PYX-201 Generates Responses and Contributes to Growing ADC Use in Solid Tumors

Glenn J. Hanna, MD

Treatment with PYX-201 generated responses and proved tolerable in a phase 1 trial (NCT05720117) in patients with heavily pretreated head and neck squamous cell carcinoma (HNSCC), according to Glenn J. Hanna, MD, who added that this agent is adding to the growing antibody-drug conjugate (ADC) treatment armamentarium.¹

The phase 1 trial evaluated PYX-201 in patients with advanced solid tumors. In the HNSCC population (n = 6) patients treated with the novel agent experienced a confirmed overall response rate of 50% per RECIST 1.1 criteria. This was made up of 1 complete response and 2 partial responses.

“It’s really encouraging to see a robust regression or shrinkage rate among a small group of patients with head and neck [cancer] who have been heavily pretreated [and have] a heterogeneous clinical profile,” Hanna explained.

In an interview with OncLive®, Hanna delved into the efficacy and safety data that have been generated with PYX-201 and forecasted its potential utility in the HNSCC armamentarium.

Hanna is the director of the Center for Cancer Therapeutic Innovation (Early Drug Development Program) and the director of Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute, and an associate professor of medicine Harvard Medical School, both in Boston, Massachusetts.

OncLive: What is the mechanism of action of PYX-201, and how does it differ from other investigational agents and approved ADCs?

Hanna: PYX-201 is a very interesting compound. What makes it unique as an ADC is that it’s a stroma-targeted ADC, with a conjugated payload, or in this case, a statin. The idea here is that many ADCs target a specific receptor on cancer cells, and once binded, they get taken into the cancer cell [where] the payload is then cleaved, released, and the cell is killed.

In this case, the stroma is the surrounding extracellular matrix, the vasculature, and the fibroblastic environment which comprises a tumor, around the tumor cells themselves. This agent targets extra domain B splice variant of fibronectin. This protein is expressed in the supporting cells that are around the tumor cells. The idea is that it would bind to that supportive cell target, then cleave and release the drug in that environment. [Because of] a bystander effect, [this would] allow the killing of the tumor. Although the molecule itself is designed similarly to many others, this idea of targeting the extracellular domain with an ADC makes PYX-201 a unique molecule.

What is the significance of the preliminary safety and efficacy data with PYX-201 in head and neck cancer?

The interesting thing about the PYX-201 data for patients with head and neck cancer is that they were heavily pretreated. These were patients who had received multiple lines of prior therapy, including immunotherapies and platinum-based chemotherapy agents. When we see single-agent drug activity for something like a novel ADC such as PYX-201, in this population, that gets the attention of those of us who do drug development and particularly as head and neck cancer experts.

Although it was a small number of patients, we can learn a fair amount from just the composition of the patients. There were a number of patients with different subtypes of head and neck cancer, including human papillomavirus [HPV]–associated and HPV-unrelated [HNSCC]. To see a signal across potentially a group of patients who may be more heterogeneous is also very interesting for head and neck cancer, suggesting the drug could have some broader applicability, although it is early.

[Considering] this idea that we’re seeing regression of cancer based on these responses, it’ll be interesting to see whether those responses end up being durable. [We’d like to see responses that] last for long periods of time, such that the antitumor effect is maintained and that the drug results in delay and progression of cancer and an improvement in survival.

What were your thoughts on the adverse effect (AE) profile of the agent?

The AE profile was pretty on par with what we would expect based on the fact that there was an auristatin payload bound to the antibody that targets extra domain B splice variant. When you look at some of the rates of AEs that you’d expect from different ADCs with a similar payload, it was encouraging that across the entire study—not just the patients with head and neck cancer, but of the approximately 60 or 70 patients who had been dosed—we didn’t see high levels of concern or rates of the feared or undesirable AEs related to ADCs that we hear about. This includes things like peripheral neuropathy and numbness or tingling in the hands and feet that can develop with some of these payloads, as well as ocular eye toxicities which can be limiting.

In addition, with any of these cytotoxic payloads, we worry about the idea of low blood counts or cell counts that can cause risk of infection, bleeding, or fatigue in the case of anemia. Although we did see some of those things, including rash, which is usually manageable, we didn’t see a lot of grade 3 or higher severe toxicity issues. In terms of the auristatin payload, there wasn’t any evidence, at least preliminarily, that there was a larger or higher number of those limiting AEs associated with the chemotherapy payload. All of that was pretty encouraging from the early data.

What are the next steps for this phase 1 trial?

The PYX-201 story deserves a fair amount of attention based on the novelty of the protein ADC, but also its emerging safety profile and the fact that it’s showing activity in head and neck cancer and some other tumors with high unmet need. The next step is for the team to finish this dose optimization plan, and home in on a schedule and a dose. I think [they are at present] figuring out how much they can push the dose without increasing the chance of toxicity while making sure that they feel like they have as much efficacy as possible. The trial will then go into a prespecified expansion, whereby different tumor types will be identified as likely successful to carry forward, and they will take their selected dose and schedule and treat a number of patients across those tumor types. For example, head and neck cancer will likely be one of them.

The company is also planning to launch a combinatorial study, and this would be PYX-201-102, which would take the single agent ADC and combine it with PD-1 inhibition; in this case, pembrolizumab [Keytruda]. The company announced that they have a collaboration that’s been approved with Merck to supply pembrolizumab. As you could imagine, it’s very interesting to think about an ADC that targets the microenvironment, or the stromal environment, that then triggers potential crosstalk with the immune system. That is where the addition of a PD-1 inhibitor could be of interest.

I know [the company is] launching a first-in-human trial early in 2025 that combines pembrolizumab with the [investigative] agent. That’s the future for the development of this molecule as it stands right now, and I know the company is also thinking about other novel ways to bring the molecule forward. I had even mentioned to them considering other high unmet need tumor types, but also thinking about things like radio sensitization. Could some of these ADCs work with radiation as a novel or new way to enhance the effects of radiation. This is just an example of how they might think about development in the future.

What do you hope your colleagues will take away from this conversation?

A few things stand out for the general oncology audience. I would say the first is to keep your eye on early drug development. It moves very quickly in oncology, and there’s lots of excitement, as it’s very fast paced. There’s a fair amount of competition, and there’s a lot of molecules that are of interest. If I was talking to the general audience, I would say, keep your eye on the ADCs, broadly. I think they have a strong chance of impacting the broader oncology field as we move forward. The future will be focused on figuring out what targets we should prioritize for different cancer types.

A lot of these drugs seem to have activity, but it’s a matter of which drug we should match to an individual patient. Maybe, similar to the molecular era, where we use targeted therapies based on gene changes and protein changes, we’ll profile patients for different expression of targets across ADCs and use them in that way and [determine] whether we can sequence them by switching out the payload of strong interest.

Reference

1. Pyxis Oncology announces favorable preliminary PYX-201 clinical phase 1 part 1 data. News release. Pyxis Oncology. November 20, 2024. Accessed December 4, 2024. https://ir.pyxisoncology.com/news-releases/news-release-details/pyxis-oncology-announces-favorable-preliminary-pyx-201-clinical