New Cytokine Approach is Synergistic With Checkpoint Inhibitors

Adi Diab, MD

Among the new agents currently being explored in clinical trials, NKTR-214, one of the agents highlighted during the “New Cancer Immunotherapy Agents in Development” session during the Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting & Associated Programs, stands out as a new cytokine therapy approach that could show additive benefit when combined with checkpoint inhibitors.

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During the session, Adi Diab, MD, presented interim results from the phase I/II first-inhuman study of NKTR-214 in patients with locally advanced or metastatic solid tumor malignancies (NCT02869295). The open-label, multicenter, dose escalation and expansion study showed that treatment with NKTR-214 has been well tolerated and is able to be administered on an outpatient basis.Of 18 evaluable patients, only 1 patient experienced a dose-limiting toxicity of grade 3 syncope and hypotension at 0.012 mg/kg.

Patients showed an increase in CD8+ T cells and natural killer cells in the tumor microenvironment. Six patients showed a 10-fold increase of CD8+ T cells and natural killer cells with minimal changes in the amount of regulatory T cells.

Across all doses given, no immune-related adverse events (AEs), treatment-related AEs leading to discontinuation from treatment, or deaths have been noted so far in the trial.

Following his presentation, Diab discussed withTargeted Oncologydetails of the current safety and efficacy data for NKTR-214, the potential to combine the agent with checkpoint inhibitors and other treatments, and what makes this agent stand apart from other cytokine therapies.

TARGETED ONCOLOGY:What is the mechanism of action and benefit of NKTR-214?

Diab:

NKTR-214 is a cytokine resembling interleukin, except that it has a pegylation so it can be given as a pro-drug every 2 to 3 weeks. Its major mechanism of action is to lead to proliferation and lower the threshold of activation of T cells. Also, it’s structured in a way to overcome some of the problems we see with interleukein-2 (IL-2). High-dose IL-2 is given to [patients with] melanoma and renal cell carcinoma. It’s delivered in the intensive care Unit [and requires] very intensive monitoring of the patient because of the high degree of toxicities we receive with these drugs.

NKTR-214 is structured to minimize the toxicity, so the pegylation site really minimizes the activation of the drug with the alpha-subunit of the IL-2 receptor. Activation with that subunit has a lot of correlation with some of the major toxicities we see with high-dose IL2. More importantly, the protract of NKTR-214 minimizes the activation of the alpha subunits, also known as CD25. It gives it bias to activate it through the other subunits of the IL-2 receptor, the beta and the gamma subunits. This bias activation allows for a preferential expansion of the effector CD8, CD4, and natural killer cells inside the tumor, without expansion of the deregulatory cells.

That gives an increased ratio of effector CD8 cells over deregulatory cells in the tumor, and that has a clinical impact. Traditionally it’s correlated with higher responses with the checkpoint inhibitors; but overall, tumors and cancers that have naturally higher ratios of CD8 cells to deregulatory cells have had better overall and disease-free survival [rates].

TARGETED ONCOLOGY:What differentiates NKTR-214 from other cytokine therapies and why is this approach effective?

Diab:

Cytokine therapies are usually administered on an inpatient basis, usually with Intensive Care Unit-like care, or very close monitoring. Also, usually you deliver more than 1 dose daily, or even 3 times daily. Here, you’re talking about a drug that can be given every 2 to 3 weeks, which is very convenient for patients.

We think that this drug will lead to synergy not only with the checkpoint inhibitors, but also with other immunotherapy strategies. I think NKTR-214 will have activity and synergy, based on preclinical data, with vaccines, with adoptive T-cell therapy, and possibly with tyrosine kinase inhibitors or small molecules.

TARGETED ONCOLOGY:What has the clinical trial of NKTR-214 demonstrated so far?

Diab:

We demonstrated that the drug has favorable safety and tolerability. It also has some encouraging clinical activity. [In] phase I you don’t really evaluate clinical activity, but we certainly saw encouraging clinical activity, including 1 patient with a partial response.

The trial is designed to obtain a longitudinal biopsy, which means you have a tumor biopsy early in the treatment and later in the treatment. You get to really evaluate the immune response dynamics for a long time, and not only snapshot pictures of 1 biopsy 1 time.

The biopsy demonstrated that inside the tumor, after you treat patients with NKTR-214, you see expansion of CD8 cells and natural killer cells, but without the expansion of deregulatory cells.

TARGETED ONCOLOGY:What have you seen in terms of the clinical activity of the single agent so far?

Diab:

We have enrolled close to 20 patients [so far] and have 18 evaluable patients to date. We’ve seen several patients who have stable disease who are on the trial for 3 or 4 months. They have some tumor reduction, a decrease of 6% to 10%. One patient has durable stable disease, he’s been on the trial for 9 months and is still gaining a clinical benefit. We also have 1 patient who achieved a partial response, which we are very excited about.

One of the patients who has stable disease is a patient with BRAF-positive melanoma. He was treated with ipilimumab and developed severe grade 3 colitis with ipilimumab, so his primary doctor was hesitant to treat him with anti—PD-1 [therapy]. They treated him with NKTR-214 and he’s been on it for 9 months.

Not only is there biological activity [with NKTR-214], there’s no reactivation of the toxicity of ipilimumab. With NKTR-214, in this patient specifically, we did not activate the immune toxicities. That mechanism of action not only affects the biological effect of this drug on the tumor, but also has an independent toxicity profile that does not overlap with a checkpoint inhibitor. That has a lot of implication when combining those drugs together. You have different toxicity profiles that allow you to give NKTR-214 with a checkpoint inhibitor without worrying about increased toxicity.

TARGETED ONCOLOGY:Is NKTR-214 best treated as a single agent or as part of a combination?

Diab:

Although we sometimes see [clinical activity with] single agents, I think for the current development of this drug, the major activity will be seen in combination with checkpoint blockers. But that does not mean that there’s no development of a single-agent activity for this drug in the future as well.

We want to approach this drug with checkpoint blockers, initially with anti—PD-1 therapy. We want to approach it in multiple solid tumors, as a first-line therapy and also in the second-line for patients who failed on checkpoint inhibitors, to see if we can reactivate and resurrect the activity of checkpoint inhibitors when combined with this drug. This is one major way to see how much the drug really contributes to the checkpoint inhibitors.

Right now phase I is open for all solid tumors histologies. Clearly melanoma and renal cell carcinoma are attractive and we see those patients more than others. But we are looking into triple-negative breast cancer, bladder cancer, and lung cancer. These patients are going to be enriched in the second phase of this trial, and we’re hoping to see some sort of activity [in these patients].

Reference:

Bernatchez C, Haymaker C, Tannir NM, et al. A CD122-biased agonist increases CD8+T Cells and natural killer cells in the tumor microenvironment; making cold tumors hot with NKTR-214. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract 387.