing the combination in patients who have been pretreated, particularly patients with melanoma who have previously had immunotherapy, in hopes that we may restore some sensitivity to immunotherapy where they’ve previously progressed. In NSCLC, we are looking to test the combination of IMM60 and pembrolizumab in patients who have a low expression of PD-L1. This is a group that is traditionally [not] expected to respond particularly well to immunotherapy. That’s where we’re headed.

Overcoming immunotherapy resistance is an area of unmet need. Treatment options for patients at this point are sadly often limited. We are keen for patients to participate in this study. If you have patients who are interested in participating in clinical trials, I encourage [you] to let us and the team know.

What is your main message for colleagues regarding this research?

The treatment we have appears to be well tolerated so far. There is some evidence of activity but it’s early days, so we will provide updates at future conferences. I ask my colleagues to keep this study in mind if they have patients who would consider participating in this study, because we are recruiting in the United Kingdom and potentially in the United States in the future.

Disclosures: Dr Coupe has no relationships to disclose.

Reference

Coupe N, Pinato DJJ, Fairchild JP, et al. IMPORT-201 (IMP-MEL): a phase 1 first-in-human dose finding/randomized phase 2 study of a novel iNKT agonist IMM60 and pembrolizumab for advanced melanoma and metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 16):2575. doi:10.1200/JCO.2023.41.16_suppl.2575